Final YOU GOT THIS DEIRDRE Flashcards

Question

15, 15' carotenoid dioxygenase

Answer 1

In the intestine, β-carotene can be broken down into all trans retinal (aldehyde) – Enzyme responsible for this is 15,15’-carotenoid dioxygenase all trans retinal can be converted to all trans retinol and then converted to retinyl ester to be sored all trans retinal can also be converted to retinoic acid directly

Answer 2

Retinol (alcohol) production – All trans retinal can be converted into all trans retinol by retinol dehydrogenase – The retinol can act like a detergent, which is unsafe for a cell. So, retinol is converted into a retinyl ester (safer for the cell) – Retinyl esters have no direct function in the body

Answer 3

converts all trans retinal to all trans retinol

Answer 4

The retinol can act like a detergent, which is unsafe for a cell. So, retinol is converted into a retinyl ester (safer for the cell) – Retinyl esters have no direct function in the body.

Answer 5

Vit A and Night vision! (aka the retinoid vidual cycle) see slide 24 of 32 and draw out process 11-cis retinal can cross to photoreceptor (rod cell) bount to interphotoreceptro RBP where it can be added to RHODOPSIN (very sensitive pigment) conversion of RHODOPSIN to OPSIN results in neuronal signalling and vision opsin can be combined w all trans retinal to make all trans retinol or can be regenerated to rhodopsin in cycle

Answer 6

Rod cells use rhodopsin to absorb light (greyish purple colour) * Opsin + 11-cis retinal combine to become rhodopsin, which is light- sensitive * When light hits rhodopsin, it reforms all- trans retinol

Answer 7

Retinol-RBP brings retinol to cells, which can then be converted into RA * RA goes to nucleus where it binds and activates both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR) transcription factors * These complexes homo- and hetero-dimerize with other nuclear hormone receptors (NHR), creating a huge number of possible combination of transcription factors, which allows the regulation of gene expression ex. is for increasing growth hormone and decreasing collagenase

Answer 8

Affects stem cell differentiateion When vit A present - normal cell differentiation - mucus secretion and keratinization When vit A deficient Keratinization, but little mucous secretion not enough mucus to form a good protective layer, so viruses and bacteria can penetrate poor differentiated function

Answer 9

Keratin is a major protein in all epithelial cells whose expression is regulated by retinoic acid.

Answer 10

1. Night blindness (lack of rhodopsin) – Reversible, one of the first signs of Vit A deficiency – Associated with Bitot’s spots, a buildup of keratin debris in the conjunctiva of the eye 2. Impaired epithelial cell differentiation – Can cause permanent blindness and life-threatening infections 3. Impaired growth (growth hormone not produced) – Impacts bone development, tooth decay, etc. 4. Impaired fertility – Decreased sperm formation, fetal resorption (early death of the embryo) 5. Fetal development defects – Birth defects due to loss of control of differentiation – Can occur with too little OR too much Vit A

Answer 11

Retinol Activity Equivalents (RAE) 1 RAE = 1 μg dietary retinol = 12 μg dietary β-carotene = 24 μg other carotenes RAE accounts for differences in the biological activity of various carotenoids No UL for B-carotene

Answer 12

Carotenoids prevent deficiency, but don’t cause toxicity. – 15,15’-carotenoid dioxygenase regulated by Vit A status. If you have enough Vit A, carotenoids aren’t converted to retinol but are stored “as is”

Answer 13

Most severe consequence is liver cell death. Retinyl esters are stored in the stellate cells of the liver and with excess Vit A intake, the cells reach capacity. Raw Vit A spills out and the local hepatocytes become damaged and die. Death from liver failure can result Why you can't eat a polar bear liver Excessive intake of β-carotene is not toxic, but can cause hypercarotenosis (skin turns yellow-orange)

Answer 14

Accutane, an acne drug that contains 13-cis retinoic acid, was shown to cause birth defects in women in the early months of pregnancy  Taken off the general market due to lawsuits

Answer 15

In humans there are 21 proteinogenic AAs (includes selenocysteine) - A “proteinogenic AA” refers to an AA that is incorporated into a protein during translation - All but selenocysteine are part of the standard genetic code

Answer 16

Non-proteinogenic AAs also exist (e.g., some neurotransmitters like GABA), but these are not used to make protein

Answer 17

Two types of amino acids in the body: 1. Standard Amino Acids: – All are used to make protein – 20 AAs are encoded in the genetic code (except for selenocysteine) 2. Non-Standard Amino Acids: – Many exist in the body, but they are rarely used to make proteins – Usually formed by post-translational modification of other AAs or as intermediates in the metabolic pathways of standard AAs * For example, the GABA neurotransmitter is a metabolite of the amino acid glutamate – We don’t talk about these in NUTR*3210 in any detai

Answer 18

L configuration of AAs is naturally occurring *D configuration of AAs is made through post-translational modifications

Answer 19

At physiological pH, AAs are ionized *Protonated amine group *Deprotonated carboxyl group *No overall charge (except R group) *This increases polarity

Answer 20

approx 50 aas in peptide chain = oligopeptide over 50 = polypeptide 1 or more polypeptides = a biologically active protein

Answer 21

A native protein corresponds to a protein in its normal 3D conformation. * Proteins can be denatured in a number of ways: – e.g., heat, salt treatment, detergents, pH (stomach acid). * When a protein is denatured, it loses its bioactivity. * Denaturation affects 2°, 3°, and 4° structures (but not 1°) ex. albumin is the protein in egg and when cooked it becomes opaque cause it's been denatured

Answer 22

Essential AA (Indispensable) – Not made by the body or can’t be made quickly enough to meet demands * 9 AAs (lys, thr, iso, leu, met, phe, trp, val, and his) IKTVLMFHW

Answer 23

Not normally required in the diet in a healthy individual, but become essential under specific contexts. For example, – A genetic problem: – Phenylketonuria: an inborn error of metabolism whereby a person is unable to breakdown Phe into Tyr. * A build-up of Phe in the body causes intellectual disability * The solution is to limit Phe in the diet and supplement with Tyr Development of a disease: – Liver disease (cirrhosis) impairs Phe and Met catabolism * Tyr and Cys are synthesized from Phe and Met, respectively * Tyr and Cys become indispensable in this context

Answer 24

HKR K Essential *Limiting in grain products *Involved in the production of carnitine, which is important for fatty acid metabolism R Preterm infants unable to synthesize arginine *Non-essential in healthy adults H Essential *Ring structure *Used to produce histamine (inflammation)

Answer 25

ACIDIC = DE (aspartate and glutamate D Non-essential *Important for amino acid catabolism *Transaminated to oxaloacetate (Krebs) *A “source” of nitrogen in the urea cycle E Non-essential *Important for amino acid catabolism *Transaminated to α- ketoglutarate (Krebs) *Used to produce GABA (neurotransmitter can react with a basic group to produce asparagine and glutamine

Answer 26

N, Q, G, A Asparagine, (non-essential) glutamine (non-essential - Important in AA catabolism because it is an inter-organ carrier of nitrogen (to the liver & kidney)) Glycine only non enantiomer Non-essential *No enantiomers *Used primarily to produce porphorin (a component of heme, which is found in hemoglobin) alanine Non-essential *Important in AA catabolism because it is an inter-organ carrier of nitrogen (to liver & kidney) *Important role in the glucose-alanine cycle

Answer 27

LIV All are essential *Not catabolized in the liver, so high levels found in circulation *Promote protein synthesis *BCAA levels are high in protein supplements

Answer 28

ST Ser is non-essential and Thr is essential -OH group on side chain is important for post-translational phosphorylation of proteins

Answer 29

Cysteine and Methionin Cysteine Non-essential *Made from methionine *“Spares” methionine when cysteine consumed in the diet *Used to form disulfide bonds *Used in glutathione synthesis (oxidant defence system) Methionine Essential *1st step in the synthesis of all proteins *Methionine is limiting in legumes

Answer 30

WYF P Phenylalanine *Essential *Used to make Tyrosine Tyrosine Non-essential *“Spares” Phe *Used to synthesize neurotransmitters Tryptophan Essential *Used to make serotonin (mood) *Used for niacin (Vit B3) synthesis Proline Non-essential *Important for collagen production (extracellular matrix) *Aliphatic side chain

Answer 31

Most proteins require some type of modification before they are biologically functional * PTMs take place in polypeptide chains, not free AA * Phosphorylation (the addition of a phosphate group) by kinase enzymes - serine, threonine and tyrosine Hydroxylation (creation of a new hydroxyl group) - lysine and proline Gamma-carboxylation Iodination ADP - ribosylation

Answer 32

Type of PTM Phosphorylation (the addition of a phosphate group) by kinase enzymes – Serine-OH – Threonine-OH – Tyrosine-OH requires phosphorus

Answer 33

Hydroxylation (creation of a new hydroxyl group) – Lysine  hydroxylysine (very important in elastin subunits, needs copper; associated with aortic rupture) - copper dependent – Proline  hydroxyproline (very important in collagen subunits, needs Vit C; associated with scurvy) - Vit C dependent

Answer 34

a tupe of PTM Required for calcium homeostasis and blood clotting – Certain proteins are modified to become Ca2+ binding proteins – Another carboxyl group is added to glutamate Vit K dependent ex. glutamate-COO- to Glutamate w 2 COO-

Answer 35

a type of PTM Critical in the formation of thyroid hormones – Crucial for regulation of the metabolic rate – About 2 billion humans are iodine deficient - iodine dependent

Answer 36

Type of PTM Adding ADP-ribose to an acceptor protein – Critical for DNA repair and regulation of protein function – Dependent on Vit B3 (niacin) – Niacin used to form NAD+. When NAD+ is broken down in the cell, ADP- ribose and nicotinamide are the products niacin dependent

Answer 37

The bioactive form of Vit D acts as a hormone (this is a “true” steroid hormone) – The bioactive molecule is made in one tissue (kidney) and acts on other tissues – Works with other hormones such as parathyroid and calcitonin

Answer 38

While Vit A and iodine are deficiencies of the developing world, Vit D is the most prevalent micronutrient deficiency in the developed world 1919–deficiencies induced in dogs and reversed with cod liver oil – Rediscovered the use of cod liver oil to prevent bone diseases – Sunlight also used to prevent rickets, which indicated that fat soluble Vit D can also be synthesized by the body

Answer 39

1. Natural plant sources (provitamin D2) Shitake mushrooms * Not very active in plants, so not a great source of Vit D *Ergocaliferol is less bioactive than cholecalciferol 2. Natural Animal Sources (Provitamin D3) - fish, fish liver oils - 7-dehydrocholesterol (7-D) is converted to cholecalciferol by sunlight (UVB and infrared) - occurs in sebaceous glands of skin However, it's difficule to achieve good vid D status by consuming animals or plants 3. Sunlight - Vid D3 is made in the skin from 7-D - Vit D3 binds to the vit D binding protein (DBP) and circulates around the body

Answer 40

are made in the skin from 7-D, but are inactive molecules that are eventually lost as we shed skin cells they can be converted back to 7-D

Answer 41

Melanin in epidermis absorbs UV rays, which slows down Vit D3 production - part of the problem for vid D deficiencies over time (migrating populations) more melanin -> less ability to make vit D

Answer 42

4. Supplementation Should use Vit D3 (cholecalciferol) * Especially important for someone who spends lots of time indoors 5. Fortification Government initiative * Milk and margarine * Insufficient for health if this is a person’s only source of Vit D3

Answer 43

Vit D3!! 7-D is rapidly converted to Vit D3 in skin – No risk of Vit D toxicity from sun – Vit D3 enters blood bound to DBP (Vit D bind protein) and can go to the: * Liver (conversion) * Adipose (storage)

Answer 44

- Primarily absorbed passively in the small intestine – Incorporated into chylomicrons and eventually ends up in the liver

Answer 45

In the liver, the 25th carbon on Vit D3 is hydroxylated to form 25-OH D3 by the enzyme 25-hydroxylase (a cytochrome p450 enzyme) * Once produced, 25-OH D3 is secreted into blood bound to DBP – This corresponds to the largest pool of 25-OH D3 in the body * If 25-OH D3 levels in the blood are low, this is the sign of Vit D deficiency (THIS IS KEY!) * When calcium levels are low in the body, 25-OH D3 will be converted into an active molecule

Answer 46

Once produced, 25-OH D3 is secreted into blood bound to DBP – This corresponds to the largest pool of 25-OH D3 in the body * If 25-OH D3 levels in the blood are low, this is the sign of Vit D deficiency (THIS IS KEY!

Answer 47

High gradient of blood to intracellular Ca2+ is essential * Low blood Ca2+ is sensed by the parathyroid gland – Releases PTH (parathyroid hormone) * PTH promotes uptake of 25-OH D3 / DBP complex into the kidney * 1-hydroxylase converts inactive 25-OH D3 into active 1,25-(OH)2 D3 * Active form known as calcitriol

Answer 48

= 1,25-(OH)2-D3 Produced in the kidneys active form of vit D that is bound to DBP in blood and sent out into the body to activate intracellular signalling pathways

Answer 49

Affects the GENOME of a cell - so must enter nucleus Calcitriol enters cell and binds Vit D receptor (VDR) is in cell cytosol and then – VDR is a type-2 steroid hormone receptor – Transcription factor that promotes calcium binding protein synthesis – Calcium-binding proteins are activated by a Vitamin K dependent PTM (post translational modification) * γ-carboxylation - CREATES Calcium binding proteins!!

Answer 50

does NOT affect Genome Calcitriol binds cell surface receptors, like MARRS (membrane- associated rapid response steroid-binding protein) – Activates intracellular signalling cascades – Very fast, no dependence on Vit K

Answer 51

membrane associated rapid response steroid-binding protein on cell surface - responds to calcitriol - activates intracellular cascade that leads to protein phosphorylation and signalling events by opening membrane channels that allow Ca2+ to rush in

Answer 52

GENOMIC AND NON-GENOMIC RESPONSES - VDR is activated and turns on the expression of genes coding for calcium binding proteins (which require Vitamin K dependent γ- carboxylation to become fully functional) * Membrane receptors are activated (e.g., MARRS) IN BONE Elevated calcitriol and PTH work together to stimulate resorption of Ca2+ and phosphorus from bone * Calcitriol causes an increase in the expression of RANK ligand (RANKL), a cytokine * Osteoblasts secrete RANKL that activates osteoclasts to degrade the bone matrix and release Ca2+ and P into the blood IN INTESTINE - Primary function is to increase absorption and reabsorption of Ca2+ * Calcitriol turns on the expression of genes that encode calcium binding proteins

Answer 53

RANK ligand Calcitriol causes an increase in the expression of RANK ligand (RANKL), a cytokine * Osteoblasts secrete RANKL that activates osteoclasts to degrade the bone matrix and release Ca2+ and P into the blood

Answer 54

Absorption (small intestine) – Minerals need transporters for absorption by intestinal enterocytes and entry into portal circulation – Proper absorption of Ca2+ depends on the expression of Ca2+ binding proteins in enterocytes Reabsorption (kidney) – Small molecules like Ca2+ circulate in blood and eventually reach the kidney, where they pass through the filter and can end up in urine (unless reabsorbed) – Reabsorption removes the molecules from the filtrate and gets them back into the blood Resorption (bone) – Dissolving bone structure to release Ca2+ into the blood * Osteoclasts resorb bone, osteoblasts build bone * Balance between break-down and synthesis allows for bone maintenance, remodeling and repair

Answer 55

KEY POINT  maintaining blood Ca2+ is more important than maintaining Ca2+ reserves in bone (as seen by a release of bone calcium with pregnancy and lactation when calcium is limited in the diet) Hormones: PTH (parathyroid hormone) Calcitriol (active vit D) Calcitonin

Answer 56

parathyroid hormone Secreted by the parathyroid glands * Serves to INCREASE blood calcium – Promotes the production of calcitriol in kidney by activating the 1-hydroxylase enyzme – Stimulates bone resorption by activating osteoclasts – Maximizes tubular reabsorption of calcium in kidney

Answer 57

VITAMIN D (Calcitriol) * Serves to INCREASE blood calcium – Stimulates Ca2+ resorption from bone – Helps to increase absorption of Ca2+ from intestine – Maximizes tubular reabsorption of Ca2+ in kidney

Answer 58

Secreted by parafollicular cells in the thyroid * Serves to DECREASE blood Ca2+ (e.g., in response to Ca2+ rebound) – Suppresses tubular reabsorption of Ca2+ in kidney – Inhibits bone resorption and facilitates remineralization

Answer 59

Consequence of Vit D deficiency varies across the lifespan Vit D deficiency in Infants = Rickets (poor mineralization) – Bones don’t mineralize properly and can’t support the infant’s body weight when they start walking (permanent and reversible only with surgery) – This was seen in Britain during the industrial revolution Vit D deficiency in Adolescents to Adult = Osteomalacia – Bones become demineralized (can be reversed with supplementation) – Bone fractures can occur more easily * Vit D deficiency in Middle-Aged to Elderly = Osteoporosis – Normal part of aging (loss of both mineral and organic parts of bone) – Diagnosed with bone density scans – Difficult to reverse due to erosion of bone (holes in bone form)

Answer 60

Mixture of solid (outer) and spongy (inner) parts – Solid part: How much is mineral and how much is organic? * Solid part is 60% mineral (Ca2+, P) and 40% organic (collagen) * In babies, bones start as collagen and gradually become infused with minerals * A Vit D deficiency concerns solid bone only, which changes the ratio of mineral to collagen in the bone matrix

Answer 61

Osteoporosis  Bone loss associated with aging  Worsened by chronic low Ca2+, Vit D, and/or Vit K intake  Fractures (e.g., hip) increase mortality in the elderly  Men generally have higher peak bone mass between 20- 30 yrs and lower bone loss  Treatments include dietary supplements or drugs that affect bone formation/resorption

Answer 62

Health Canada tripled the RDA based on overwhelming scientific evidence – Used input from research, stakeholders, and scientists Tested in 5300 Canadians (age 6-79 yrs) -Very low levels of Vit D, with some ethnicities having lower levels than others Vit D surveys and human intervention studies suggest that ↑ Vit D3 improves bone mass; decreases colon, prostate and breast cancers; diminishes MS, psoriasis, rheumatoid arthritis; decreases hypertension & CVD; decreases diabetes; improves muscle strength and motor nerve function in the elderly

Answer 63

- no risk from sun exposure since prod. of Vit D3 is limited by amounts of 7-D present in the skin Also produces the inactive lumisterol and tachysterol metabolites with prolonged sun exposure, which have no bioactivity RARE but... Can get much higher levels of circulating 25-OH D3 with high dietary intake – Vit D3 is absorbed and incorporated into chylomicrons and eventually ends up in the liver where it is hydroxylated at position 25 and returned to circulation as 25-OH D3 bound to DBP. – Very high dietary levels can cause hypercalcemia, leading to a possible calcification of soft tissues * People with Vit D intake > 10,000 IU (or more) / day for several months experience toxicity (hypercalcemia) and acute kidney injury.

Answer 64

- a type I vitamin Vitamin K named after the Danish word “koagulation”, which means coagulation (so Vit K important for bone formation & blood coagulation) Obtained through consumption of green leafy plants (as phylloquinone) – However, phylloquinone is sensitive to light and heat * Vit K is also made by gut bacteria, in the form of menaquinone

Answer 65

Vit K is also made by gut bacteria, in the form of menaquinone - unsaturated side chain passive uptake into colonocytes deficiency is very rare due to this production

Answer 66

Newborn infants have poor Vit K status. Why? – Little Vit K in mother’s milk and babies aren’t eating leafy plants yet – Babies also haven’t developed their colonic (gut) bacteria, so no menaquinone – Babies given Vit K via a heel prick at birth (lasts 3-6 months

Answer 67

Baby chickens fed a low-fat and cholesterol-free diet bled excessively and their blood took a long time to clot. When Vit K was added to their diet, the problems disappeared. – Dam and Doisy won the Nobel prize in Medicine in 1943 for this discovery

Answer 68

Vit K in PLANTS - saturated side chain - requires no digestion

Answer 69

hylloquinone requires no digestion – Incorporated into micelles and absorbed in the small intestine – Absorbed via NPC1L1 apical transporter (also involved in cholesterol absorption) * Menaquinones produced by bacteria in the large intestine – Passive uptake into colonocytes * Both are incorporated into lipoproteins (e.g., chylomicrons) and delivered to various tissues around the body

Answer 70

Dietary intake (or from bacteria) Vit K (quinone) is the starting molecule - inactive form 1. Vit K quinone is reduced by quinone reductase and NAD(P)H - electron donor to Vit K hydroquinone (active f0rm) 2. Vit K hydroquinone (active) / reduced form now passes its electrons onto something such as in gamma-glutamyl carboxylase reaction (glutamic acd to gamma-carbocyglutamic acd) via this electron donation adn addition of CO2 So hydroquinone acts as a reducing agent, and gets oxidized to vitamin K epoxide (inactive) / oxidized form of Vit K 3. Vit K epoxide (inactive/oxidized) gets converted back to vit K quinone (starting point from step 1) via epoxide reductase the cycle then continues

Answer 71

- blocks Vit K cycle - used in rat poison - prevents coagulation - causes excessive bleeding - blocks epoxide reductase enzyme

Answer 72

a protein precursor with a glutamate side-chain undergoes a post translational modification reaction VIt K hydroquinone (active vit K) donates its electrons and CO2 is also added to the protein with help of enzyme γ-glutamyl carboxylase Now, the protein has another COOH group! (2 total), and a gamma-glutamyl carboxylase side chain At phys. pH these groups are COO- and form Gla residues! /calcium binding protein

Answer 73

Produced via gamma-carboxylation and help of Vit K hydroquinone Calcium binding residues on proteins w 2 COO- groups that bind Ca2+ Gla residues on blood clotting proteins bind Ca2+. Ca2+ allows Gla-containing proteins to bind to phospholipids on membranes of blood platelets and endothelial cells

Answer 74

ewborn infants (injected with phylloquinone at birth) * Little Vit K in breast milk * Vit K can’t cross the placenta for delivery to the developing fetus * Gut bacteria population not established – People who take antibiotics chronically * Antibiotics destroy the gut bacterial community – People with malabsorptive illnesses (IBD, Crohn’s, pancreatitis)

Answer 75

Virtually no instances of toxicity in adults

Answer 76

Deficiency symptoms related to role in γ-carboxylation – Impaired blood clotting * Possible hemorrhagic syndrome (mostly seen in newborns) – Impaired activation of calcium binding proteins * Accelerate development of osteoporosis (mostly seen in elderly adults)

Answer 77

Represents ~40% of the body’s mineral mass – 1-2% of human adult body weight corresponds to calcium – Bones and teeth contain about 99% of the calcium – The remaining 1% is critically important for signalling pathways

Answer 78

Predominantly obtained from dairy products, but also high in sardines, salmon, and some green leafy vegetables (e.g., spinach) – Present in these foods as an insoluble salt – Stomach acid creates soluble Ca2+

Answer 79

Absorption (about 25-30% of dietary calcium is absorbed) in the small intestine – Saturable, carrier-mediated, active transport * Absorption regulated by calcitriol; Most calcium absorbed this way – Diffusion via paracellular route is a secondary pathway for Ca2+ uptake

Answer 80

Calcium is transported around the body in various ways: – ~40% bound to albumin – ~10% found complexed with sulfate, phosphate, etc – ~50% found in free (ionized) form

Answer 81

BONE Calcium (99%) – Minerals (calcium, phosphorus, fluoride, magnesium, potassium, etc) make up hydroxyapatite (a crystal-like structure) - functionas as a reservoir for calcium If intra- and extra-cellular levels of Ca2+ drop, bone will be sacrificed otherwise death occurs.

Answer 82

INTRA- and EXTRACELLULAR Calcium (1%) – Ionized calcium is active and used for: * Blood clotting (formation of “Gla” residues on coagulation proteins) * Skeletal muscle contraction (release of calcium stores) * Nerve potential (acting through ion channels) * Intracellular signalling pathways – e.g., Ca2+ activates PLA2, which cleaves arachidonic acid from phospholipids to produce eicosanoids

Answer 83

is an apical transporter of calcium on enterocyte most calcium is absorbed through here to get into intestinal cell

Answer 84

Is like a ferry for the Calcium in the enterocyte - produced in the enterocyte it picks up the calcium after it's been absorbed through TRPV5/6 and then brings it to the Ca2+ transporter on basolateral side where it's absorbed ito blood - calcitriol (active Vit D3) receptor is located in nucleus of enterocyte and calcitriol has positive regulatory effect of the expression of calbindin D3 in the enterocyte - It uses vit K to bind calcium/can only bind Ca2+ thanks to vit K - Trpv5/6 and calbindin expression decrease naturally with age

Answer 85

[Ca2+] Lowest in intestinal cell (nM) [Ca2+] higher outside cell in intestinal lumen (mM) this makes it easy to rush in! and [Ca2+] high in blood (mM)

Answer 86

Most is present in mitochondria and the endoplasmic reticulum – Released from stores in response to an extracellular signal (e.g., receptor binding) to ultimately promote an intracellular response (e.g., gene expression, neurotransmission, etc.)

Answer 87

- IN BLOOD! Maintained at a very constant level; ~10,000× the concentration of intracellular calcium*** – Nearly identical to the concentration of phosphorus

Answer 88

The majority (around 99%) of the calcium in the body is in the bone and teeth – In bone, 99% is in mineral phase (hydroxyapatite), and 1% is in a pool that can readily exchange with extracellular calcium

Answer 89

Most recent changes related to UL? ↑ UL in children ↓ UL in adults (51-70 yrs) ↓ UL in >70yrs to prevent developing kidney stones

Answer 90

Caffeine ↓ Some fibres ↓ Magnesium & Zinc ↓ PTH (Vit D) ↑ Pregnancy & lactation ↑

Answer 91

DEFICIENCY * Profoundly affects bone and muscle Bone * Inadequate mineralization in bone – Rickets in children (commonly associated with Vit D deficiency) – Osteomalacia in adults (and increases risk of developing Osteoporosis) Muscle * Tetany – A condition characterized by involuntary muscle contractions * Evidence for association with hypertension * Evidence for association with colon cancer (current research supports association in high-risk populations)

Answer 92

Constipation, bloating, and/or gas * Hypercalcemia – Kidney stones

Answer 93

Widely distributed in food, so deficiency and toxicity are very rare; however, very important in physiology (2nd most abundant mineral in body) * Found in both animal products (as phosphorus) and in grains (as phytic acid)

Answer 94

Most phosphorus is absorbed in the small intestine in its ionic form (PO4-3) * Passive diffusion (primary method) * Saturable, carrier-mediated, active transport (NaPi cotransporter) – 50-70% of the phosphorus in foods is absorbed – Absorption inhibited by magnesium, aluminum, & calcium (cause they're phosphate binders)

Answer 95

Primarily transported in the blood as organic phosphate (e.g., incorporated into phospholipids) * Found largely in bone (hydroxyapatite), but also in molecules key for metabolism (ATP, DNA, RNA, cAMP, etc.) * Plays a key role in protein phosphorylation (common PTM in proteins)

Answer 96

Fluoride present in the body in trace amounts; not essential * Community water fluoridated (with ~1 ppm or ~1mg/L) for the past 60 years due to the inverse relationship between fluoride intake and dental caries – water not fluoridated in Guelph because groundwater contains low levels of naturally occurring fluoride * Absorption in stomach by passive diffusion (nearly 100% efficiency) * Transported in the body as ionic fluoride or bound to plasma proteins * Major function related to effects on mineralization of teeth and bones – Increases resistance of enamel to acid demineralization by forming fluoroapatite (protective layer) * Deficiency? – Increased incidence of tooth decay * Toxicity? – Fluorosis (mottling of the teeth); a cosmetic problem – Tolerable upper limit in adults is 10mg/day

Answer 97

Deficiency? – Increased incidence of tooth decay * Toxicity? – Fluorosis (mottling of the teeth); a cosmetic problem

Answer 98

Micronutrients Involved in Oxidant Defense Vitamin E, Selenium, Vitamin C (Sulfur amino acids, Niacin, Riboflavin, Iron/Zinc/Copper)

Answer 99

Reactive oxygen species ROS produced as a by-product of the ETC when proper electron flow fails (~1% “leakage”) *Occurs in an O2-rich environment, where oxygen can react with electrons *Radicals have unpaired electrons *Mutations in SOD cause Lou Gehrig’s *H2O2 converted to H2O by glutathione peroxidase and catalase (selenium dependent enzymes) Normally, O2 would react with 4 electrons to make 2 H2O BUT SOMETIMES... 1. O2 reacts with 1 electron from mitochondrial leaked e-, producing superoxide anion radical (modest reactivity) 2. superoxide anion radical (modest reactivity) reacts with another electron (from Cu+, Zn2+ - metal cofactors that act as electron donors) and superoxide dismutase enzyme (SOD) to make hydrogen peroxide (modest reactivity - no unpaired electrons, pretty stable) 3. Hydrogen peroxide reacts with an electron (such as Fe2+ that's accumulated --> fenton reactions) to produce OH. hydroxyl radical that is incredibly reactive and attacks macromolecules (DNA, lipids) leads to cancer, cell death

Answer 100

Vitamin E is actually a general term that describes 8 structurally-related compounds (known as vitamers) – 4 tocopherols * Have saturated side chains with 16 carbons – 4 tocotrienols * Have unsaturated side chains with 16 carbons * Vitamers in both classes (α, β, γ, δ) * Only α-tocopherol has significant activity in the body * No inter-conversion of vitamers in animals – For example, β-tocotrienol cannot be converted into α-tocopherol * All are found naturally in foods * The word “tocopherol” is derived from Greek words: – Tokos = “childbirth” & Phero = “to bear or bring forth” – This was based on work showing that rats couldn’t reproduce when Vitamin E was absent from the die

Answer 101

are Vitamin E vitamers 4 tocopherols * Have saturated side chains with 16 carbons – 4 tocotrienols * Have unsaturated side chains with 16 carbons * Vitamers in both classes (α, β, γ, δ) * Only α-tocopherol has significant activity in the body

Answer 102

are chemical compounds that have a similar molecular structure, each showing vitamin activity to some extent.

Answer 103

Vitamin E Saturated side chain (phytyl tail) * Nomenclature used to describe # and position of ring methyl (CH3) groups * α isoform has the most methylated ring * The hydroxyl group is the antioxidant site! * Transport-mediated uptake in the small intestine (e.g., NPC1L1) * Natural α-tocopherol is RRR (3 chiral carbons) – Fits into the binding pocket of the tocopherol transfer protein (TTP) - the only one that can get sent out into the body cause it's the only one that can fint!!

Answer 104

Vitamin E Unsaturated side chain (phytyl tail) * Nomenclature rules the same as previous slide * Lower levels in food compared to tocopherols * Transport-mediated uptake in the small intestine (e.g., NPC1L1) * Tocotrienols have ANTI-OXIDANT ABILITY IN THE LIVER ONLY (not converted to α-tocopherol or able to fit in the TTP binding pocket)

Answer 105

Food sources: nuts, seeds, vegetable oils, avocado – Sensitive to food preparation & storage (e.g. roasting nuts ↓ Vit E levels) – Mostly obtained from plants because Vitamin E accumulates in adipose tissue in animals (and we don’t normally eat the fat)

Answer 106

RDA based on only α-tocopherol – Determined with tests that examined the hemolysis (breakdown) of red blood cells in the presence of dilute H2O2 – (>20% RBC hemolysis means there is a Vit E deficiency) RDAs can be reported as mg or IU

Answer 107

UL = 1,000 mg / day (above this amount will cause increased bleeding) – However, gastrointestinal problems can be seen at lower levels than the UL

Answer 108

Vitamin E deficiencies are very rare, but can occur in: – Pre-mature infants (kept in oxygen-rich incubators, which increases oxidative stress), who are then at risk for hemolytic anemia – People with fat malabsorption disorders or gallbladders removed, which can reduce absorption of dietary fats – People with genetic defects in lipoproteins or TTP, which prevents transport of α-tocopherol around the body

Answer 109

Requires bile acids for emulsification and incorporation into micelles * Absorbed in small intestine by transporters (e.g., NPC1L1) * Packaged into chylomicrons * Chylomicron remnants, containing Vit E, are taken up by the liver * Liver makes TTP, which is needed to get α-tocopherol into VLDL – Other vitamers can help a bit with anti-oxidant activity in the liver only, but they are quickly degraded * No specific “storage” organ for Vit E, but most of it accumulates in lipid droplets in adipose tissue

Answer 110

tocopherol tranfer protein is the thing that carries RRR-a-tocopherol around in the VLDL in the body is needed to get α-tocopherol into VLDL – Other vitamers can help a bit with anti-oxidant activity in the liver only, but they are quickly degraded Liver makes TTP

Answer 111

1. GSH peroxidase 2. Vitamin E 3. FA peroxidase

Answer 112

is the first line of defencse when fighting against the production of ROS = glutathione peroxidase - it donates an electron to hydrogen peroxide to produce 2 H2O - it's a selenoprotein (only functions thanks to selenium in it's structure)

Answer 113

it donates an electron (via its OH group) to PUFA peroxy radical this still produces PUFA hydroperoxide BUT it prevents another PUFA from donating the electron to produce more PUFA free radicals TOC(OH) --> TOC(O*)

Answer 114

Is the third line of defense against the formation of ROS = fatty acid peroxidase - it with glutathione 2GSH --> GSSG helps convert PUFA hydroperoxide to PUFA alcohol

Answer 115

1. Initiation - Hydroxyl radical steals an electron from a PUFA (polyunsaturated fatty acid) to produce a PUFA free radical 2. PUFA free radical very reactive and short lived - there's a collapse of the douple bond structure and it goes to react with O2 to produce PUFA peroxy radical theres no time to mount defense cause it's so short lived 3. Propagation - PUFA peroxy radical is less reactive and longer lived - it can steal an electron from another PUFA to produce another PUFA free radical in this vicious cycle and then becomes PUFA hydroperoxide which 4. PUFA hydroperoxide is super chemically unstable, but not a radical - it's broken down to short chain aldehydes which kills cell! i think?

Answer 116

Vit E donates its electron from OH group to PUFA peroxyradical to produce PUFA hydroperoxide Vit E radical (lost it's electron) is relatively stable and 2/3 are vit E dimers excreted by bile 1/3 are quinone (single ring) and excreted through urine

Answer 117

Plants incorporate selenium from the soil into methionine and cysteine amino acids instead of sulfur – Therefore, selenium content in food is determined by selenium levels in the soil SelenoAA are absorbed in the small intestine by amino acid transporters and travel freely in the blood The body uses selenocysteine

Answer 118

China and Africa (low Se in soil) – Keshan disease (cardiomyopathy from cell damage by free radicals)

Answer 119

Selenium toxicity is rare: – Selenosis – chronic consumption of lots of brazil nuts which are rich in selenium can lead to hair and nail loss (most common symptoms)

Answer 120

= GLUTATHIONE Glutathione (GSH) is the major intracellular reducing agent. (it is a tripeptide) Two important selenoproteins involved in oxidant defense: – Glutathione peroxidase = 1st line of defence against lipid peroxidation – Fatty acid peroxidase = 3rd line of defence against lipid peroxidation * Both use glutathione (GSH) as a substrate, which helps to protect cells against oxidative damage * Selenoproteins work with GSH (which acts as the reducing agent) - The reaction site of these proteins is where the selenium is in their structure Structure of glutathione is crucial, where glutamate and cysteine amino acids are linked through a gamma-carbon – This gamma peptide bond is resistant to cellular proteases Note that glutathione itself does not have selenium in its structure

Answer 121

GSH is a single electron donor, so 2 GSHs are needed per reaction H2O2 --> H2O via GSH peroxidase 2GSH (red.) --> GSSG (ox.) GSH is oxidized and reacts with another GSH to form GSSG same reaction occurs when FA peroxidase converting PUFA hydroperoxide to PUFA alcohol

Answer 122

NADPH (+ H+) donates electrons to GSSG to become NADP+ and and regenerate 2 GSH via glutathione reductase (riboflavin) Vit B12 Pentose phosphate pathway (hexose monophosphate shunt) regenerates NADPH (which requires niacin)

Answer 123

A healthy cell has >90% GSH and <10% GSSG – High cellular levels of GSSG indicative of high oxidative stress

Answer 124

ascorbic acid At physiological pH, Vit C is known as “ascorbate" Exists as both D- and L-isomers – The L-isomer is biologically active in humans

Answer 125

not active in humans way of synthesizing Vit C from glucose Glucose (or galactose) -> gulonolactone --> ascorbic acid (vit C) via gulonolactone oxidase) Many mammals can synthesize Vit C from glucose, except: – Humans, primates, fruit bats, guinea pigs, and some birds – This is because we lack the specific enzyme gulonolactone oxidase

Answer 126

Primary sources of Vitamin C are fruits and vegetables * Vitamin C is very sensitive to heat, light, oxidation, and alkaline solutions

Answer 127

Vitamin C doesn’t require digestion prior to absorption * Uptake via sodium-dependent vitamin C (SVCT) 1 and 2 transporters in the small intestine (feedback mechanism exists) – 70-90% dietary Vit C is absorbed * There appears to be a maximum amount of Vit C that can be absorbed * Found in circulation primarily in “free form” (i.e., not bound to a protein)

Answer 128

oxidized form of Vit C another biologically active form Foods contain mostly ascorbic acid, but can have small amounts of the oxidized form (dehydroascorbic acid)

Answer 129

Involved in several biological processes, such as: – Collagen synthesis – Tyrosine synthesis – Neurotransmitter synthesis * Vit C acts primarily as a reducing agent in these processes – “2 electron donor” (via its OH groups) Vit C concentrations are high in white blood cells, as well as in many tissues

Answer 130

procollagen w a proline residue undergoes PTM where prolyl hydroxylase adds an OH group to proline (proline-OH) Pro-OH is then exported to extracellular space and pro-OH is what allows the collagen molecules to stick tg and make collagen WALL

Answer 131

ascorbic acid donates electrons to 2-prolyl hydroxylase-Fe3+ (ferric inactive) which activates the enxyme to 2 prolyl hydroxylase-Fe2+ (ferrous active) that active enxyme donates its electron then to proline and is what converts proline to proline-OH on pro collagen, activating collagen so basically, Vit C indirectly donates an electron to form proline-OH

Answer 132

The role of Vitamin C in oxidant defense is unclear, but the following evidence suggests a possible role: – We just learned about the reactions of lipid peroxidation, with free radicals “stealing” electrons from PUFA in cell membranes. If Vit C is around, there is some evidence that this happens to a lesser extent. This is seen by reduced levels of lipid peroxidation products being measured in the urine . – In white blood cells, where we have a lot of oxygen radicals, there are higher levels of Vit C. Coincidence? – With a Vit C deficiency, there is some increase in GSSG levels (oxidized dimer form that is inactive) and reduced GSH levels (the active form)

Answer 133

RDA: The goal is to maximize tissue concentrations and minimize urinary excretion higher in men than women RDA is increased in pregnant and lactating women to support mother and fetus/infant

Answer 134

> 2 g/d, above this amount increases risk for digestive problems (diarrhea) and kidney stones

Answer 135

curvy (plasma Vit C levels < 0.2 mg/dL) * If you consume 10 mg Vit C per day, signs of scurvy would develop in 1 month – Increased risk of hemorrhages (skin, follicles, gums) – Increased hair loss, loose teeth – Swollen joints, poor wound healing **due to problems producing hydroxyproline (i.e. collagen)

Answer 136

micronutrients that act as enzyme cofactors Niacin, thiamine, riboflavin, B6, folate, B12, biotin, pantothenic acid

Answer 137

= Vitamin B3 - type III micronutrient Discovered through the study of the condition pellagra in humans and a similar condition, called black tongue, in dogs – Niacin was considered the “anti-black tongue” factor The term “niacin” is a generic term and used interchangeably with Vitamin B3. In plant foods, Vitamin B3 is predominantly found as nicotinic acid, which is the provitamin. In animal-derived foods, Vitamin B3 is commonly found as: – Nicotinamide – Nicotinamide adenine dinucleotide (NAD) – Nicotinamide adenine dinucleotide phosphate (NADP)

Answer 138

Dietary sources for niacin? Most fish, meats, breads and cereals, coffee and tea – In coffee, trigonelline is converted to nicotinic acid by heat (i.e., coffee bean roasting Niacin can also be produced in the liver from the amino acid tryptophan (but only about 1/60th of tryptophan is converted into nicotinamide)

Answer 139

Digestion of NAD and NADP is required before absorption – Hydrolyzed by the glycohydrolase enzyme to release free nicotinamide * Nicotinic acid and nicotinamide are absorbed a bit in the stomach, but most is absorbed in the small intestine through facilitated diffusion * In plasma, niacin circulates primarily as free nicotinamide

Answer 140

free nicotinamide

Answer 141

kidney and red blood cells (where it is carrier-mediated)

Answer 142

Once NAD(P) is synthesized, niacin is essentially trapped within the cell. In their reduced forms, the main functions are: – NADH: the transfer of electrons to ETC – NADPH: a reducing agent in biochemical pathways

Answer 143

nicotinic acid is the provitamin B3 form found in plants nicotinamide is vit B3 form found in animal foods Both nicotinic acid and nicotinamide are precursors for NAD in the body

Answer 144

Two steps (from Nicotinic acid): 1. Convert the acid to an amide 2. Build into a dinucleotide structure: nucleotide structure contains a sugar (ribose), a nitrogenous base and a phosphate (NAD or NADP)

Answer 145

NAD+ (oxidized) >> NADH NADPH (reduced) >> NADP+

Answer 146

NAD+ reduced to NADH in: – Glycolysis, Kreb’s cycle, B- oxidation – Role in CATABOLISM NADP+ reduced to NADPH in the hexose monophosphate shunt and used for: – Fatty acid synthesis, glutathione regeneration, etc. – Role in ANABOLISM But both are 2 electron acceptors Over 200 enzymes require NAD(H) or NADP(H) as cofactors

Answer 147

Corn/Maize – Contains significant amounts of niacin, but it’s bound and not absorbed – Also deficient in Tryptophan – Use of lime (from limestone, not the fruit) helps to release niacin in corn

Answer 148

NIXTAMALIZATION Use of lime (from limestone, not the fruit) helps to release niacin in corn * A process known as nixtamalization * Lime is alkaline and causes the breakdown of hemicellulose in corn, releasing niacin * Used by Indigenous peoples in food practices, but not initially in Europe or Africa

Answer 149

leads to PELLAGRA - the 4 Ds: dermatitis, dementia, diarrhoea, death - most symptoms are reversible

Answer 150

RDA recommendations include the small amount of niacin produced from tryptophan (Trp) – Therefore, we consider Niacin Equivalents (NE) – NE = mg preformed niacin + mg Trp/60 – 14/16mg per day NE adult women/men

Answer 151

Vitamin B2 a type III micronutrient Riboflavin stems from “ribo” (ribose-like side chain) + “flavus” (yellow colour FAD FMN are coenzymes derived from ribofflavin

Answer 152

aka riboflavin Rich in foods of animal origin – Milk, milk products, meat, etc. (Source of free riboflavin) – Other foods contain flavins, found as either flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD), which are essentially bound riboflavin – Riboflavin is degraded with sunlight – Fun Fact: this is why milk is no longer widely sold in glass bottles

Answer 153

Riboflavin that is bound to proteins must be released prior to its absorption – This is done by HCl (protein denaturation) in the stomach * Free riboflavin is absorbed from the gut lumen by an active transport mechanism known as the riboflavin transporter 2 (RFT2)

Answer 154

Riboflavin, FAD, FMN are transported in the body bound to proteins (in particular albumin) * Riboflavin is stored a little bit in the body (in tissues like the liver, kidney, and heart), but extra riboflavin is generally excreted in urine – Sufficient amounts in the body to last 2-6 weeks when riboflavin is no longer consumed in the diet

Answer 155

FMN and FAD are made in cells: – FMN and FAD are involved in redox reactions – FAD is the primary form of riboflavin in the body (60-95%) – Production is positively regulated by T3 hormone, which increases the activity of the flavokinase enzyme

Answer 156

FAD is the primary form of riboflavin in the body (60-95%)

Answer 157

This is how riboflavin becomes FMN and FAD 1) Riboflavin is converted to Riboflavin PO4 (flavin mononucleotide = FMN) via an ATP dependent reaction involving enzyme flavokinase and Mg2+ or Mn2+ (this step activates in and makes it a nucleotide) 2) Riboflavin PO4 / flavin mononucleotide / FMN is converted to FAD by ATP dependent reaction using FAD synthetase (Mg2+ or Mn2+) (FAD considered a dinucleotide = FMN + adenine + sugar + P)

Answer 158

- riboflavin functions in many biochemical pathways ex. b-oxidation, and Kreb's Cycle - delivery of electrons to ETC Glutathione reductase GSSG + NADPH --> 2GSH +NADP+ basically, NADPH transfers its electrons to FAD, reducing it to FADH2 and getting oxidized to NADP+ riboflavin (FAD) is bound within the glutathione reductase enzyme FADH2 then passes its electrons to GSSG to reduce it to GSH (regenerates glutathione) FMN & FAD function similar to NAD(P) in electron transfer * The primary difference is that FMN and FAD are typically bound to the active site of an enzyme * To regenerate glutathione, FAD accepts 2 electrons from NADPH, temporarily becoming FADH2 * Reforming glutathione requires both niacin (NADP) and riboflavin (FAD

Answer 159

Ariboflavinosis – Signs of deficiency appear after ~3-4 months – Deficiency relatively common when dietary intake is insufficient because riboflavin is continuously excreted in the urine – No clear riboflavin deficiency has been characterized because typically occurs with other vitamin deficiencies. Reversible! – Cracked and red lips, inflammation of the lining of mouth and tongue, mouth ulcers, cracks at the corners of the mouth.

Answer 160

Populations “at risk” for a deficiency? – People with hypothyroidism or thyroid disease, because they can’t make thyroid hormones to activate flavokinase – Chronic alcoholism, which reduces riboflavin digestion & absorption – People who are lactose intolerant (reduced consumption of dairy foods and beverages) No UL for riboflavin

Answer 161

Vit B1 Need for thiamine first discovered in the 1800s when birds fed a diet of cooked polished rice developed neurological problems (now known as beriberi) – Polished rice has had the husk, bran and germ removed In plants, the thiamine provitamin exists in a free form * In animals, thiamine exists in phosphorylated form (known as thiamine pyrophosphate or TPP) – this is the active form – Phosphate group must be removed to allow for its absorption

Answer 162

In animals, thiamine exists in phosphorylated form (known as thiamine pyrophosphate or TPP) – this is the active form – Phosphate group must be removed to allow for its absorption * Absorption occurs in the small intestine – Typically controlled by thiamine transporters * In plasma, TPP is found in free form or bound to albumin

Answer 163

thiamine (plant provitamin) is converted by addition of 2 phosphates (from ATP--> AMP) to thiamine pyrophosphate / TPP (the active form) active form has a carbanion (acts as the point of sword)

Answer 164

Thiamine is an important cofactor for many enzymes, such as: 1. - Pyruvate dehydrogenase (pyruvate  acetyl CoA) 2. - Alpha-ketoglutarate dehydrogenase (Kreb’s cycle) These enzymes also require riboflavin (FAD), niacin (NAD), and pantothenic acid (CoA) as cofactors * Critical in the movement of sugars and amino acids into energy metabolism pathways Thiamine is also required in the non- oxidative phase of the hexose monophosphate shunt (transketolase step --> we did not discuss this enzyme in the course), thus playing a role in the synthesis of nucleotide precursors

Answer 165

3 enzymes in PDH complex: * Pyruvate dehydrogenase (PDH) * Dihydrolipoyl transacetylase * Dihydrolipoyl dehydrogenase 1. PDH bound TPP stabs the carbonyl carbon of pyruvate and it's a decarboxylation/ looses CO2 group producing an intermediate 2. Co-ASH is added to this intermediate in a transacetylation reaction (brings CoA from pantothenic acid) to produce acetyl Co-A! this step also uses FAD and NAD+ to NADH in a dehydrogenation! Micronutrients: * Pyruvate dehydrogenase needs Thiamine * Transacetylase needs Pantothenic acid * Dihydrolipoyl dehydrogenase needs Riboflavin (FAD) and Niacin (NAD)

Answer 166

Thiamine deficiency interferes with critical energy metabolism pathways (pyruvate and alpha-ketoglutarate dehydrogenase complexes) – Ultimately prevents ATP production and acetyl-CoA synthesis – Causes an accumulation of pyruvate, lactate, and alpha-ketoglutarate in blood causes 3 types of beriberi (dry, wet and acute)

Answer 167

caused by a thiamine deficiency 3 TYPES: 1. Dry beriberi – Predominantly in adults due to chronic low thiamine intake – Muscle weakness, affects the nervous system 2. Wet beriberi – Predominantly in children and young adults – More severe than dry beriberi and affects the cardiovascular system 3. Acute beriberi – Occurs primarily in infants – Anorexia, vomiting, lactic acidosis, and eventually death if left untreated

Answer 168

Who is susceptible to a thiamine deficiency? – Chronic alcoholism – People depending on polished (white) rice as a major source of food

Answer 169

HAHA GOT YOU THERE IS NONE!

Answer 170

Vitamin B5 EVERYWHERE! so no jameson supplement :( lol Derived from the Greek word pantos, which means “everywhere” – Present everywhere (found in virtually all plant & animal foods); therefore deficiency is next to impossible – Little to no toxicity associated with dietary and supplemental pantothenic acid * Occurs ubiquitously in foods in both free and bound forms – Most pantothenic acid in food occurs as part of coenzyme A (CoA)

Answer 171

aka pantothenic acid is Absorbed in the jejunum by passive diffusion * Found free in blood * Uptake into tissues occurs through the sodium-dependent multivitamin transporter (SMVT) * Precursor in the synthesis of Coenzyme A (CoA)

Answer 172

Essential in energy metabolism (formation of acetyl CoA), allowing Kreb’s cycle to take place. *Cysteine required to make CoA (which is the active SH group) *Important component of acyl-carrier protein in the fatty acid synthase complex *Energy production *Formation of acetyl-CoA 1. Pantothenic acid is converted to 4-phosphopantetheine (active form in fatty acid synthesis) - this requires phosphate from ATP and cysteine!! CO2 is extruded 2. 4-phosphopantetheine is converted to Coenzyme A (CoA, CoASH) upon donation of AM from ATP! Releases PPi Coenzyme A/ CoA is active form in oxidative reactions involved in - energy production - formation of acetyl-CoA

Answer 173

its an intermediate in the conversion of pantothenic acid to CoA but it's the active form in fatty acid synthesis - Important component of acyl-carrier protein in the fatty acid synthase complex

Answer 174

Vitamin B7 Discovered in 1931 during experiments examining the cause of “egg white injury” – Eating raw eggs led to hair loss, dermatitis, etc. This led to the discovery of avidin, a biotin-binding protein Sources of Biotin: 1. Biotin is made by intestinal bacteria * although not enough is made to meet the needs of humans 2. Widely found in foods bound to proteins

Answer 175

aka vit B7 absorption Must be removed from proteins prior to its absorption – Proteolysis by pepsin in the stomach breaks down proteins and releases biotin * Free biotin is absorbed to near completion – Alcohol inhibits biotin absorption Circulates in blood in the free form (~80%), with a bit bound to albumin

Answer 176

GOTCHA again! no RDA cause biotin is so prevalent!! (its made in intestinal bacteria)

Answer 177

Involves 2 reactions!! RXN #1 we load a bicarbonate/HCO3- onto biotin with help of ATP --> ADP / carboxylate the N in biotin ring structure RXN#2 we transfer the carboxyl group to another molecule/ substrate (such as pyruvate to oxaloacetate (carboxylated substrate)) and this regenerates the OG biotin

Answer 178

Two rings (with N and S) and a side chain with a carboxyl group * The carboxyl group interacts with the NH2 group of a lysine side chain in an enzyme (e.g., pyruvate carboxylase) the enzyme i s joined by a peptide bond to biotin at the lysine residue

Answer 179

1. Pyruvate carboxylation (production of oxaloacetate) 2. Malonyl CoA formation 3. Conversion of propionate into glucose (important in ruminants)

Answer 180

Pyruvate carboxylase requires a biotin cofactor to be active. * Two active sites on the enzyme! * The biotin is anchored to a lysine side chain, allowing it to “reach” into the carboxylation reactive site (active site #1), where it is carboxylated. * The cofactor can then swing to the active site #2, bringing the carboxyl = group into close proximity with the substrate (in this example, pyruvate)

Answer 181

Conversion of propionate (a SCFA( into glucose (important in ruminants) its the main pathway for making glucose in ruminants and involves BIOTIN!! this pathway feeds into citric acid cycle like its a type of like gluconeogenesis

Answer 182

Vit B9 Folate and Vit B12 were discovered during the search to cure megaloblastic anaemia, a problem that was first described in the late 1800s * Folate is a generic term that refers to both natural folates in food and the synthetic form used in supplements and fortified foods called folic acid - Folic acid refers to the oxidized form of the vitamin found in fortified foods and supplements (100% bioavailable) – Folate refers to the reduced form of the vitamin found naturally in foods (~50% bioavailable) Folate is the precursor for tetrahydrofolate (THF) and 5-methyl THF - folate is important for production fo nucleic acid precursors and several amino acids as well as in methylation reactions so its really important in bone marrow and the developing fetus

Answer 183

“folate” and “folic acid” are structurally different (see next slide) – Folic acid refers to the oxidized form of the vitamin found in fortified foods and supplements (100% bioavailable) Only 1 glutamate residue “pteroylmonoglutamate” – Folate refers to the reduced form of the vitamin found naturally in foods (~50% bioavailable) Multiple glutamate residues “pteroylpolyglutamate” Folate vs. Folic Acid (You don’t need to memorize these structures)

Answer 184

Natural folates have multiple glutamate residues (i.e., polyglutamates) which must be removed for absorption in its simplest form (monoglutamate) – Polyglutamate hydrolase removes the glutamate residues * This enzyme is sensitive to alcohol and inhibitors naturally present in certain foods (legumes, lentils, etc.) – Folic acid is already a monoglutamate structure, so no digestion is required

Answer 185

is the enzyme that removes the glutamate residues on folate to be absorbed

Answer 186

Once the extra glutamate residues have been removed, folate/follic acid is absorbed through a proton-coupled folate transporter (PCFT) in the small intestine In the intestine, most natural folates and folic acid are converted into the bioactive compound 5-methyltetrahydrofolate (5-methyl THF) * In plasma, you mostly detect 5-methyl THF and a bit of folate (more on this later) – Generally transported in blood bound to proteins, such as albumin * 5-methyl THF is the bioactive form of folate

Answer 187

the bioactive form of folate

Answer 188

dietary folate equivalent Total DFE = μg food folate + (1.7 × μg folic acid) the 1.7 takes into account the bioavailability of folate DFE is much higher in pregnant women and lactating women there is no DFE for infants

Answer 189

is not that much higher than the RDA!! This is important cause exceeding the UL supports the development of cancer!/increases cancer risk! (related to Vit B12) Very easy to exceed the UL if taking supplements and eating fortified foods

Answer 190

= Vit B12! BIGGEST VITAMIN Vit B12 was the last vitamin to be discovered * Generic term for a group of compounds called corrinoids (because of a corrin nucleus that contains cobalt, which is very rare) – Most complex vitamin structure and is unique in that it contains a metal ion. * Only bacteria produce Vit B12 * Vit B12 is present in animal products, like meat, poultry and eggs – Strict vegetarians/ vegans are at risk of a deficiency * No plant provitamin B12 exists

Answer 191

A “functional” deficiency for folate (the two work together) – Neurological problems

Answer 192

In the stomach, a specific binding protein is secreted from the gastric lining, known as intrinsic factor (IF) * The Vit B12-IF complex goes to a receptor in the small intestine * Complex broken down in the enterocyte. Vit B12 is absorbed, while IF is released back into the intestinal lumen * Vit B12 is stored in the liver and can undergo enterohepatic circulation * High storage in the liver, so deficiencies can take years to surface

Answer 193

a specific binding protein is secreted from the gastric lining of the stomach that helps in Vit B12 absorption The Vit B12-IF complex goes to a receptor in the small intestine * Complex broken down in the enterocyte. Vit B12 is absorbed, while IF is released back into the intestinal lumen

Answer 194

Two causes leading to a Vit B12 deficiency: 1. Not enough in your diet – in strict vegans (resolved with megadoses of Vit B12) 2. Improper absorption due to defects in Intrinsic Factor Deficiencies shown in blood in the form of megaloblastic anemia (discussed later)

Answer 195

Inside the intestinal enterocytes, most natural folate and folic acid are methylated to the N5- methyl tetrahydrofolate (5-methyl THF) form and released into the blood stream. When taken up by cells, the N5-methyl group is removed by methionine synthase thanks to the Vitamin B12 (cobalamin) cofactor. The cobalamin temporarily becomes methyl-cobalamin. (it accepts methyl from N5-methyl THF Consequently, the cell now has free tetrahydrofolate (THF), which is important in a wide variety of reactions THF can pick up a methyl group from an intracellular methyl donor (e.g. serine or choline) to form N5N10-methylene THF. Two things can happen to N5N10-methylene: 1) dUMP to dTMP to dNTPs 2) irreversible reaction converted to N5-methyl-THF. This secondary pathway is thought to exist as a means for the cell to funnel extra methyl groups back to the SAM cycle

Answer 196

-Folate (N5-methyl THF or N5,N10- methylene THF) -Vit B12 (“prosthetic” group) -S-adenosyl methionine (SAM)

Answer 197

1) The major outcome is that the N5N10-methylene THF passes the methyl group to dUMP, forming dTMP, which is required for DNA synthesis. The enzyme coordinating this is known as thymidylate synthase. Losing a methyl group allows THF to be reformed, which can then pick up another intracellular methyl group from another serine (for example), and the cycle continues. 2) An alternate minor outcome is that N5N10 undergoes an irreversible reduction reaction where it is converted to N5-methyl-THF. This secondary pathway is thought to exist as a means for the cell to funnel extra methyl groups back to the SAM cycle.

Answer 198

DNA synthesis and cell division slow down, and this has a major impact in tissues which depend on rapid cell division, including; 1. bone marrow; leading to megaloblastic anaemia (few, large red blood cells, overstuffed with haemoglobin) 2. developing fetus; improper neural tube closure, defects such as spina bifida and just impaired DNA synthesis and repair: uracil misincorporation, megaloblastic anemia

Answer 199

is methionine synthase - Vit B12 dependent When someone is Vit B12 deficient, N5-methyl THF is “trapped” and can’t be converted to THF

Answer 200

Occurs in precence of Vit B12 basically end goal is to methylate a substrate, be it DNA, or what not methyl-cobalamin (methylated B12 after having accepted that methyl group from N2-methyl THF) donates the methyl to homocysteine, producing methionine and converting itself back to cobalamin methionine then gets converted to S-adenosyl-methionine (SAM) which donates its methyl to a substrate like DNA to become S-adenosylhomocysteine important for like: - phosphatidylcholine epinephrine creatine DNA metabolism drug methylation drug metabolism

Answer 201

When someone is Vit B12 deficient, N5-methyl THF is “trapped” and can’t be converted to THF Only reaction that can metabolize N5-methyl THF is methionine synthase (Vit B12 dependent) The problem? Large doses of folate (from supplements) can hide a Vit B12 deficiency. 5× the RDA for folate overwhelms the ability to form N5-methyl THF in the gut, so you get more folate going to the liver where it is converted into THF (this will bypass the trap) * However, there is still a problem with the SAM cycle!

Answer 202

Folate is critically important in dividing cells, which supports the production of specialized cells that form the neural tube. This takes place during early pregnancy, so folate deficiency leads to severe birth defects (neural tube defects; NTD). In the embryo, the neural tube is the CNS, which becomes the brain and spinal cord. NTD is an opening of the spinal cord or brain Closed vs. open NTD (open more common): the brain or spinal cord are exposed

Answer 203

Initially found while trying to understand dermatitis in rats * Exists as 6 vitamers (which are interchangeable and comparably active) – Pyridoxine (plant provitamin), pyridoxal, pyridoxamine – All can be found phosphorylated and unphosphorylated We’ve already seen Vit B6 (transamination reactions use pyridoxal phosphate; PLP) PLP is the main form found in blood, bound to albumin * High levels of Vit B6 are found in the muscle

Answer 204

pyridoxal phosphate; PLP found bound to albumin

Answer 205

Pyridoxine (plant provitamin), pyridoxal, pyridoxamine – All can be found phosphorylated and unphosphorylated * All isomers are found in foods

Answer 206

Vit B6 is dephosphorylated prior to absorption – Passive diffusion in the jejunum * PLP is the main form found in blood, bound to albumin * High levels of Vit B6 are found in the muscle

Answer 207

this is Vit B6!! Conversion occurs primarily in the liver Pyridoxine (alcohol) is the plant provitamin B6 its converted to pyridoxal (aldehyde) pyrodoxal is then converted to pyrodoxal phosphate (PLP!!) /it's phosphorylated and this is the active form and used as a co-enzyme

Answer 208

= pyridoxal phosphate the active form of Vit B6 it's a co-enzyme PLP is a cofactor for many enzymes, including aminotransferases * Also involved in the 1st step in porphyrin (heme) synthesis – *uses glycine and succinyl CoA from the Kreb’s cycle – Heme is incorporated into hemoglobin, myoglobin, as well as cytochromes in ETC Synthesis of neuroactive amines (epi & norepinephrine, serotonin, histamine, GABA) – Relationship with serotonin is why you’ll find Vit B6 is sometimes sold to “treat mood disorders”

Answer 209

rare but causes microcytic anemia

Answer 210

Stem cells in bone marrow are differentiated in the presence of erythropoietin (EPO) * Normally, differentiation causes red blood cells to shrink, nucleus is removed, and able to carry O2 * Process is very sensitive to micronutrient deficiencies, which leads to anaemia

Answer 211

3 types of anaemia 1. Megaloblastic anaemia - def. in folate, vit B12 - impaired DNA synthesis and RBC production 2. Hemolytic anaemia - vit E, selenium, cysteine def. - oxidant stress 3. Microcytic anaemia - vit. B6 def. - impaired porforin - problem making heme

Answer 212

Megaloblastic anemia (problem with DNA synthesis) * RBCs are too big but too few, become stuffed with hemoglobin. * In this anemia, there is a deficiency of folate and B12, which ultimately impairs the activity of the enzyme thymidylate synthase, which is required for DNA synthesis. As a result, RBCs can’t be made in the initial stages

Answer 213

Hemolytic anemia (problem with oxidative damage) * There are not enough RBCs due to premature destruction of the cells. * This is due to a deficiency in antioxidant nutrients like Vitamin E and selenium, as well as cysteine (which is required for glutathione). The high level of oxygen in RBCs encourages the production of free radicals. When antioxidant nutrients are deficient, there is a lot of lipid peroxidation of the membrane which ends up destroying RBCs

Answer 214

Problem w protein production Microcytic hypochromic anemia (problem with protein production) * RBCs are small and pale due to a deficiency of Vit B6 affecting the synthesis of porphyrin. Without adequate porphyrin, you don’t have normal synthesis of hemoglobin and the cells are very pale. They are also very small because the hemoglobin is what gives them bulk

Answer 215

essential trace minerals iron, copper and zinc

Answer 216

Iron is found in a lot of different foods at low levels – Rich in liver, meats, and plant sources (e.g., leafy green vegetables, fruits, nuts) * In foods, iron can be found in one of two forms: 1. Heme (within the porphyrin ring of hemoglobin and myoglobin) (from animals) 2. Non-heme (from plants)

Answer 217

Functions of iron in the body include: 1. Oxygen transport (i.e., important for hemoglobin and myoglobin) 2. Redox reactions – is an active component of the electron transport chain (iron sulfur centers and cytochrome heme proteins) 3. Iron metalloenzymes

Answer 218

Only two states of iron are stable in the aqueous environment of the body and in food: Fe3+ (ferric, oxidized) and Fe2+ (ferrous, reduced)

Answer 219

unique cause higher in women by more than double due to menses and even higher in pregnant women to cover the needs of the fetus

Answer 220

Between 10-18% of the iron ingested is absorbed – How much is absorbed will depend on a person’s iron status

Answer 221

HCl and proteases cleave non-heme iron from food components in the stomach to release mostly ferric (Fe3+) iron – The acidic environment of the stomach converts most Fe3+ into ferrous iron (Fe2+) – Any remaining Fe3+ is reduced into Fe2+ by a reductase enzyme in the small intestine – Fe2+ is taken up into intestinal cells by the divalent metal transporter 1 (DMT1)

Answer 222

Released from hemoglobin/myoglobin by proteases in the stomach and small intestine – Heme (porphyrin ring) is taken up in the small intestine by heme carrier protein 1 (HCP1) – Inside intestinal cells, the heme porphyrin ring is broken down by heme oxygenase, releasing Fe2+ and protoporphyrin

Answer 223

in non-heme iron... Fe2+ is taken up into intestinal cells by the divalent metal transporter 1 (DMT1) In heme iron... Heme (porphyrin ring) is taken up in the small intestine by heme carrier protein 1 (HCP1 Inside intestinal cells, the heme porphyrin ring is broken down by heme oxygenase, releasing Fe2+ and protoporphyrin In both cases - Fe2+ is either used in intestinal cells (i.e., functional), stored in intestinal cells (as ferritin) or transported into blood (via ferroportin) Ferroportin HCP1 Heme oxygenase

Answer 224

Chelators are small organic compounds that form a complex with a metal ion – This can affect iron absorption – If the iron-chelate is soluble, then absorption is enhanced – If the iron-chelate is insoluble, then absorption is inhibited

Answer 225

Chelators are small organic compounds that form a complex with a metal ion – This can affect iron absorption – If the iron-chelate is soluble, then absorption is enhanced – If the iron-chelate is insoluble, then absorption is inhibited

Answer 226

Examples of enhancers: Vitamin C, and some evidence for specific soluble fibres (pectin). – Vitamin C acts as a reducing agent that helps convert Fe3+ into Fe2+ (which is more readily absorbed)

Answer 227

Examples of inhibitors: Polyphenols (in tea and coffee), oxalic acid (in spinach), and insoluble fibres. – Coffee just after a meal reduces iron absorption by ~50%. – Oxalic acid binds with iron (and other metals too), preventing its absorption

Answer 228

ron is transported in the blood in the ferric (Fe3+) form bound to transferrin, which is a carrier protein. It's important that iron is bound by a carrier (instead of being free)? – Unbound ferrous (Fe2+) iron has a high redox activity and can readily lose an electron, increasing free radical production (e.g., H2O2 to OH●)

Answer 229

liver, bone marrow, and spleen

Answer 230

1) In intestinal lumen, iron is reduced from Fe3+ to Fe2+ by reductase enzyme Fe2+ is then absorbed by enterocyte and into blood 2) In blood, Fe2+ is oxidized by ceruloplasmin to attach Fe3+ to transferrin transferrin-Fe3+ can now bind transferrin receptor on target tissue and it gets taken in to cell via receptor mediated endocytosis 3) in target tissue cell, Fe3+ is reduced by NADH, FADH2 or vit C now Fe2+ can go: to iron sulfur centres iron metalloenxymes heme to make cytochromes, hemoglobin or myoglobin OR transferrin-Fe3+ can pass Fe3+ directly on to ferritin-Fe3+ for storage!! (key storage of iron - readily available) and ferritin-Fe3+ can create a complex w other ferritins and denatured proteins (less accessible/available)

Answer 231

Iron status in blood High iron = when >40% of transferrin is bound with iron. - Iron remains in intestinal cells as ferritin Low iron = when <15% of transferrin is bound with iron. - Iron transported by ferroportin, where it is picked up by transferrin

Answer 232

the thing that transfers iron in the blood Transferrin actually has two binding sites for 2 Fe3+ = diferric transferrin via a reaction w ceruloplasmin, transferrin can bind Fe3+

Answer 233

a protein that prevents iron absorption by inhibiting ferroportin transporter on basolateral side of enterocyte, preventing iron from entering blood Liver senses diferric transferrin levels * High levels cause production and secretion of hepcidin, which inhibits ferroportin does not let iron be absorbed if transferrin levels over 40%

Answer 234

Important to control absorption because iron is not excreted from the body.

Answer 235

Haematopoiesis is the formation of blood cellular components (e.g., iron needed for red blood cells) * Iron is critical due to its presence in heme, which enables oxygen transport to tissues (hemoglobin), oxygen storage within a tissue (myoglobin), and transport of electrons through ETC (cytochromes) BASICALLY... in plasma, iron is transported as Fe3+ bound to transferrin, can go to: BONE marrow - where it is reduced Fe2+ and used to make heme and be incorporated into red blood cells In LIVER - where it can be stored as ferritin-Fe3+ --> accessible or hemosiderin-Fe3+ (less acceble) RBCs circulate and eventually are degraded in spleen by reticuloendothelial cells - releasing hemoglobin and subsequently iron back to blood

Answer 236

Porphyrin synthesis starts with glycine & succinyl-CoA (from pantothenic acid) and requires vitamin B6 (which is why a B6 deficiency can lead to anemia) Ferrous iron (Fe2+) is then added to porphyrin to produce heme which can now be used to make hemoglobin, cytochromes or myoglobin

Answer 237

(1) Catalase (an enzyme in our oxidant defense system) Converts H2O2 into H2O (2) Thyroid peroxidase Addition of iodides to thyroglobulin protein

Answer 238

Worldwide problem (~30%), esp. premenopausal women, infants, adolescents Deficiencies most often seen in four groups: 1) Infants and young children 2) Adolescents in their early growth spurts 3) Females during childbearing years 4) Pregnant women

Answer 239

General symptoms: fatigue, pallor, weakness, hair loss, irritability, brittle or grooved nails, impaired immune function

Answer 240

Lower test scores on mental development * Lower test scores on motor development * Some improvements in test scores after treatment with iron. – In other words, some of the outcomes of iron deficiency may be permanent

Answer 241

Toxicity (eventually causes liver failure) * Hemochromatosis (increased iron absorption) * Hemosiderosis (iron deposition in tissues) * Can be treated with iron chelators and blood-letting Microcytic anemia

Answer 242

Content varies widely in foods, and is sensitive to how food is produced and handled * Good sources of copper include oysters & shellfish, whole grains, beans, nuts, potatoes, organ meats, and dark leafy greens

Answer 243

Copper functions as a component of many important enzymes, including: 1. Ceruloplasmin (necessary for iron metabolism) 2. Cytochrome c oxidase (key enzyme in the electron transport chain) 3. Superoxide dismutase (necessary for oxidant defense system) 4. Dopamine Monoxygenase (key for norephinephrine production) 5. Tyrosinase (involved in melanin formation, i.e., pigments)

Answer 244

Acts as an enzyme cofactor in many redox reactions

Answer 245

Cu2+ bound to amino acids – HCl and pepsin release Cu2+ * Cu2+ must be reduced to Cu1+ to be absorbed by enterocyte – Most is absorbed in the small intestine * Specific transporters exist Enhancer Chelators – E.g., Vit C Inhibitor Chelators – High levels of metal ions in the diet promote the production of metallothionein, which binds all metal ions (e.g., copper) and prevents their absorption * Absorbed copper is transported to the liver bound to protein (albumin), where it gets incorporated into ceruloplasmin

Answer 246

is a protein produced by the liver that transports Cu+ around tissues and helps w the metabolism of iron

Answer 247

General symptoms? Anaemia, hypopigmentation of skin, bone abnormalities, thrombosis, etc. Can be treated with copper supplements some people got menke's disease/kinky hair disease but that's cause they born w genetic mutation that causes body to not be able to absorb enough copper

Answer 248

Menke’s Disease (aka Menke’s Kinky Hair Syndrome) X linked genetic disease (i.e., genetic mutation in the ATP7A gene on X chromosome) Inborn error of metabolism in which the body cannot absorb enough copper Low serum copper and ceruloplasmin

Answer 249

WILSON'S DISEASE!! Symptoms? Drooling Slurred speech Problems swallowing Problems walking Cognitive impairment Treatments? Low copper diet Chelation therapy Zinc therapy Causes Wilson disease is caused by a buildup of copper in the body. Normally, excess copper is excreted in bile. But people who have Wilson disease cannot do this, due to a mutation in the ATP7B gene. When the copper storage capacity of the liver is exceeded, copper starts to accumulate in other organs – including the brain, kidneys, and eyes.

Answer 250

ound in all organs, tissues, and body fluids (typically as Zn2+) * Sources: – Oysters contain more zinc per serving than any other food, but red meat and poultry provide most of the zinc in the North American diet. Other good food sources include beans, nuts, crab, lobster, whole grains, fortified breakfast cereals, and dairy products – Found complexed with nucleic acids and protein

Answer 251

Main functions: 1. Zinc-containing metalloenzymes - more than 200 known at present and involved in all metabolic pathways * Provides structural integrity (stabilizes tertiary structure of a protein,) and/or * Plays a role at reaction site of an enzyme 2. Oxidant defense system 3. DNA binding (formation of zinc fingers)

Answer 252

Examples of zinc-dependent enzymes: carboxypeptidase (protein digestion), superoxide dismutase (oxidant defense), polyglutamate hydrolase (folate digestion), nucleic acid synthesis (DNA and RNA polymerase)

Answer 253

Absorption: – Like iron and copper, zinc must be released from amino acids before absorption * Done by HCl in the stomach & digestive enzymes in the small intestine – Zinc can be absorbed via two mechanisms: 1) carrier-mediated (ZIP4; primary mechanism) and 2) simple diffusion – Absorption decreases when a person’s zinc status is high (feedback regulation reduces ZIP4 levels in the intestine)

Answer 254

Enhancer chelators * Organic acids, Prostaglandins Inhibitor chelators * Antacids, phytic acid, oxalic acid * Metallothionein induced by high dietary zinc in intestinal cells (see Copper and Absorption Transport slide) is also induced by high dietary copper, so a high copper diet can cause a zinc deficiency

Answer 255

- Used locally – Sequestered by binding with metallothionein (and then eventually lost) – Secreted into circulation and transported bound to albumin (first destination is the liver, then other tissues)

Answer 256

Major role regulating gene expression * Zinc fingers – Describes the shape of regions of transcription factor proteins that interact with DNA – Interactions between zinc and side chains of histidine & cysteine – Enables basic amino acids to interact with DNA

Answer 257

(higher RDA in men to support testosterone function) (highest RDA in pregnant women to support fetal development)

Answer 258

Common in humans (especially older adults, vegetarians, & children) * Poor absorption can be caused by phytic acid in grains * In children, zinc deficiency can slow growth (inadequate cell division), poor wound healing, delayed sexual maturation (deficient testosterone synthesis), and impaired taste (insufficient taste proteins).

Answer 259

Zinc toxicity leads to neurological problems, numbness, metallic taste, nausea, etc. – Causes a copper deficiency due to the activation of metallothionein

Answer 260

Mouth – No enzymatic digestion – Mechanical breakdown * Stomach – HCl in gastric juice – Pepsin (endopeptidase) * Pancreas – Pancreatic juice containing zymogens (inactive digestive proenzymes) * Small Intestine – Zymogens are activated – Enzymes break-down peptides – Absorption of AAs

Answer 261

Stomach produces “gastric juice” – HCl is secreted from parietal cells; its release is triggered by gastrin, acetylcholine, and histamine – Pepsin is secreted as pepsinogen, which is an inactive zymogen

Answer 262

Secreted from parietal cells its release is triggered by gastrin, acetylcholine, and histamine HCl has two functions: 1. Denatures proteins - disrupts H-bonds and electrostatic bonds 2. Activates pepsin

Answer 263

is secreted as pepsinogen, which is an inactive zymogen Active in an acidic pH, inactive at a neutral pH – HCl causes a conformational change in pepsinogen, allowing it to then autoactivate itself – Pepsin is an endopeptidase, i.e., in other words, it cleaves peptide bonds within a polypeptide chain – Generates mostly oligopeptides and some free AAs

Answer 264

Pancreas secretes zymogens and proenzymes: trypsonogen, chymotrypsinogen, proelastase, procarboxypeptidase A & B these are secreted into the small intestine and trypsinogen is activated by enteropeptidase (located in brush border) to trypsin which activates all the other zymogens theres also aminopeptidase (an ezokinase) and yeah the polypeptides are broken into free aas and small peptides

Answer 265

ENDOPEPTIDASES break basic - trypsin neutral aliphatic - elastase large neutral amino acids - pepsin, parapepsin, chymotrypsin

Answer 266

EXOPEPTIDASES amino-peptidases break amino tail off carboxy-peptidase - break carboxy tail off

Answer 267

Most AAs are absorbed in upper small intestine * Two ways AAs are absorbed – Facilitated diffusion (doesn't require Na+ or ATP, will not concentrate against gradient) – Active transport (>60% of AAs are absorbed this way) * Sodium-dependent transporters (indirect ATP requirement) - cause they go through PEPT1 = peptide transporter 1 which is on intestinal cell membrane like uses an Na+ gradient which is why Na+ has to be actively transported back out - requires ATP - concentrate against gradient

Answer 268

Essential AAs may be absorbed faster than non-essential AAs – Competition for absorption exists between AAs – Free AAs have no absorptive advantage (i.e., protein supplements) over AAs in foods

Answer 269

AAs are either transported out of the intestinal cell or used directly within the enterocyte for: 1. Synthesis of new protein 2. Energy *Estimates indicate 30-40% of essential AAs are used in the small intestine

Answer 270

1. Generate energy for the cell 2. Stimulate cell proliferation (to replace shed enterocytes) 3. Increase synthesis of heat shock proteins (chaperones) 4. Drive mucus production, which helps to prevent bacterial translocation

Answer 271

The liver is very effective at taking up AAs from circulation. they travel from the small intestine to the liver through the portal vein Liver uses ~20% of the AAs to: - Make new proteins/enzymes - Albumin and other transport proteins - Make peptide hormones Liver catabolizes the remaining 80% of AAs, where: - NH3 sent to the urea cycle - Carbon skeleton sent to Kreb’s cycle (for energy) or used for gluconeogenesis or lipogenesis BCAAs are not taken up by liver, and instead are anabolic signals for tissues like muscle BCAAs are not taken up by the liver, and instead are anabolic signals for tissues like muscle

Answer 272

AA composition Digestibility Presence of toxic factors Species consuming the protein

Answer 273

is a measure of quality for the protein Any protein that provides all essential AA is considered “high quality”. Animal protein > plant protein. For example, grains are limiting in lysine, legumes are limiting in sulfur-containing AA (methionine).

Answer 274

a measure of protein quality Some proteins are more digestible than others. More digestible, means higher quality. Animal protein > plant protein. Some materials, like hair, have a great amino acid balance but are indigestible.

Answer 275

measure of quality think soy Less toxic factors means higher quality. Animal protein > plant protein. Plants contain thousands of phytochemicals. For example, soybeans contain inhibitors that interfere with trypsin, thus preventing protein digestion.

Answer 276

Is one of the aspects of protein quality Humans, pigs and chickens have similar protein needs. Ruminants have bacteria in the rumen that can make all AAs, so none are considered essential (remember that ruminants can use low quality protein sources).

Answer 277

way of assessing protein quality Official method in Canada for the evaluation of protein quality * With this method, young rats are fed a diet for 4 weeks. The diet has all nutrients present at adequate levels except for protein, which is included at 10% kcal of the diet * 10% protein is lower limit for health. If there is anything wrong with the protein source, the growth of rats will be impaired * Rats are weighed at the beginning and end of the 4 weeks. Food consumption is carefully monitored PER = gain in body mass (g) / total protein intake (g) ex. Rat gains 10 g and eats 14g PER = 10g/14g=0.71 At 10% “perfect protein” you get 2g of rat growth per gram intake ***(whole egg is optimal to get a value of 2.0

Answer 278

Protein Efficiency Ratio (PER) PROs - Simple *Cheap *Very sensitive to AA balance, digestibility, toxic factors CONS - Rats are not humans *Growth, not maintenance You don’t know WHY a protein is poor quality

Answer 279

second way of assessing protein quality the test protein is chemically digested into free amino acids - these are then quantified by chromatography, and mathematically compared to the composition of whole egg protein (reference) CS = abundance of first limiting AA in test protein / abundance of same AA in whole egg x 100

Answer 280

PROS: *Simple and cheap *Identifies the limiting AA in the food *Used to optimize feeds by mixing different sources of protein CONS: *Doesn’t account for digestibility (e.g. hair) or toxins *Assumes whole egg is an ideal protein

Answer 281

Nitrogen balance is a measure of N intake (diet) and N loss (urine, feces, sweat) Nitrogen Balance (NB) = Nitrogen Intake – Nitrogen Loss * During growth, pregnancy, and times of tissue repair (NB > 0) * When you don’t have enough protein (NB < 0) – The problem is exacerbated with poor protein quality because body proteins are used as a source of essential AA (in other words, body proteins are broken down to “free up” essential AA, ultimately leading to a loss of function) – NB < 0 is seen in people with serious tissue injuries, wasting diseases like sarcopenia, and long-term fasting * For most adults, NB = 0 (people are generally in balance) * Problems with poor protein quality may be overcome with high protein quantity (commonly observed in developed countries like USA)

Answer 282

Higher protein requirements in: *Infancy, childhood, and in teenagers *During pregnancy and lactation NOTE: Recommendations for protein requirements based on ANIMAL sources of protein. Plant sources may be less digestible due to differences in the nature of protein and other components (fibre). If these recommendations used plant sources of protein, the values would be higher

Answer 283

What happens when you consume too much or too little protein? 1)Excessive Intake - High protein diets (Atkins, South Beach) - Protein Supplementation 2)Deficient Intake - Deficient in both protein quantity and energy / overall malnutrition - Deficient in only protein quantity

Answer 284

High protein diets are very popular. * Typically, high protein diets are low in carbs. * 3 common high protein diets: – Atkins Diet (most criticized) (C:F:P = 3:64:33) - South Beach diet - The Zone Diet

Answer 285

Atkins Diet (most criticized) (C:F:P = 3:64:33) - a high protein diet * Different phases where macronutrient content varies. * CHO intake very low, while fat and protein intake very high (~ 30% protein). * Criticized because no attention to type of CHO or fat consumed

Answer 286

South Beach diet (C:F:P = 30:40:30) a high protein diet * Different phases where macronutrient content varies. * For CHO intake there is an emphasis on low GI foods. * Protein is consistent throughout the various phases (~30%)

Answer 287

The Zone Diet * Not really a high protein diet, rather a balanced diet.

Answer 288

Short term weight loss is comparable to other diet approaches. – Some studies show improved insulin sensitivity with high protein as compared to high CHO diets (probably due to reduced burden on the pancreas to generate insulin to deal with CHO). – Conflicting results with respect to effects on cardiovascular health. A moderate increase in protein appears to be cardioprotective, but high protein may be a concern in the long-term. – People with kidney diseases should avoid high-protein diets

Answer 289

Does weight lifting change the RDA for protein (0.8g protein / kg body weight / day)? * Protein supplements are widely used by athletes. * Supplements help to ensure that the correct balance of AAs are delivered to the muscle. * HOWEVER, this would be the same if a person ate a high quality protein (eggs, meat, fish). * Most protein supplements deliver high levels of BCAAs. BCAAs are rapidly absorbed and delivered to the muscle. * Protein supplements and aging – Anabolic response of the muscle to a protein meal gradually diminishes after 40 years of age – Can be improved with protein supplements

Answer 290

overall malnutrition basically Protein and Energy Deficiency * Marasmus (Protein/Calorie malnutrition). – Very low intake of a balanced diet with around 8-10% protein (so just a bit below what is needed). * Because everything is in balance, the body switches to starvation mode. – Well organized utilization of body fuel stores allows survival, eventually leading to a complete loss of body fat which causes a wrinkled appearance to the skin * Adults cope with Protein/Calorie malnutrition better than children. * Characterized by a complete loss of body fat and muscle, peeling skin, uneven pigmentation

Answer 291

Protein deficiency * Pronounced “kwash – ee – or –kor” * Diet has sufficient Calories, but is deficient in protein * Only 1-2% protein in the diet * Typically seen in developing countries where agriculture is key to the diet * High CHO foods (e.g., tuber cassava) – When a child is weaned from mother’s breast milk (very balanced source of nutrients) to cassava porridge (no protein or fat), problems can emerge – Lots of CHO, but no protein to metabolize or transport nutrients * Patients are characterized by a enlarged abdomen, ‘burns’ on the skin and diarrhea

Answer 292

Decreased plasma proteins causes an osmotic imbalance in the gut (edema), leading to a swelling of the gut – Liver is enlarged due to the inability to export fat from the liver (can’t make VLDL)

Answer 293

See slide 21 of proteins part 2

Answer 294

NH4+ is toxic and needs to be transported safely between organs 3 differences between fed and fasted states: 1. FASTED state involves the formation of both glutamine and alanine, while the FED state is mostly glutamine. 2. FED state involves both the liver and kidneys. (while FASTED only kidneys) 3. FED state mainly involves the excretion of the amino group as urea, whereas the FASTED state mainly involves the excretion of the amino group as ammonium (NH4+) directly.

Answer 295

Catabolizing an α-ketoacid leads to the production of bicarbonate (HCO3-) Bicarbonate is a weak base that reacts with a H+ (if this happens, no change in pH) However, the fed state promotes a mild alkalosis! High dietary protein intake increases amino acid catabolism, which can increase HCO3- (because H+ is used up). This can increase pH a bit (to ~7.8) α-ketoacids enter the Kreb’s cycle in all cells, resulting in CO2 production; however, @ physiological pH the CO2 is actually HCO3-

Answer 296

1. The liver converts the amino group to urea in a process that consumes HCO3-. 2. Catabolism of sulfur-containing AA produces a bit of sulphuric acid to neutralize pH.

Answer 297

With a long-term fast / starvation, minor amounts of protein are catabolized to release glucogenic amino acids (for gluconeogenesis) - However, remember that the primary source of energy is TAG from adipose tissue - The breakdown of TAG leads to the production of acidic ketone bodies. So, long-term fasting promotes a mild acidosis (pH can drop to ~7.0)! - This is also known as nutritional ketosis Products of TAG breakdown (long hydrocarbon chains) are not very water soluble. The liver converts these long hydrocarbons into small soluble ketone bodies (which the brain can use for energy during starvation).

Answer 298

long-term fasting promotes a mild acidosis (pH can drop to ~7.0)! - This is also known as nutritional ketosis  When AAs are catabolized in a fasted state, the amino group is brought directly to the kidney (thus bypassing the urea cycle where HCO3- is used up). This means that HCO3- produced in the Kreb’s cycle can be used to neutralize the weak acidosis state caused by ketone bodies.

Answer 299

Glutamate – Incredibly important in AA catabolism – It is a common end product of transamination reactions * α-ketoacid for glutamate is alpha-ketoglutarate Aspartate – Donates an amino group in the urea cycle * α-ketoacid for aspartate is oxaloacetate Alanine – Inter-organ nitrogen carrier * Muscle to the liver * α-ketoacid for alanine is pyruvate Glutamine – Most abundant AA in the body – Inter-organ nitrogen carrier (goes to liver & kidney) – Can donate an amino group to other reactions

Answer 300

1) transamination 2) oxidative deamination 3) a) glutamine production b) glutamate regeneration 4) Urea cycle

Answer 301

reactions move nitrogen from catabolized protein between organs for excretion TRANSAMINATION: transfer of an amino group to an AA carbon skeleton (i.e., α-ketoacid) --> catalyzed by “aminotransferases” --> most AA undergo transamination (except lysine, proline, and threonine) DRAW GENERAL TRANSAMINATION REACTION from slide 26 on proteins part 4 TRANSAMINATION, cont. * Bi-directional reactions * Active in all tissues * Always produces an AA (usually glutamate) and α-ketoacid * At least 1 transaminase exists for each AA, with each using glutamate/alpha-ketoglutarate as one of the pairings

Answer 302

Most abundant aminotransferases in the liver: * Glutamate pyruvate transaminase (GPT) (also known as ALT) * Glutamate oxaloacetate transaminase (GOT) (also known as AST) GPT converts a-ketoglutarate and alanine to glutamate and pyruvate GOT converts alpha ketoglutarate and aspartate to glutamate and oxaloacetate

Answer 303

- glutamate is the main AA to undergo oxidative deamination since it is the main product of transamination Amino group is released from the glutamate backbone Reaction favours the formation of alpha-ketoglutarate Process is very active in all tissues in the body REACTION glutamate gets converted to alpha ketoglutarate + NH4+ via glutamate dehydrogenase enzyme and reduction of NAD+ to NADH

Answer 304

In extrahepatic tissue (EHT), the NH4+ is used in the synthesis of glutamine In the liver, NH4+ is used for urea synthesis In kidneys, NH4+ is excreted directly as is into urine

Answer 305

Formation of glutamine (primary inter-organ nitrogen carrier) * Muscle produces ~90% of the glutamine found in the body SO MOSTLY HAPPENING IN MUSCLE Glutamate is converted to glutamine via glutamine synthetase NH4+ group is added ATP --> ADP + Pi H2O is removed Glutamine is the most abundant aa In the fed state, primarily travels to liver In the fasted state, primarily travels to kidney

Answer 306

Opposite reaction to last slide; however, a different enzyme is required SO MOSTLY HAPPENING IN LIVER AND KIDNEY after glutamine has inter-organ transferred * Releases amino group from the glutamine side chain (i.e., deamination) Glutamine is converted back to glutamate via the addition of H2O and excretion of NH4+ and the enzyme GLUTAMINASE * Active in liver in the fed state (amino group used for urea synthesis) * Active in the kidney during fasting (amino group secreted as NH4+

Answer 307

Toxic NH4+ is converted to less toxic urea in the liver * Urea transported to kidney for excretion NH4+ and HCO3- are added to carbarnyl phosphate via ATP hydrolysis reaction producing citrulline CItruline condenses with aspartate and donates amino group to produce arginine Fed state: 80-90% of urinary N will be in form of urea NH4+ from oxidative deamination and glutamate regeneration from glutamine Aspartate condenses with citrulline and donates an amino group Urea cycle uses HCO3-, thereby preventing alkalosis Urea cycle requires energy (ATP) Defects in any of the enzymes in the urea cycle leads to developmental neurotoxicity due to a build-up of NH4+ in the body.

Answer 308

aka the Glucose-Alanine Cycle SPECIFIC TO MUSCLE glucose is converted to pyruvate (releasing 2 atp) pyruvate is converted to alanine e via GPT transamination = pyruvate + glutamate --> alanine + a-ketoglutarate alanine then acts as an interorgan transporter and can go through blood to LIVER to undergo another transamination --> being reconverted to pyruvate (and glutamate so NH4+ is excreted via oxidative deamination) pyruvate that was produced can now be converted to glucose (via gluconeogenesis - consuming 6ATP) and released by liver to muscle where it can be used as energy or like redo cycle (pyruvate to alanine, alanine to liver, alanine to pyruvate)

Answer 309

When the body’s energy sources are low, protein is broken down. AA catabolism releases (1) Amino group (NH4+), and (2) α-ketoacid. α-ketoacids can be formed by: Deamination – removal of amino group from AA. The carbon skeleton that remains is the α-ketoacid (mostly seen with glutamate). Transamination – transfer of an amino group from an AA to an α-ketoacid. In the process, the “donating” AA becomes an α-ketoacid and the “receiving” α-ketoacid becomes an AA. α-ketoacids contain KETONE and CARBOXYLIC ACID functional groups. Ketogenic --> a degraded AA that can be converted into Acetyl CoA Glucogenic --> a degraded AA that can be converted into Glucose

Final YOU GOT THIS DEIRDRE Flashcards

(334 cards)