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MFM > Purine and Pyrimidine Metabolism > Flashcards

Purine and Pyrimidine Metabolism Flashcards

1
Q

function of nucleotides

A
  1. polymerize to make DNA and RNA 2. energy via ATP and GTP 3. carriers of active intermediates in the metabolic pathways (UDP glucose in glycogen synthesis, SAM) 4. component of coenzymes (coa, FAD, NAD, NADP) 5. second messengers cAMP and cGMP 6. allosteric regulation of metabolic pathways (ATP inhibits PFK1)
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2
Q

difference between a nucleoside and nucleotide

A

nucleoside is a base plus ribose nucleotide is a base plus ribose plus phosphate

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3
Q

name the purines

A

xanthine, hypoxanthine, guanine, adenine

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4
Q

name the pyrimidines

A

thymine, uracil, cytosine

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5
Q

how are nucleotides made? (2 processes)

A
  1. salvage pathway - nonhepatic tissues - salvaging nucelotides from degradation of nucleic acids or available through the diet. 2. de novo synthesis
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6
Q

how does purine biosynthesis begin?

A

synthesis of 5-phosphoribosyl-1-pyrophosphate (PRPP) from ribose 5-phosphate (PPP) using PRPP synthase.

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7
Q

inhibition of PRPP synthetase?

A

increased purine nucleotides - AMP, ADP, ATP, GMP, GDP, GTP, IMP

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8
Q

what activates PRPP synthetase?

A

free phosphate

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9
Q

what form of folate is used for purine synthesis?

A

formate - formyl tetrahydrofolate (N10-formyl-FH4)- during making of IMP

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10
Q

what is the starting point for AMP and GMP synthesis?

A

IMP (inositol monophosphate)

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11
Q

how is AMP synthesized?

A

IMP + aspartate + GTP —–> adenylosuccinate monophosphate via adenylosuccinate synthetase

then adenylosuccinate monophosphate cleaves fumarate——-> AMP via adenylosuccinase

(aspartate donates amine with GTP and fumarate leaves)

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12
Q

how is GMP synthesized?

A

C2 is oxidized, oxidation is followed by replacement of the O by N from glutamine

IMP into xanthosine phosphate (XMP) by IMP dehydrogenase and NAD.

xanthosine phosphate to GMP by GMP synthase and glutamine and ATP.

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13
Q

how is de novo purine synthesis regulated?

A
  1. PRPP synthetase
  2. glutamine phosphoribosyl amidotransferase
  3. adenylosuccinate synthetase and IMP dehydrogenase
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14
Q

what inhibits PRPP

A

GDP and ADP.

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15
Q

what inhibits glutamine phosphoribosyl amidotransferase

A

all end products - AMP, ADP, ATP, GMP, GDP, GTP

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16
Q

what inhibits IMP dehydrogenase?

A

GMP

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17
Q

what inhibits adenylosuccinate synthetase?

A

AMP

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18
Q

what is meant by “cross regulation” between GMP and AMP synthesis

A

synthesis of GMP requires ATP, synthesis of AMP requires GTP.

GMP inhibits IMP dehydrogenase.

AMP inhibits adenylosuccinate synthase.

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19
Q

how does the cell make dADP and dGDP from ADP and GDP?

A

ribonucleotide reductase - reduces 2-OH producing dGDP and dADP for DNA synthesis

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20
Q

why is ribonucleotide reductase a cancer drug target?

A

if this enzyme is inhibited, deoxyribose nucelotides cannot be made from ribose nucleotides. therefore, reduces cell replication through decreased dna synthesis.

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21
Q

what drug is a potent inhibitor of RR?

A

hydroxyurea, used to treat CML

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22
Q

what are purines catabolized to?

A

adenosine and guanosine are converted to uric acid

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23
Q

describe the catabolism of adenosine

A
  1. adenosine converted to inosine by adenosine daminase
  2. inosine is converted to hypoxanthine by purine nucleoside phosphorylase. ribose-1 phosphate is produced.
  3. hypoxanthine is converted to xanthine by xanthine oxidase and releases hydrogen peroxide
  4. xanthine is converted to uric acid by xanthine oxidase and releases hydrogen peroxide
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24
Q

what happens to the hydrogen peroxide that is produced by hypoxanthine to xanthine and uric acid (xanthine oxidase)?

A

glutathione reduces H2O2 to water

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25
Q

describe uric acid solubility

A

poorly soluble in plasma (excreted in urine) especially at lower temperatures. the accumulation of this causes gout, crystalizes in cold temps and accumulates in fingers and toes. (gouty arthritis)

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26
Q

describe the catabolism of guanosine?

A
  1. guanosine converted to guanine by purine nucleoside phosphorylase and releases a ribose 1 phospate.
  2. guanine is converted to xanthine by guanine deaminase.
  3. xanthine is converted to uric acid by xanthine oxidase which releases a hydrogen peroxide.
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27
Q

what can cause hyperuricemia?

A

uric acid underexcretion or overproduction due to enhanced tissue turnover

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28
Q

what can cause underexcretion of uric acid?

A

lactic acidosis, alcohol, some drugs (thiazide diuretics)

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29
Q

what causes overproduction of uric acid

A

cancer, psoriasis

30
Q

what causes gouty arthritis

A

serum urate levels exceed the solubility limit, Na-urate crystalizes in soft tissues and joints and causes an inflammatory reaction.

31
Q

describe the tumorlysis syndrome?

A

drugs given to shrink tumors cause cells to die, and increasing DNA degradation. increased DNA degradation results in increased production of uric acid.

32
Q

how would a gain of function mutation in PRPP synthetase present as gout?

A

PRPP synthetase makes PRPP to begin purine synthesis. increase in purine synthesis means there will be an increase in purine degradation, leading to an increase in uric acid.

33
Q

how does lactic acidosis cause hyperuricemia?

A

the body favors lactic acid excretion over uric acid excretion, so uric acid excretion decreases. making hyperuricemia.

34
Q

MOA of allopurinol

A

structural analog of hypoxanthine, so it inhibits (competitively or mechanism based) xanthine oxidase. inhibits hypoxanthine and xanthine going to uric acid. hypoxanthine and xanthine are more soluble than uric acid and are easy to excrete in urine.

35
Q

how are acute gout attacks treated?

A

colchicine or indomethacin to reduce inflammation (reduces formation a little)

36
Q

how are hyperuricemic patients treated if they are under-excreting uric acid?

A

uricosuric drugs (probenecid)

37
Q

if gout is due to overproduction of uric acid, how are patients treated?

A

allopurinol or febuxostat, non purine inhibitor of xanthine oxidase

38
Q

what occurs if activity of glutamine phosphoribosyl amidotransferase is reduced?

A

purine synthesis reduces, therefore there is not as much purine degradation, therefore no increase in uric acid.

39
Q

what occurs if activity of glucose 6P dehydrogenase is inhibited/reduced?

A

ribose 5 phosphate would not be made, so no purines made, no increased degradation of purines, therefore no increase in uric acid.

40
Q

what occurs if activity of PRPP synthetase is reduced?

A

no ribose backbone, so no purine, no degradation of purine, no increase in uric acid

41
Q

what occurs if activity of purine nucleoside phosphorylase inhibited/reduced?

A

guanosine and adenosine not broken down to inosine and guanine, so no hypoxanthine or xanthine or uric acid produced.

42
Q

what occurs if activity of glucose 6 phosphatase is reduced?

A

glucose 6P would be shunted to the PPP, increasing production of ribose backbone for purines, and increase in purines would lead to degradation of purines, therefore increased uric acid. would also lead to hypoglycemia due to lack of gluconeogenesis and glycogenolysis.

43
Q

what is the purine salvage pathway

A

nucleosides or bases from the diet or degradation of nucleic acids are used to re-synthesize purines. major source of nucleotide generation in lymphocytes

44
Q

how do lymphocytes mainly generate nucleotides?

A

through purine salvage pathway - major form

45
Q

explain the purine salvage pathway

A

free purines that are released during nucleotide catabolism are salvaged by reattaching the bases to PRPP.

46
Q

what is the major pruine nucleotide salvage pathway?

A

hypoxanthine-guanine phosphoribosyltransferase (HGPRT).

take PRPP adn put it back on the hypoxanthine to make IMP. or put it on guanine to make GMP.

47
Q

which amino acid salvage pathway is minor?

A

adenine by adenine phosphribosyltransferase. APRT

48
Q

how are hypoxanthine and guanine salvaged to the purine synthesis pathway?

A
  1. hypoxanthine becomes IMP through HGPRT
  2. guanine becomes GMP through HGPRT
49
Q

how is adenine salvaged through the purine salvage synthesis pathway ?

A

adenine is made into AMP through APRT (not major)

50
Q

how is adenosine salvaged through purine synthesis salvage?

A

adenosine is converted to AMP via adenosine kinase ATP gives a phosphate (phosphorylated directly)

51
Q

what is lesch-nyhan syndrome

A

x linked, recessive, genetic mutation that decreases or abolishes HGPRT activity. because of this, PRPP levels are increased. increased PRPP stimulates glutamine phosphoribosyl pyrophosphate amidotransferase, increasing de novo purine synthesis. purines are synthesized in excess, leading to increased degradation, resulting in high plasma and urine uric acid

52
Q

characteristic of lesch-nyhan syndrome

A

high plasma and urine uric acid.

intellectual disability

self mutilation

53
Q

what occurs with adenosine deaminase deficiency

A

ADA is deficiency, so adenosine accumulates.

adenosine can be phosphorylated directly back to AMP by adenosine kinase, which increases AMP. increased AMP means increased ADP and ATP.

54
Q

describe why ADA causes severe combined immunodeficiency disease. SCID

A
  1. adenosine builds up, leading to increased AMP due to adenosine kinase phosphorylating it.
  2. increased AMP leads to increased ADP and ATP.
  3. increased AMP ATP ADP are made into dAMP dATP and dADP via ribonucleotide reductase. 100 fold increase in dATP.
  4. dATP is a potent inhibitor of ribonucleotide reductase.
  5. inhibition of RR results in decreased dADP and dGDP, resulting in inhibition of dna synthesis and cell division.
  6. immune system cells have a short half life, and need to divide fast. inhibition of cell division affects these cells first.
55
Q

describe pyrimidine synthesis

A

TLDR: pyrimidine ring assembles first then combines with PRPP to form UMP.

  1. glutamine, CO2 and 2 ATP combine to make carbamoyl phosphate via carbamoyl phosphate synthetase II in the cytosol
  2. carbamoyl phosphate is made to N-carbamoyl asparate via aspartate transcarbamoylase
  3. N-carbamoyl aspartate is dehydrated and dehydrogenated to form orotate.
  4. orotate is tranferred to PRPP by UMP synthase, forming UMP.
56
Q

how is CPSII regulated?

A

activated by PRPP

inhibited by UTP

57
Q

compare CPSI and CPSII

A

CPSI: in mitochrondria urea cycle. uses NH4 as source of nitrogen and is activated by N-acetylglutamate.

CPSII: in cytosol during pyrimidine synthesis. uses glutamine as source of nitrogen. activated by PRPP and inhibited by UTP.

58
Q

trace the formation of UTP from UMP

A

UMP made into UDP to UTP

59
Q

explain the synthesis of CTP

A

CTP synthase forms CTP from UTP

60
Q

explain the syntheis of CDP

A

CDP is formed from CTP, and CDP is made into dCDP from RR, then dCTP is made from dCDP

61
Q

describe the synthesis path of UDP

A

UDP is made into dUDP using RR, dUDP is made into dUMP. thymidylate synthase forms dTMP from dUMP (methylation of uracil from methylene FH4)

62
Q

what form of folic acid is used with pyrimidine synthesis, specifically dUMP to dTMP?

A

thymidylate synthase uses methyleneFH4

63
Q

MOA of 5-flurouracil

A

5-fluorouracil is a pyrimidine analog that is converted to FdUMP which causes thymidineless death. used in chemo

64
Q

catabolism of pyrimidines

A

pyrimidine rings can be cleaved to make highly soluble end products, beta alanine and beta aminoisobutyrate

65
Q

describe salvage of pyrimidines

A

salvage is minor pathway. pyrimidine nucleosides can be salvaged by nucleoside kinases (nucleoside + ATP –> nucleotide + ADP)

66
Q

describe UMP synthase deficiency.

A

pyrimidine synthesis can’t happen because the conversion of orotate to UMP cannot happen. therefore, orotatic aciduria happens.

67
Q

what 2 deficiencies can cause orotic aciduria?

A
  1. ornithine transcarbamoylase
  2. UMP-synthase
68
Q

describe how folate deficiency can lead to megaloblastic anemia

A

folate is needed for the conversion of dUMP to dTMP. if is not present, no TMP. cell cannot undergo DNA synthesis/proliferation/differentiation.

69
Q

differentiation of ornithine transcarbomylase and UMP synthase deficiency.

A

OTC deficiency would cause hyperammonemia II, decreased BUN, increased glutamine, increased orotic acid, megaloblastic anemia.

UMP synthase deficiency would have normal ammonia, BUN. increased orotic acid, megaloblastic anemia.

70
Q

how would administration of uracil help a patient with UMP synthase deficiency

A

since UMP synthase is deficiency, cannot make UMP. exogenous skips this step, so UMP is made and then dUMP and dTMP is made. UMP exogenously inhibits CPSII and orotate decreases d/t decreased “pyrimidine synthesis.”

71
Q
A

MFM (39 decks)

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