Midterm 3 Flashcards
(39 cards)
- Understand the relationship between ascorbic acid, dehydroascorbate, and 2, 3-diketogulonic acid
Ascorbic acid→ ascorbate free radical (Lost one electron) → dehydroascorbate (Lost 2 electron) → 2,3-diketogulonic acid (inactive) (Irreversibly oxidized)..
- What are the differences in the absorption of ascorbic acid and dehydroascorbate, which form is better absorbed? How is it transported in blood/plasma?
a. Ascorbate is absorbed by a Na-dependent, saturable, active transport system; ascorbate may be oxidized to dehydroascorbate and absorbed by GLUT1 or GLUT3.
b. Dehydroascorbate appears to be better absorbed; once absorbed, it is rapidly reduced back to ascorbate by ascorbate reductase involving NADPH.
c. Up to 200 mg is absorbed, but absorption at higher doses (>10g) is limited (<20%), and may result in malabsorption and lead to osmotic diarrhea.
d. Once in the enterocyte, vitamin C is transported across the basolateral membrane by Na-independent facilitated transport, and exist in plasma mainly as free ascorbate.
- What are the major co-enzyme functions associated with vitamin C; what are the mechanisms in these functions; what is the non-coenzyme function, why is the general antioxidant activity of vitamin C not considered a vitamin function?
a. Vitamin functions – The vitamin roles of ascorbate are defined as its functions that are required in the prevention of scurvy; it acts as a reducing agent, and in many cases, it is involved in hydroxylases in hydroxylation reactions of various substrates.
i. Collagen synthesis – Ascorbate is important in the post-translational hydroxylation of proline to hydroxyproline, and lysine to hydroxylysine. Hydroxyproline is important in the formation of the triple-helical structure of collagen; hydroxylysine is important in the cross-linking of collagen fibers. Ascorbate, in these reactions, is specifically involved in the reduction of ferric iron to ferrous iron.
1. Proline → Hydroxyproline
2. Lysine → Hydroxylysine
ii. Carnitine synthesis – Ascorbate is important in two reactions in the conversion of trimethyllysine to carnitine. The first step involves the hydroxylation of trimethyllysine to 3-OH trimethyllysine by trimethyllysine hydroxylase; the final reaction is the conversion of 4-butyrobetaine to carnitine by 4-butyrobetaine hydroxylase – both these enzymes are vitamin C dependent.
1. Trimethyllysine → trimethyllysine hydroxylase → 3-OH-trimethyllysine
2. 4-butyrobetaine → 4-butyrobetaine hydroxylase → Carnitine
iii. Tyrosine synthesis & metabolism –
1. Ascorbate is involved in the conversion of phenylalanine to tyrosine by phenylalanine hydroxylase.
2. Other vitamin C dependent, tyrosine-related enzymatic reactions include: P-hydroxyphenylpyrubate → p-hydroxyphenylpyruvate hydroxylase → homogenitase
3. Homogentisate → homogentisate → 4-maleylacetoacetate.
iv. Cholesterol metabolism – The hydroxylation of cholesterol to 7-OH cholesterol by cholesterol a-7 hydroxylase; impaired function of this enzyme results in decreased bile synthesis and elevated cholesterol.
b. Non-vitamin functions – Plays a role as a general antioxidant in aqueous phases, but is not considered a vitamin function, as it can be substituted by other antioxidants; increases in non-heme iron absorption (can be done by other acids).
- What is the estimated total body pool size for ascorbate; how much dietary ascorbate is needed to maintain this pool, how are mega doses of ascorbate handled by the body?
a. The body pool is believed to be between 1,500 – 3,000 mg
b. This can be maintained by 100 – 200 mg/day
c. Concentrations are highest in the organs.
d. Increasing ascorbate intake (mega doses) does not appear to increase urinary oxalate excretion and large amounts of dietary/supplemented ascorbate appears to be excreted unmetabolized as free ascorbate in urine.
- What is the mechanism of ascorbate’s enzymatic role, how are Fe and Cu involved?
a. Ascorbate’s enzymatic role: both iron and copper are important in several hydroxylation reactions responsible for ascorbate’s major functions. Ascorbate is also important in the absorption of non-heme iron and facilitates its absorption by maintaining it in the reduced form (Fe+2).
b. Alternatively it may increase elemental iron absorption by forming a soluble complex with ascorbate. Ascorbate is also important in the distribution and mobilization of iron stores within the body.
c. Absorbate is important in getting iron in the proper form to be released from ferritin and transferrin molecules.
d. Absorbate is also thought to interfere with the movement of copper into its transport protein ceruloplasmin. Ascorbate supplementation of 1.5 to 2 g/ day resulted in lower plasma concentrations of copper as ceruloplasmin
- What is the importance of ascorbate in the amidation of peptides with C-terminal glycine residues (be able to cite a few of the important products)?
a. Ascorbate is important in keeping Cu in its proper form (Cu+) in the Cu-dependent enzyme peptidylglycine alpha-amidating monooxygenase. In this reaction the C terminal glycine of polypeptides is cleaved between its amino group and the central alpha carbon leaving the C-terminal end of the peptide amidated.
b. The products are important neurotransmitters, hormones, and hormone releasing factors such as CCK, gastrin, oxytocin, calcitonin, bombesin, corticotropin releasing factor, and growth hormone releasing factor.
- What is the deficiency disease associated with vitamin C, what are some of the symptoms, how might these be related to its functions?
a. Scurvy – This results when the total body pool of ascorbate falls below 300 mg; it is estimated that as little as 10 mg/day would prevent the symptoms of scurvy.
b. 4H’s represent the symptoms of scurvy – hemorrhage, hyperkeratosis, hypochondriasis, and hematologic.
- What are the potential toxicities associated with mega doses of ascorbate; to what extent do these represent toxicities? (be able to support your opinion)
a. Ascorbate is poorly absorbed at large doses (>1g), and may cause osmotic diarrhea.
b. A putative toxicity reported is the occurrence of kidney stones (oxalate stones) in individuals who are susceptible. Nevertheless, there is no biochemical/metabolic evidence
- What environmental factor is important in assessing an individual’s requirement for vitamin C?
a. Individuals who smoke have a greater need for ascorbate due to the destruction of the vitamin by oxidative products of smoking. The estimated increase for smokers is an additional 35 mg/day.
- What are the major association between vitamin C and chronic disease; what problems are associated with acceptance of these interpretations?
a. Common cold – There is no evidence that vitamin C prevents the common cold; nevertheless, there is some evidence to indicate that vitamin C reduces the symptoms/durations of the cold by acting as an anti-histamine at higher doses, with equal evidence that indicates otherwise.
b. Cancer – vitamin C can potentially prevent cancer development, as evidenced by in vitro and animal studies; evidence is inconclusive in humans, and potential evidence that vitamin C protects against cancer is confounded with high fruit/vegetable intake. Vitamin C may have an important role in gastric and colon cancers.
- What is the oxidation state of Ca; what are the major inorganic forms?
a. Oxidation state: Ca+2
b. Major inorganic forms: ionized: Ca+2, calcium phosphate: Ca3(PO4)2, hydroxyapatite: Ca10(PO4)6(OH)2
- What is the estimated body content, how is this distributed in the body; what are intracellular and extracellular concentrations, what regulates this distribution of Ca in the body?
a. Estimated body content: 14,000,000 ppb; 980-1000g
b. Distribution: 99% of the calcium is in the skeletal system with the remaining 1% distributed in intra and extracellular compartment
c. Intracellular and extracellular concentrations: intracellular concentrations of ionized Ca are maintained at very low levels about 0.1uM, while extracellular concentrations of ionized calcium are approx. 2-2.6 mM
d. Regulation of distribution:
i. Calbindin system- the system is regulated by need and can increase Ca absorption from an average of 30% to as much as 60-70%.
ii. Non-cellular transport- operates primarily in the distal jejunum and ileum and is paracellular in nature. This mechanism is non-saturable and non-carrier mediated and dependent solely on concentration gradient.
iii. Parathyroid hormone and gland regulate the concentration of calcium in the plasma
iv. If increased absorption is not enough, vitamin D will stimulate the differentiation of monocytic stem cells into mature osteoclasts. The osteoclast will cause the removal of calcium and phosphorous from the bone.
- What are major dietary sources, and what influences the bioavailability of Ca?
a. Dietary sources: dairy products including milk, cheese, yogurt, and ice cream, seafood
b. Influences of bioavailability: an acid pH favor Ca absorption, while at alkaline pH as is found in small intestine, Ca may complex with other small ions and food constituents that reduce its availability
- How is Ca absorption regulated hormonally, what is the average absorption from foods and supplements?
a. Calcium from foods and supplements are absorbed at a 30% rate under normal conditions.
b. There are two major transport systems responsible for Ca absorption.
i. Calbindin system: Active transport system that is regulated by 1,25 (OH)2-D; active when Ca intake is low or as a result of a fall in serum Ca. Absorption is regulated based on need and solubility – Calbindin can increase Ca absorption to 60-70% Vitamin D co-ingestion with calcium can significantly increase absorption.
ii. Ca/Mg ATPase pump in the proximal small intestines; Na/Ca ATPase pump in the distal small intestines.
iii. Non-cellular transport – non-saturable and non-carrier mediated and dependent on concentration gradient.
iv. Colonic absorption
- How is Ca involved in bone mineralization and remodeling?
a. 99% of Ca is present in bone is found as crystalline salts – calcium phosphate, hydroxyapatite.
b. Osteoblasts secrete several proteins which bind calcium to the surface of the bone at the site mineralization until the critical concentration of Ca, PO4, and mg are met, thus beginning the crystallization of the salts.
- What are the major non-osseous roles for Ca?
a. Of the 1% of Ca not found in bone;
b. Enzyme activation/deactivation
c. Changes in membrane permeability
d. Activation of clotting factors
e. One function is in enzyme activation/deactivation – covalent modification.
i. Protein kinase C will activate this enzyme, causing phosphorylation.
ii. Ca/Mg ATPase (+)
iii. Glycerol-3- phosphate dehydrogenase.
iv. Pyruvate kinase (– in kidney and liver)
v. Pyruvate carboxylase (+ influence in liver and kidney)
vi. Pyruvate dehydrogenase (–)
vii. Glycogen synthase (–)
viii. Glucose-6- phosphatase (+)
f. Muscle contractions.
g. Microfibril contractions.
h. Cellular secretion (i.e. insulin secretion from Beta-cells).
i. Activation of clotting factors.
j. Nerve conduction.
- What are the important interactions between Ca and other nutrients in digestion and absorption, and in bone mineralization?
a. Ca absorption is interfered with by excess Mg, Fe, Zn, P, fatty acids, proteins, and phytates.
b. Ca decreases heme and non-heme iron absorption.
c. Sodium increases Ca excretion; potassium decreases calcium excretion.
d. Dietary protein increases Ca absorption as well as increasing Ca excretion; high protein diets are thought to increase risk of premature osteoporosis – evidence for this (?)
e. Rena calcium reabsorption is controlled hormonally by PTH>
f. Calcium is excreted through urine and feces, not sweat.
- What is the relationship between Ca and development of osteoporosis; what factors influences accrual of bone minerals over an individual’s lifespan; what is meant by the statement: osteoporosis is a disease of the youth, manifested in old age?
a. Bone is in a continual state of turnover, and being remodeled. The renewal rate is ~100% in infant and 18-20%/yr in adults.
b. Bone mineral accumulates during the early part of our lives and reaches a peak between 25-35 age,10-15 yrs after cessation of linear growth. Afterwards, bone resorption exceeds bone deposition and bone loss occur, resulting in the loss of bone mineral and bone protein content.
c. This slow and insidious process of bone loss is accompanied with changes in the micro-architectural structure, thinning of both cortical and trabecular bone – developing osteoporosis.
d. Higher peak bone density results in the delaying of osteoporotic level – important to accumulate bone
minerals during the critical years.
- What is the importance of gravity on bone mineralization?
a. Osteoporosis is defined as “a systematic skeletal disease characterized by low bone mass and microarchitectural deterioration with consequent increase in bone fragility and susceptibility to fracture” by the NIH.
i. Type I – Rapid bone loss, primary trabecular, mostly in women post-menopausal 51-65 yrs. Increased compression of bone and loss of height.
ii. Type II – Slow loss of both cortical and trabecular bone, both men and women > 75 yrs.
b. Importance is placed on the younger years (10-15) – this results in greater peak bone density. Individuals with highest peak bone mass at adolescence have the greatest protective advantage against the development of osteoporosis.
c. However, milk consumption in youth has declined over the past few years.
d. Gravity is constantly putting pressure on our bones which causes our body to add bone mass into our bone which causes a stronger bone.
- You should be able to explain the process of bone mineralization and remodeling in general terms (this includes integrating what you have learned about the importance of other nutrients in the process)
a. Parathyroid hormone is released by the parathyroid gland which stimulate the conversion of 25-OH vitamin D to 1, 25 (OH)2 Vitamin D. 1, 25 (OH)2 Vitamin D stimulates the differentiation of monocytes into osteoclast which is responsible for the removal of calicum in the bone. They also form osteoblasts which the mineralization of bone.
- What is the oxidation state of P; what are the major inorganic forms?
a. Oxidation state: -3, +3, +5
b. Major inorganic forms: amorphous calcium phosphate, magnesium phosphate, hydroxyapatite.
- What is the estimated body content, how is this distributed in the body; what are its important intracellular roles?
a. A 70 kg individual contains between 700-770 g of phosphorous – 85% is found in bone as calcium phosphate and hydroxyapatite; the rest (15%) is distributed in soft tissue – most present in the form of phospholipids of cell membranes.
b. Most phosphorous is free filterable phosphate, while 10% is bound to protein, and 5% bound to Ca and Mg.
c. Inorganic phosphate is important in that it acts a buffer.
- What are major dietary sources; what are the major forms; how is it absorbed; how is this regulated? (you should be able to answer this in very general terms)
a. Phosphorous is widely distributed, particularly in animal products, including meats, fish, poultry, eggs,and milk, as organophosphates. Plant sources include nuts and whole grains, although its bioavailability from whole grains is low because much of it is bound phytate, and thus unavailable for absorption.
- How is P involved in bone mineralization and remodeling?
a. 85% of phosphorous is found in bone as amorphous calcium phosphate, magnesium phosphate or hydroxyapetite.
