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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
what compound at the specificity site of ribonucleotide reductase activates the reduction of CDP/UDP?
ATP or dATP
26
what compound at the specificity site of ribonucleotide reductase activates the reduction of GDP?
dTTP
27
what compound at the specificity site of ribonucleotide reductase activates the reduction of ADP?
dGTP
28
what compound binding to the specificity site of ribonucleotide reductase inhibits the reduction of CDP and UDP?
dTTP or dGTP (essentially only activated by ATP/dATP)
29
what is the effect of dATP binding to the activity site on the specificity and catalytic site?
specificity site: any effector can bind catalytic site: inhibits reduction of ALL ribonucleotides (ADP, GDP, UDP, CDP)
30
why do the reduced ribonucleotides/deoxyribonucleotides need to be in a 1:1:1:1 ratio?
allows EQUAL abundance of all building blocks for DNA replication (else will have wrong incorporation of ribonucleotides in DNA replication→ mutations)
31
how are nucleic acids catabolised?
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
what are the diseases related to purine metabolism (esp catabolism)? (3)
1. lesch-nyhan syndrome (purine salvage) 2. gout (due to increase uric acid/purine breakdown) 3. scid
33
what is the pathophysiology of lesch-nyhan syndrome?
- 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
what are the symptoms of lesch-nyhan syndrome?
neurological abnormality: mental retardation, bizarre behaviour (aggression, destruction etc)
35
what is the pathophysiology of gout?
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
what are the symptoms of gout? (2)
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
what are the treatment options of gout? (2)
1. colchicine (anti-inflammatory agent) 2. allopurinol
38
what is the MOA of allopurinol? (3)
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
what is SCID (severe combined immunodeficiency disease)?
- 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
what is ADA deficiency?
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
what is the pathophysiology of orotic aciduria?
inhibits pyrimidine synthesis type 1: deficiency in both OPRT & OMP decarboxylase type 2: deficiency in OMP decarboxylase
42
what is the treatment of orotic aciduria?
- supply uridine or cytidine (bypass OPRT & OMPDC) - use salvage enzymes to bypass denovo pathway
43
how does acyclovir work?
- 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
how does AZT (3'-azido-3'-deoxythymidine) work?
- treats AIDS (similar to acyclovir): viral kinase activates AZT that gets incorporated into HIV→ blocks HIV replication
45
how does hydroxyurea work?
- treats cancer - quenches free radicals on NDP reductase's catalytic site→ inactivates catalytic residue→ no more DNA replication lol
46
how does 5-fluorouracil work?
- 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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