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Week 4 Flashcards

1
Q

Describe the necessity for protein in our diet.

What are the three pathways of use in the body?

A
  • Protein → free AA → →
    • Essential nitrogenous compounds (trivial)
    • Participate in the equilibrium of cell and plasma proteins/nucleic acids/hormone turnover (major)
    • Degradation to provide energy from carbon skeleton (10-15%)
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2
Q

Describe the maintenance of the pools of amino acids required for protein synthesis. (in terms of KM)

A
  • KM of aminoacyltransferases is low and therefore prefers to charge tRNA to attract AAs
    • Degradation has high KM, or low affinity
    • tRNA formation has low KM, or high affinity, favoring protein synthesis
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3
Q

What is nitrogen balance?

A
  • For normal individuals: intake of nitrogen = urea excretion of nitrogen
  • Nitrogen balance depends on three things
    • N only comes from other AAs (N is never fixed to AAs from outside sources)
    • Most waste N excreted as urea
    • No dedicated N storage
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4
Q

What is negative nitrogen balance?

Why does it happen?

A
  • Description: nitrogen intake < nitrogen excretion
  • Why: individuals are degrading proteins for energy
    • Surgery
    • Disease
    • Trauma (i.e. burns or fractures)
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5
Q

What is positive nitrogen balance?

Why does it happen?

A
  • Description: nitrogen intake > nitrogen excretion
  • Why: individuals are in period of growth
    • Childhood growth
    • Pregnancy
    • Post-traumatic event
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6
Q

Describe why some AAs are essential while others are nonessential.

A
  • Essential AAs cannot be synthesized or the body cannot make them in sufficient quantities
    • R MLK had HIV WTF
  • Nonessential are synthesized in appropriate quantities by the body
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7
Q

What is the relationship of most nonessential AAs to common intermediary metabolites.

A
  • The carbon skeletons of the nonessential amino acids are largely related to common intermediates of metabolism [consider alanine and pyruvate. The reason that the essential amino acids are essential is that we cannot make their carbon skeletons]
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8
Q

What is the general equation for creating different metabolites from AAs?

What is the cofactor?

Name some specific examples?

A
  • General: AA1 + alpha-keto acid2 = alpha-keto acid1 + AA2 (PLP or vitamin B6 as cofactor)
    • The Keq of reactions using aminotransferases is ~1, meaning the reaction is dependent on concentrations
  • Alpha-ketoglutarate + aspartate = glutamate + oxaloacetate (using aspartate aminotransferase and PLP as cofactor)
  • Alpha-ketoglutarate + alanine = glutamate + pyruvate (using alanine aminotransferase and PLP as cofactor)
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9
Q

What does high ALT and AST indicate?

A

High levels of serum aminotransferases indicate tissue/organ damage (i.e. MI)

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10
Q

How is PLP affected by certian TB treatments?

A

Isoniazid – used to treat TB – competitively binds to PLP, inducing a B6 deficiency

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11
Q

Describe the importance of the AA composition in the diet.

A

Any AAs that are not made endogenously are considered essential AAs, and those essential AAs need to be consumed through diet

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12
Q

Describe the inadequacy of certain diets based on vegetable protein.

A

Vegetarians – have an inadequate consumption of essential AAs

Cereal is low in lysine

Beans low in methionine

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13
Q

Describe Kwashiorkor?

A
  • Inadequate protein intake
  • “the disease of the deposed baby when the next baby is born” so no nutrients through breast milk
  • Characterized by retention of water in the stomach, failure to thrive, composition of gut bacteria
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14
Q

Describe Marasmus?

A
  • Inadequate energy intake
  • Characterized by failure to thrive and delayed mental development
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15
Q

Describe Marasmic Kwashiorkor?

A

Inadequate energy and protein intake

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16
Q

Describe the occurrence of protein energy malnutrition in anorexia nervosa, bulimia, severe illness, aging.

A

Occurs in more advanced societies due to inadequate energy and protein intake

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17
Q

Describe the diversity of AA derivatives including post-translational modifications and metabolic products. Give 6 examples.

A
  • 20 AAs are produced through translation into proteins, but lots of AAs are transformed by post-translational modification OR are produced through metabolic processes
  • Examples
    • Hydroxyproline and hydroxyproline: collagen stability
    • Trimethyl-lysine: epigenetic regulation and carnitine synthesis
    • Acetyl-lysine: epigenetic regulation
    • 3-methylhistidine: modicication on actin and myosine
    • Phosphoserine: enzyme regulation
    • Gla: binding Ca++
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18
Q

What are proteases?

A

Proteases hydrolyze the peptide bond

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19
Q

Name some example of extracellular proteases.

A
  • Pepsin in stomach
  • Trypsin and chymotrypsin in intestine
  • Proteases can be given via oral therapeutics
    • CF treated with pancreatic proteases
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20
Q

Name some examples of intracellular proteases?

A
  • Ubiquitin-proteasome pathway: intracellular proteins
    • Multiple ubiquitin units must be added to a protein before recognized for degradation to proteasome
  • Lysosomes (cathespins): endocytosed proteins and membrane proteins
  • Mitochondrial proteases: mitochondrial proteins
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21
Q

What is the urea cycle?

Explian the cycle. (Intermedates and major enzymes)

A
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22
Q

Describe the role of glutamine in movement of nitrogen.

A
  • Glutamate + NH3 + ATP = Glutamine + ADP+ Pi via Glutamine Synthetase in periphery
  • Glutamine + H2O → glutamate + NH3 via Glutaminase in liver and kidney tissue
  • Therefore, glutamate acts as a shuttle carrier for NH3
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23
Q

Describe the glucose-alanine cycle and its roles.

A
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24
Q

What is the difference between NH4+ detoxification in normal people and those with liver cirrhossis? (Describe the pathways)

A
  • Normal: portal vein is high in NH4 → liver detoxifies NH4 → detoxed blood in inferior vena cava
  • Liver Cirrhosis: portal vein is high in NH4 → liver cirrhosis → new vasculature forms from portal vein to inferior vena → increased NH4 → blood toxicity
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25
What are some consequences of hyperammonemia?
* Episodic ataxia—muscle weakness * Dysmetria—uncoordinated movement * Stupor * Hepatic coma (encephalopathy) * Liver Cirrhosis
26
Describe glucogenic AAs.
Glucogenic: breakdown of glucogenic AAs provide carbon skeletons that enter into pathways making net glucose * AAs that breakdown to pyruvate or oxaloacetate
27
Describe ketogenic AAs.
* Ketogenic: breakdown of ketogenic AAs provide carbon skeletons that enter into pathways giving rise to ketone bodies * AAs that breakdown to acetyl-CoA and acetoacetyl-CoA
28
Describe the degradation and use of AAs as energy sources.
* Glucogenic: pyruvate or oxaloacetate create a net gain of glucose * Ketogenic: acetyl-CoA and acetoacetyl-CoA enter into citric acid cycle with no net gain of glucose
29
What is the source of NO and pathway?
Source: arginine Arginine + O2 + NADPH → citrulline + nitric oxide + NADP+
30
Function of NO (4)
Vasodilation (nitroglycerin) Vascular tone Inhibition of platelet aggregation Cytotoxic agent in immune system
31
What is the importance of Vitamin K? What does deficiency lead to?
* Vitamin K is a cofactor for post-translational modification of glutamate to Gla * Vitamin is oxidized, and in order to be used as a cofactor again, it must be reduced through 2 enzymatic steps * Gla is used in clotting and in osteocalcin (Ca++ binding protein in bone) * VKDB (Vitamin K Deficiency Bleeding): internal bleeding due to lack of blood clotting (can be mistaken for child abuse)
32
What are Vitamin K inhibitors?
Dicumerol Warfarin
33
Describe translational research.
Bench-to-bedside (i.e. warfarin) ARSH SAYS -- remember the story about the dead cow blood. :)
34
What are the five metabolites that trypotphan breaks down into?
1. seretonin 2. melatonin 3. xanthuenote 4. NAD+ 5. acetoacetyl CoA
35
How tryptophan broken down?
* Tryptophan is broken down into alanine (glucogenic) and acetoacetyl CoA (ketogenic) * Degradation: * Urine color via xanthurenate * Feces odor * Halitosis (bad breath)
36
How is Nicotinate created? How is it regulated?
* Tryptophan → kynurenine + formate → → nicotinate mononucleotide → NAD+ * Regulation: 1st step - via Tryptophan oxygenase * Substrate activation * Enzyme stabilization (increasing [enzyme]) * Nicotinamide nucleotides
37
What is serotonin? and how is created?
Neurotransmitter and vasoconstrictor (released by platelets) * Tryptophan → 5-hydroxytryptophan → serotonin * 1st step: tryptophan hydroxylase with BH4 as a cofactor * 2nd step: PLP with a decarboxylase
38
How does Sumatriptan work?
5-HT1 agonist. Treatment for migraines.
39
How does Prozac work?
serotonin specific reuptake inhibitor
40
What is melatonin and how is it created?
* Regulates sleep/wake cycles * Tryptophan → serotonin → N-acetylserotonin → melatonin * Regulation: via SAM * Inhibited by light
41
Describe the nutritional disease pellagra.
* Diet deficient in niacin and tryptophan can cause pellagra * Nicotinate and nicotinamide, which are precursors to NAD+, protect against pellagra * Starving people do not develop pellagra because their body is breaking down proteins into AAs (aka: tryptophan) * Symptoms * Dermatitis * Diarrhea * Dementia * Death
42
Describe the relationship of phenylalanine and tyrosine?
* Phenylalanine (essential) synthesizes tyrosine (non-essential as long as there is enough F) * F → Y via phenylalanine hydroxylase and BH4 oxidation * BH2 must be reduced back to BH4 in order to act as a cofactor in future reactions
43
PKU causes?
* Phenylketonuria * Malignant: mutation in the dihydrobiopterine reductase (BH2 to BH4) * Mutation in phenylalanine hydroxylase, so there is an accumulation of its alpha-ketoacid, phenylpyruvate
44
Describe alkaptonuria and the first concept of inborn errors of metabolism.
* First concept of inborn errors of metabolism – it is genetically based * Alkaptonuria: benign disease resulting from a defect in tyrosine degradation * Deficiency in homogentisate oxidase → buildup up of homogentisate → black urine and pigment accumulation in sclera
45
What is the pathway of catecholamines?
* Tyrosine → L-Dopa → Dopamine → Norepinephrine → Epinephrine * 1st Step: tyrosine hydroxylase uses BH4 as cofactor * Negative feedback by all catecholamines * 3rd Step: vitamin C is a cofactor * 4th Step: SAM methylates norepinephrine * Lack of dopamine causes Parkinson’s, which can be treated with L-Dopa because it can cross the blood brain barrier
46
Pathway for melanin?
Tyrosine → → → Melanin using tyrosinase by adding 2O2
47
How are thryroid hormones created?
* Derived from post-translationally modified tyrosines * Thyroglobulin degrades into T4
48
Describe the symptoms and basis of oculocutaneous albinism.
* Deficiency in tyrosinase * Symptoms * Sensitivity to sunlight * Decreased visual acuity
49
How are catecholamines inactivated?
* Monoamine oxidase inhibitors (MAOIs) * Catecholamines must be degraded to become inactive * MAO and COMT AND COMT and MAO act together to inactivate these compounds * MAOIs are used to treat depression * May interfere with metabolism of monoamines
50
Describe the sources and uses of C1 units
Cofactors/Sources * THF * SAM * Vitamin B12 Uses * Methylated compounds (proteins, nucleic acids, lipids, hormones) * Thymine * Purine rings
51
Describe how tetrahydrofolate (THF) carries C1 units at (3) different oxidation levels.
* C1 level at methanol * C1 unit is passed from N5-methyl-THF to another cofactor, S-adenosylmethionine (SAM) * B12 deficiency creates a “folate trap” that prevents 5-methyl-THF from making dTMP and methionine * C1 level at formaldehyde * Glycine/serine interconversion * C1 level at formate * Two reactions in purine biosynthesis
52
Describe why sulfanilamide inhibits bacterial folic acid synthesis
.
* Bacteria treated with sulfanilamide mis-incorporate this compound in place of PABA during synthesis of folic acid * Humans do not have this enzyme to synthesize folic acid, so unaffected
53
Describe the transfer of C1 units from THF to SAM.
* Homocysteine + 5-methyl-THF → methionine via homocysteine methyltransferase (with B12) * Methionine + ATP → SAM + PP + Pi via methionine adenosyl transferase
54
Describe the critical role of vitamin B12.
* Used as a cofactor in only two reactions in the body * Homocysteine methionine (for DNA synthesis) * L-methylmalonyl-CoA → succinyl-CoA (oxidation of some AAs or beta-oxidation of odd-numbered fatty acids) * B12 deficiency leads to build up of methylmalonyl-CoA, which can go on to degrade myelin sheaths
55
Describe effects of deficiencies in vitamin B12 and folic acid and their roles in spina bifida
Spina bifida: an incomplete closure of the neural tube, which can result in paralysis Each deficiency presents as independent risk factors
56
Describe the use of creatinine levels to measure kidney function
Creatinine is neither absorbed or secreted, so it is filtered out of the blood and is a good measure of the glomerular filtration rate (GFR)
57
Describe the synthesis of pyrimidine bases and nucleotides
58
Describe the synthesis of purine nucleotides
59
Formation of deoxyribonucleotides by ribonucleotide reductase
* Ribonucleotide reductase converts NDPs (ribose) to dNDPs (deoxyribose) * 3 different classes of RNRs * Reaction proceeds via free radical mechanism of action
60
Describe thymidine (as TMP) synthesis
61
The biochemical basis of pernicious anemia and megaloblastic anemia
* Pernicious anemia – anemia associated with neurological problems (assoc. with B12) * Megaloblastic anemia – cells that are unable to divide but produce proteins (assoc. with B9 and B12)
62
How does Trimethoprim work and what does in inhibit?
* Trimethoprim * Antibiotic * Binds to bacterial DHF reductase strongly, inhibiting it in bacteria * Binds weakly to human version * Selectively inhibits bacterial growth
63
How does Hydroxyurea work and what does in inhibit?
* Hydroxyurea * Free radical scavenger * Inhibits ribonucleotide reductase → decreasing dNTP pool (especially in proliferating cells)
64
How does Methotrexate work and what does in inhibit?
* Methotrexate * DHF reductase inhibitor * Competes with DHF for binding DHF reductase * Can't convert to THF * Recovery and reversal by giving high levels of nucleosides and folate * Anti-cancer (inhibits DNA synthesis, stopping cell division)
65
How does 5-fluorouracil work and what does in inhibit?
* 5-fluorouracil * FdUMP a derivative of 5-fluorouracil * “suicide inhibitor” for thymidylate synthase (UMP → TMP)
66
How does 5-azacytidine work and what does in inhibit?
* 5-azacytidine * Prodrug * Pyrimidine biosynthesis inhibitor
67
How does 6-mercaptopurine work and what does in inhibit?
* 6-mercaptopurine * Inhibits purine synthesis at multiple steps * Cells starve of purines and die​
68
How are purines catabolized in the body?
69
Factors effecting onset on gout?
* Onset * Men over 30yo and post-menopausal women * Hyperuricemia
70
Factors effecting presentation of gout?
* Presentation * Present at physiological pH as sodium urate * Alcohol consumption – beer has yeast, which produces high levels of purines * Dehydration * High purine diet (meat, seafood, asparagus, spinach) * “Tophi” – monosodium urate tissue aggregates that eat through bone * Sodium urate precipitate in joints and kidney stones
71
Describe the salvage pathway for purines.
72
Describe the salvage pathway for pyrimidines.
73
Describe the essential role of salvage pathways in achieving pool balance.
* Pool balance is important because there needs to be a level of concentration of nucleotides for DNA and RNA synthesis * Salvage pathways recycle bases
74
Treatments for chronic gout?
Chronic Gout * Xanthine oxidase inhibitor – inhibits purine degradation * Allopurinol * Febuxostat * Uricosuric agent – increase excretion of uric acid in urine * Pegloticase
75
Treatments for acute gout?
Acute Gout * NSAIDs – COX1 & COX2 inhibitor – reduce pain and inflammation * Indomethacin * Colchicine – Reduces gout symptoms * Intra-articular Corticosteroids – Reduce inflammation
76
What is Azanthioprine (AZA)? Whats the mechanism? and effect? How is it affected by Xanthione oxidase inhibitors?
Azathioprine (AZA) * Prodrug * Immunosuppressant * Cyclosporin is often used in conjunction with AZA * Decreases uric acid excretion, leading to higher prevalence of gout in transplant recipients * Xanthine oxidase inhibitors (allopurinol) are used then to decrease uric acid production * Can lead to AZA toxicity because some AZA metabolites use xanthine oxidase
77
What is Cytosine Arabinoside (AraC) and Alanine Arabinose (AraA)? Whats the mechanism? and effect?
Cytosine Arabinoside (AraC) and Alanine Arabinose (AraA) * Arabinose is substituted in place of ribose * Results in cell death in leukemia tumors * Must be phosphorylated to nucleoside triphosphates to be incorporated into DNA
78
What is 2-cholorodeoxyadenosine? Whats the mechanism? and effect?
2-cholorodeoxyadenosine * Used in treatment of hairy cell leukemia * Cytotoxic, especially in inhibition of DNA repair of double-strand breaks * As resists breakdown by adenosine deaminase as a chemotherapeutic drug
79
What is 5-Iodouridine? Whats the mechanism? and effect?
5-Iodouridine * Functional analogue of thymidine (not uridine!) that must be metabolized to a dNTP before it is incorporated into DNA * Pairs with G instead of A due to aberrant hydrogen bonding properties * Mispairs in DNA and RNA * Treats herpesvirus infections
80
What is Acyclovir? Whats the mechanism? and effect?
Acyclovir * Analogue of guanosine that lacks most of ribose ring * Missing 3’-OH group causes chain termination of DNA strand once incorporated * Treats herpesvirus infections * Must be in monophosphorylated form * Only virally-encoded thymidine kinase phosphorylates acyclovir (human thymidine kinase does not)
81
What is Azidothymidine (AZT)? Whats the mechanism? and effect?
Azidothymidine (AZT) * Analogue of thymidine and has no 3’-OH group on ribose ring * DNA elongation is terminated * Treats HIV * Anti-viral because the HIV DNA reverse transcriptase has 100x increase in affinity for AZT triphosphate than normal DNA polymerases
82
What is Hydroxyurea? Whats the mechanism? and effect?
Hydroxyurea * Inhibits ribonucleotide reductase, decreases dNTP pool, especially in proliferating cells * Helps drugs like AZT, which competes with endogenous TTP supply
83
Connect elevated uric acid levels to Lesch-Nyhan Syndrome.
HGPRT deficiency → increased [hypoxanthine] → increased [uric acid]

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