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nucleotide metabolism Flashcards

1
Q

what are the components of nucleotides?

A
  1. phosphate group
  2. 5C sugars (ribose or deoxyribose)
  3. nitrogenous bases (purine or pyrimidine)
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2
Q

what are the DNA and RNA purines?

A
  1. guanine (G)
  2. adenosine (A)
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3
Q

what are the DNA and RNA pyrimidines?

A

DNA pyrimidines:
1. thymine (T)
2. cytosine (C)

RNA pyrimidines:
2. cytosine (C)
3. uracil (U)

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4
Q

what is the metabolism of cyclic AMP?

A

ATP→ [adenylate cyclase]→ 3’5’cAMP→ [phosphodiesterase]→ AMP

phosphodiesterase is inhibited by caffeine or theophylline→ accumulation of ATP

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5
Q

what are the components of nucleosides?

A
  1. 5C sugar (ribose/deoxyribose)
  2. nitrogenous bases
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6
Q

where do the C and N atoms of the purine ring originate from?

A

C2, C8: formate
N1: aspartate amine
C6: HCO3-
C4-C5-N7: glycine
N3, NH9: glutamine amide

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7
Q

what is needed in the conversion of ribose-5-phosphate to PRPP?

A

ATP! (ATP dependent)

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8
Q

what is the rate limiting enzyme of purine nucleotide synthesis?

A

GPAT (glutamine-phosphoribosyl pyrophosphate (PRPP) amidotransferase)

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9
Q

how is GPAT regulated?

A

inhibited by: AMP, GMP
activated by: PRPP

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10
Q

what is required as a substrate to GPAT?

A

glutamine (→ glutamate)

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11
Q

what are the compounds needed in the steps from 5-phosphoribosylamine to IMP? (5)

A
  1. Glycine (C4, C5, C7)
  2. Formyltetrahydrofolate (C8, C2)
  3. glutamine (N3, N9)
  4. CO2 (C6)
  5. aspartate (N1)

Go Forward, Go Create An IMP

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12
Q

how is formyltetrahydrofolate synthesised?

A

diet→ folic acid→ [dihydrofolate reductase]→ dihydrofolate→ [dihydrofolate reductase]→ tetrahydrofolate→ N10-formyl THF

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13
Q

what drug inhibits dihydrofolate reductase? what are its effects?

A

methotrexate
- treats cancers (attacks rapidly dividing cells)
- folate analog→ inhibits dihydrofolate reductase (DHFR)→ interferes with H2/H4folate→ inhibits metabolic steps requiring tetrahydrofolate eg purine/DNA synthesis

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14
Q

how are NTPs synthesized from NMPs? (eg GTP from GMP)

A
  • specific NMP kinase (e.g. GMP kinase)
  • non-specific NDP kinase (ie. nucleoside diphosphate kinase)
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15
Q

what does mycophenolic acid (drug) do?

A
  • reversibly inhibits IMP dehydrogenase
  • deprives purine from nucleic acid synthesis of T and B cells
  • used as immunosuppressant!
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16
Q

what regulates CPS2 in pyrimidine nucleotide synthesis?

A

inhibits: UTP
activates: PRPP

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17
Q

what disease causes a deficiency of OMPDC? effects?

A

orotic aciduria
- inherited disorder
- excretion of large amounts of orotic acid in urine
- retarded growth, severe megaloblastic anemia

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18
Q

what enzymes convert UMP to UTP?

A

UMP→ UDP: nucleoside monophosphate kinase
UDP→ UTP: nucleoside diphosphate kinase

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19
Q

what enzyme converts UTP to CTP? what substrate is required?

A

CTP synthetase
glutamine (→ glutamate)

20
Q

what enzyme reduces ribonucleotides to deoxyribonucleotides?

A

ribonucleotide diphosphate reductase/NDP reductase (NDP→ dNDPs)
*reduction is at DIphosphate level (instead of TRIphosphate)

21
Q

what compounds are needed for NDP reductase? (3)

A
  1. iron (Fe-dependent)
  2. thioredoxin (main physiological reducing agent, a protein)
  3. NADPH (produces reducing equivalents)
22
Q

what is the structure of ribonucleotide reductase?

A
  • 4 polypeptides (2a, 2B)

3 sites:
1. specificity site: determines which SUBSTRATE can bind
2. activity site: determines whether ENZYME is active/inactive (ie on/off switch)
3. catalytic site: active site

23
Q

what compounds activate/inhibit activity site of ribonucleotide reductase?

A

activate: ATP
inhibits: dATP

24
Q

what is the sequences of nucleotides being reduced by the active site of ribonucleotide reductase?

A
  1. dCTP (fr CDP)
  2. dTTP (fr UDP)
  3. dGTP (fr GDP)
  4. dATP (fr ADP)

Can They Go Away

25
Q

what compound at the specificity site of ribonucleotide reductase activates the reduction of CDP/UDP?

A

ATP or dATP

26
Q

what compound at the specificity site of ribonucleotide reductase activates the reduction of GDP?

A

dTTP

27
Q

what compound at the specificity site of ribonucleotide reductase activates the reduction of ADP?

A

dGTP

28
Q

what compound binding to the specificity site of ribonucleotide reductase inhibits the reduction of CDP and UDP?

A

dTTP or dGTP
(essentially only activated by ATP/dATP)

29
Q

what is the effect of dATP binding to the activity site on the specificity and catalytic site?

A

specificity site: any effector can bind
catalytic site: inhibits reduction of ALL ribonucleotides (ADP, GDP, UDP, CDP)

30
Q

why do the reduced ribonucleotides/deoxyribonucleotides need to be in a 1:1:1:1 ratio?

A

allows EQUAL abundance of all building blocks for DNA replication (else will have wrong incorporation of ribonucleotides in DNA replication→ mutations)

31
Q

how are nucleic acids catabolised?

A

DNA/RNA→[DNase/ phosphodiesterase]→ mononucleotides→ [mononucleotidase phosphatase]→ Pi + nucleosides

1) nucleoside→ [nucleosidase]→ ribose/deoxyribose + purine/ pyrimidines
OR
2) nucleoside + Pi→ [phosphorylase]→ ribose/deoxyribose-1-P + purines/ pyrimidines→ [mutase]→ ribose/deoxyribose 5-P

32
Q

what are the diseases related to purine metabolism (esp catabolism)? (3)

A
  1. lesch-nyhan syndrome (purine salvage)
  2. gout (due to increase uric acid/purine breakdown)
  3. scid
33
Q

what is the pathophysiology of lesch-nyhan syndrome?

A
  • sex linked congenital defect (affects mostly males)
  • affects purine salvage pathway
  • caused by severe HGPRT deficiency:
    1. accumulate hypoxanthine & guanine→ increase xanthine (purine breakdown pathway)→ accumulate uric acid production
    2. lack of HGPRT→ accumulation of PRPP→ increases rate of purine synthesis→ increases purine catabolism→ increase uric acid
34
Q

what are the symptoms of lesch-nyhan syndrome?

A

neurological abnormality: mental retardation, bizarre behaviour (aggression, destruction etc)

35
Q

what is the pathophysiology of gout?

A

cause by high levels of uric acid (fr purine breakdown) in blood due to:
1. impaired uric acid excretion
2. excessive uric acid production (all pertaining to PRPP):
- HGPRT deficiency, PRPP accumulation (eg lesch-nyhan syndrome)
- G6Pase deficiency (von gierke’s glycogen storage disease) (G6P increase→ R5P increase→ PRPP increase→purine synthesis increase→ uric acid increase)
- PRPP synthetase overactivity

36
Q

what are the symptoms of gout? (2)

A
  1. painful arthritic joint inflammation (acute arthritis) due to deposition of sodium urate crystals (tophi)
  2. sodium urate and uric acid may precipitate in kidneys & ureters as stones→ renal damage & UT obstruction
    - mainly affects males
37
Q

what are the treatment options of gout? (2)

A
  1. colchicine (anti-inflammatory agent)
  2. allopurinol
38
Q

what is the MOA of allopurinol? (3)

A

to decrease uric acid: either decrease purine synthesis or purine breakdown

1.hypoxanthine analogue (purine catabolism)→ competitively inhibits xanthine oxidase→ product: oxypurinol/alloxanthine remains tightly bound to the enzyme→ prevents breakdown of purine
2. inhibits PRPP amidotransferase activity→ decreases purine synthesis
3. forms allopurinol ribonucleotide (allopurinol + PRPP)→ reduces PRPP→ decreases purine synthesis

39
Q

what is SCID (severe combined immunodeficiency disease)?

A
  • inherited disorder
  • fatal in infancy
  • lack of immune response to infection
  • T & B cells can’t proliferate
  • 30% of SCID patients associated with adenosine deaminase (ADA) deficiency
40
Q

what is ADA deficiency?

A

adenosine deaminase deficiency

ADA used to convert adenosine/deoxyadenosine to inosine/deoxyinosine

ADA blocked:
adenosine/deoxyadenosine→ AMP/dAMP→ ADP/dADP→ dATP→ binds to activity site of NDP reductase→ inhibits reduction of NDPs to dNDPs to dNTPs for DNA synthesis (inactivates all DNP reduction)

41
Q

what is the pathophysiology of orotic aciduria?

A

inhibits pyrimidine synthesis
type 1: deficiency in both OPRT & OMP decarboxylase
type 2: deficiency in OMP decarboxylase

42
Q

what is the treatment of orotic aciduria?

A
  • supply uridine or cytidine (bypass OPRT & OMPDC)
  • use salvage enzymes to bypass denovo pathway
43
Q

how does acyclovir work?

A
  • purine analog, treats HSV/chickenpox
  • converted to active/phosphorylated form by specific HSV-thymidine (VIRAL!) kinases→ acycloguanosine triphosphate
  • serves as substrate for HSV-specific DNA polymerase→ incorporated into growing viral DNA chain→ termination of viral DNA replication
44
Q

how does AZT (3’-azido-3’-deoxythymidine) work?

A
  • treats AIDS

(similar to acyclovir):
viral kinase activates AZT that gets incorporated into HIV→ blocks HIV replication

45
Q

how does hydroxyurea work?

A
  • treats cancer
  • quenches free radicals on NDP reductase’s catalytic site→ inactivates catalytic residue→ no more DNA replication lol
46
Q

how does 5-fluorouracil work?

A
  • treats cancer
  • uracil analog→ converted to 5FdUMP→ inhibits thymidylate synthase→ inhibits dTMP synthesis→ blocks thymidine formation required for DNA synthesis

metab (11 decks)

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