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MM Test 2 > B6.038 Metabolism of Purine and Pyrimidine Nucleotides > Flashcards

B6.038 Metabolism of Purine and Pyrimidine Nucleotides Flashcards

1
Q

purines

A

adenine

guanine

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2
Q

pyrimidines

A

thymine (DNA)
cytosine
uracil (RNA)

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3
Q

starting substrate for de novo purine synthesis

A

ribose 5-P

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4
Q

manifestations of gout in clinic

A

acute gouty arthritis

nephropathy

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5
Q

what causes symptoms of gout?

A

crystal deposition in joints and/or kidneys

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6
Q

urate crystal formation in urine

A

at low pH: uric acid predominates in urine and uric acid crystals precipitate (common)
at high pH: urate predominates and Na+ urate crystals precipitate (rare)

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7
Q

urate crystal formation in joints

A

urate predominates and Na+ urate crystals precipitate in synovial fluid and auricles

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8
Q

who is most likely to develop gout?

A

adult men

95% are under-excreters

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9
Q

diseases w associations w gout

A

hypertriglyceridemia
hypertension
metabolic syndrome
all related to obesity

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10
Q

factors that lead to chronic urate underexcretion

A

decreased glomerular filtration in patients with renal failure
inhibition of excretion by organic acids (ketoacidosis, aspirin, excessive alcohol)
chronic dehydration
anything that can decrease amt of urine excreted in general

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11
Q

diagnosis of gout

A

aspirating fluid from affected joint and finding negatively birefringent crystals under polarizing microscope

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12
Q

benefits of urate

A

normally in body @ 7-10% concentration
antioxidant properties
when this conc increases in when symptoms emerge

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13
Q

hyperuricemia

A

too much urate in blood
due to:
-urate overproduction
-under excretion

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14
Q

chronic hyperuricemia

A

gout

  • acute arthritis
  • kidney stones
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15
Q

where is ribose-5-p for purine synthesis derived from

A

pentose phosphate pathway

from glucose-6-p

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16
Q

general overview of de novo synthesis of ATP and GTP

A

ribose-5-P > PRPP > IMP > AMP or GMP

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17
Q

enzyme which converts ribose-5-p to PRPP

A

PRPP synthase

  • inhibited by ADP
  • activated by phosphate
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18
Q

enzyme which converts PRPP to IMP

A

glutamine-PRPP amidotransferase

  • non-reversible
  • inhibited by AMP and GMP (feedback)
  • activated by PRPP
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19
Q

molecules needed for conversion of PRPP to IMP

A

folate molecules (N10-formyl-THF)

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20
Q

mycophenolic acid in purine synthesis

A

inhibits conversion of IMP to GMP
acts as an immunosuppressant
reduces synthesis of DNA/RNA in lymphocytes (primary cells that utilize de novo purine synthesis)

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21
Q

degradation of GMP

A

GMP > guanine > xanthine (taken up by liver) > urate

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22
Q

degradation of AMP

A

AMP > hypoxanthine (taken up by liver) > urate

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23
Q

salvage of GMP

A

guanine from GMP breakdown travels through blood to new cell

guanine > GMP

24
Q

salvage of AMP

A

hypoxanthine from AMP breakdown travels through blood to new cell
hypoxanthine > IMP > AMP

25
Q

what % of production of IMP is de novo?

A

3%

97% salvage

26
Q

how is salvage preferred over de novo synthesis?

A 
enzyme controls
HGPRT (salvage enzyme)
-greater affinity for PRPP
-higher max activity
glut PRPP amidotransferase (rate limiting enzyme in de novo synthesis)
-cooperativity toward PRPP
-only active at high PRPP concentrations
27
Q

HGPRT activity in Lesch-Neyhan

A

<2% of normal activity

little ability to salvage

28
Q

enzyme used to degrade hypoxanthine to urate

A

xanthine dehydrogenase (oxidase)

29
Q

drug used to increase excretion of urate

A

probenecid

inhibits reuptake of urate

30
Q

lifestyle modifications in gout treatment

A 
reduce purine load by avoiding liver, kidney, sweetbreads
limit sugar intake
limit ethanol (particularly beer)
31
Q

urate lowering drugs

A 
xanthine dehydrogenase (oxidase) inhibitors
uricase (less common)
32
Q

xanthine dehydrogenase (oxidase) inhibitors

A

allopurinol

febuxostat

33
Q

lesch-nyhan syndrome

A 
X-linked recessive
HGPRT deficiency
-recycle almost no hypoxanthine
-increased de novo synthesis
-increased urate production
34
Q

symptoms of lesch-nyhan syndrome

A

mental retardation
profound motor disability
self mutilation
gout

35
Q

what is UMP

A

uridine monophosphate

precursor for all pyrimidine nucleotides

36
Q

pyrimidine nucleotides in DNA

A

dCTP

dTTP

37
Q

pyrimidine nucleotides in RNA

A

UTP

CTP

38
Q

pyrimidine nucleotides in phospholipids

A

CTP

39
Q

pyrimidine nucleotides in glycogen

A

UTP

40
Q

where does pyrimidine synthesis occur

A

liver

dividing cells

41
Q

general process of UMP synthesis

A

PRPP + orotate > UMP > uridine

42
Q

synthesis for UTP and CTP from UMP

A

UMP + 2ATP > UTP

UTP + ATP + glutamine > CTP

43
Q

what is UTP used in

A

RNA

glycogen

44
Q

what is CTP used in

A

DNA
RNA
phospholipids

45
Q

reduction of ribonucleotides to deoxyribonucleotides

A

NTP (UDP,CDP,ADP, or GDP) > dNTP

enzyme: ribonucleoside diphosphate reductase

46
Q

inhibitors of ribonucleoside diphosphate reductase (ribonucleotide reductase)

A

hydroxyurea
gemcitabine
dATP
dUDP, dCDP, dADP, dGDP

47
Q

hydroxyurea mechanism

A

leads to a decreased rate of deoxyribonucleotide production

reduces a protein tyrosyl radical that is crucial for enzyme activity

48
Q

gemcitabine mechanism

A

leads to a decreased rate of deoxyribonucleotide production
2 mechanisms:
1. dephosphorylated inhibits enzyme irreversible
2. triphosphorylated is incorporated into DNA and chain terminates

49
Q

synthesis of dTTP

A

dUMP > dTMP
enzyme: thymidylate synthase
enzyme 2: dihydrofolate reductase regenerates THF for reaction

50
Q

what is clinically significant about the synthesis of dTTP

A

DNA replication and repair are the only processes that depend on production of dTTP
-persons who are folate deficient do not make enough dTTP (not as big of an issue in AMP and GMP bc of the possibility of salvage)

51
Q

what happens if you deprive cells of dTTP

A

inhibit tumor synthesis
5-FU and premetrexed inhibit thymidylate synthase
MTX inhibits reduction of DHF to THF

52
Q

how does 5-FU inhibit dTTP synthesis

A

integrates into the molecule and acts as a suicide substrate

53
Q

drugs metabolized into 5-FU

A

capecitabine

tegafur

54
Q

mechanism of pemetrexed

A

inhibits thymidylate synthase directly

55
Q

mechanism of MTX

A

competitive inhibitor with a similar structure of DHF

56
Q

breakdown of UMP

A

liver dephosphorylates UMP to uridine
in the blood, uridine is salvaged and re-phosphorylated to UMP
-CTP made from UTP
-dTMP synthesis requires thymidylate synthase and DHF reductase

57
Q

result of RNA and DNA degradation

A

break down into pyrimidine mononucleotides that can be re-phosphorylated and reused

MM Test 2 (23 decks)

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