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Molecular and Cellular Princples of Medicine > Unit 6 - One Carbon Metabolism > Flashcards

Unit 6 - One Carbon Metabolism Flashcards

1
Q

what biologically important compounds can be made from tyrosine?

A

dopamine, norepinephrine - nt
epinephrine, thyroxine - hormone
melanin - pigment

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2
Q

what biologically important compounds can be made from glutamate?

A

GABA - nt

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3
Q

what biologically important compounds can be made from histidine?

A

histamine - vasodilator

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4
Q

what biologically important compounds can be made from tryptophan?

A

melatonin - hormone
serotonin - vasoconstrictor
niacin - vitamin
also makes oxidized nicotinamide adenine dinucleotide (NAD+)

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5
Q

formation of dopa (dihydroxyphenylalanine)

-what cofactors are needed?

A
  1. tyr is hydroxylated to dopa by tyrosine hydroxylase with tetrabiopterin cofactor
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6
Q

what is the rate-limiting step of catecholamine biosynthesis?

A 
tyrosine hydroxylase (tyrosine --> dopa); mixed function enzyme
-enzyme is allosteric, with dopamine, NE, and E acting as negative effectors
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7
Q

how is dopamine formed from dopa?

A

aromatic AA decarboxylase (PLP dependent)

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8
Q

how is NE formed from dopamine? what are its cofactors?

A

dopamine-beta hydroxylase (mixed function enzyme)

-has Cu, and needs vit C and O2

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9
Q

how is E formed from NE? what is needed?

A

phenylethanolamine N-methyltransferase

-uses SAM as methyl donor

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10
Q

how are catechols degraded?

A

monoamine oxidase

-inhibitors of MAO used as antidepressants

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11
Q

biosynthesis of melanins

-defect

A

biological pigments; made only in melanocytes

  • made from tyrosine by sequence of several RXNs divergent from catechols
  • albinism if cannot convert tyrosine to melanin
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12
Q

what amino acid can cause B3 deficiency?

A

tryptophan (since precursor to B3) can cause pellagra

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13
Q

how is GABA made from glutamate? what are its cofactors?

A

L-glutamate –glutamate decarboxylase–> GABA + CO2

-requires PLP

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14
Q

how is hidstamine made?

A

histidine –histidine decarboxylase–> histamine + CO2

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15
Q

how do antihistamine drugs work?

A

are compounds that are structurally similar to histamine to prevent physiologic changes it normally produces

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16
Q

what does the body need single carbon fragments for?

A
  1. form met from homocysteine
  2. biosynthesis of purines
  3. biosynthesis of pyrimidines
  4. biosynthesis of glycine from CO2 and NH4+ by glycine synthase
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17
Q

what are the one-carbon carriers?

A
  • biotin
  • tetrahydrofolate
  • S-adenosylmethionine
18
Q

what is biotin?

A

carrier of CO2 (most oxidized 1 C group)

19
Q

what is tetrahydrofolate?

A

carries 1 C groups of all oxidation states except CO2 (most oxidized)
-serves as acceptor of 1-C fragments in degradative reactions, and as donor of 1-C fragments in biosynthetic RXNs

20
Q

why can’t humans make tetrahydrofolate?

A

cannot make pterin ring, so THF formation dependent on folate (pteroylglutamate, folic acid) intake

21
Q

how is THF made from the diet?

A

dietary folate is usually polyglutamines, with moieties attached in gamma-peptidyl linkages

  • cleaved by conjugase (in intestinal mucosal cells) to leave single glutamate moiety on absorbed vitamin
  • reduced via 2-step dihydrofolic acid reductase, using up 2 NADPH+
22
Q

how many protons does the active form of THF have?

A

4: has them on positions 5, 6, 7, and 8 of ring

23
Q

what do sulfa drugs do?

A

inhibit biosynthesis of folate by mimicking p-amino benzoic acid

24
Q

what are the different oxidation states, groups, and carriers for 1-carbons?

A

most reduced: CH3 methyl via N-5

intermediate: CH2 methylene via N-5/10
- most oxidized: CHO formyl, CHNH formino, CH methenyl via N-5 (and N-10 for methenyl)

25
Q

what is the significance of N5-methyl-THF?

A

formation by N5,N10-methylene-THF reductase is non-reversible in humans, and consumed in only one reaction to make methionine

  • more than 12% of population is partially deficient in this enzyme
  • -have higher risk of heart disease, lower risk of colon cancer (b/c can’t make as many nucleotides)
26
Q

what are some drugs that cause folate deficiency?

A
  • oral contraceptives
  • barbiturates (impairs absorption and utilization)
  • methotrexate, aminopterin (antimetabolite used in cancer chemotherapy)
  • -inhibit dihydrofolate reductase, to cause deficiency in THF in rapidly dividing cells that need it for nucleotide synthesis
  • -most vulnerable are bone marrow, hair follicles, and GI mucosa with limited THF
27
Q

what is S-adenosylmethionine?

A

the major carrier of methyl groups, and important methyl donor to variety of biomolecules

28
Q

what are 5 of the 30+ reactions SAM is involved in?

A
  • NE –> E
  • guanidinoacetate –> creatine
  • acetylserotonin –> melatonin
  • phosphatidylethanolamine –> phosphatidylcholine
  • methylation of DNA
29
Q

what are elevated levels of homocysteine correlated with?

A

increased risk of atherosclerosis

-vitamin supplementation with B12, folate, and PLP can reduce levels by activating enzymes that remove it

30
Q

how is methionine regenerated from homocysteine? cofactors involved?

A

homocysteine methyltransferase; needs B12

  • methyl group is donated by N5-methyl-THF
  • B12 is methylated to methylcobalamin form, which donates to homocysteine to make methionine
  • deficiency can cause homocystinuria
31
Q

what does cystathionase do? deficiency?

A

hydrolyzes cystathionine to cysteine and a-KG

-deficiency causes cystathioninuria

32
Q

what is the central core of B12?

A

tetrapyrrole with central cobalt atom bonded to 4 pyrrole nitrogens

  • 5th bond is to 5’-deoxyadenosine unit above plane of the molecule
  • 6th bond to dimethylbenzimidazole
33
Q

what do most B12 vitamin supplements have structure wise?

A

CN group in 5th bond above plane of the ring

34
Q

what are the 2 reactions in the human body that need cobalamin? what form are they in?

A
  1. MMCoA to SCoA via MMCoA mutase (adenosyl form)

2. homocystine to methionine via homocystine methyltransferase (hydroxy form)

35
Q

what does deficiency of THF and B12 lead to?

A

megaloblastic/pernicious anemia
-immature RBC released into circulation

B12 deficiency only is associated with demyelination and degeneration of spinal cord

this is part of the folate trap

36
Q

what is transcobalamine?

A

protein that transports B12 in body (less commonly a problem)

37
Q

what is the folate trap?

A

when B12 is deficiency, it traps folate in N5 methyl form, and manifests as anemia
-if folate is supplemented, it is never deficient, thus causes B12 deficiency and irreversible neurological problems without anemia

38
Q

what does deficiency in cystathionine beta-synthetase do?

A

homocystinuria (cannot convert HC to cystathionine)

-children die by age 3-4 from heart disease or stroke (high atherosclerosis)

39
Q

what does deficiency in gamma-cystathionase do?

A

cystathionuria (cannot convert cystathionine to cysteine)

-die of atherosclerosis at not-child age

40
Q

what AA need B12 to degrade carbon skeletons?

A

valine, isoleucine and methionine

Molecular and Cellular Princples of Medicine (42 decks)

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