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Fall-Foundational Sciences Year 1 > Nucleotide Metabolism > Flashcards

Nucleotide Metabolism Flashcards

1
Q

nucleoSIDE

A

ribose ring + nitrogenous base at 1’

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2
Q

nucleoTIDE

A

nucleoside + phosphate esterified at 5’

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3
Q

deoxyribonucledotides

A

have H instead of OH at 2’ of ribose ring

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4
Q

pyrimidine

A

one ring w/ 2 nitrogens

cut of py

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5
Q

purine

A

two ring structure each w/ 2 N’s

pur as gold

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6
Q

roles of nucleotides

A
  1. energy metabolism (ATP, GTP)
  2. nucleic acids (NTPs and dNTPs)
  3. coenzymes (NAD, FAD, coA)
  4. activated intermediates (UDP-glucose, GDP-mannose, SAM)
  5. allosteric modulators (AMP, ATP, cAMP, cGMP)
  6. physiological modulators (ADP, adenosine)
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7
Q

salvage pathways

what it do

A

allow generation of nucleotides from free bases and nucleosides from diet

since de novo synthesis energetically expensive

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8
Q

de novo synthesis

purines-basic

A

ring strucutre assembled on a base (PRPP)

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9
Q

de novo synthesis

purine pathway

A
  1. assemble PRPP, start w/ ribose-5-phosphate from PPP, w/ PRPP synthetase
  2. committed step, convert to PRA using glutamine
  3. make IMP w/ carbons and nitrogens from amino acids, carbon and oxygen from HCO3-, carbon from N10formyl THF, ATP hydrolysis
  4. convert IMP to AMP or GMP
  5. convert to ATP and GTP w/ NMPs aka adenylate kinase or guanylate kinase

GTP and ATP are readily interconverted

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10
Q

regulation of purine synthesis

A
  1. PRPP synthetase, feedback inhibition by ADP and GDP
  2. commited step (amidophosphoribosyltransferase) aka PRA by allosteric effectors
    -inhibitors: AMP and GMP bc end prodcuts
    -activators: PRPP

ADP and GDP are the purine nucleotides

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11
Q

purine degradation

GMP

A

@ liver
1. GMP to guanosine via 5’nucleotidase removing P
2. convert to free base (guanine) via purine nucleoside phosphorylase removing ribose

GMP>guanosine>guanine

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12
Q

purine degradation

AMP

A

route 1:
1. AMP to adenosine via 5’-nucleotidase remove P
2. convert to inosine via adenosine deaminase
3. convert to free base hypoxanthine via pruine nucleoside phosphorylase removing ribose

route 2:
1. AMP to IMP via AMP deaminase
2. IMP to inosine via 5’-nucleotidase dephosphorylating
3. convert to hypoxanthine via purine nucleoside phosphorylase

adenosine deaminase = lymphocytes
AMP deaminase = muscle

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13
Q

purine degradation

final steps

A
  1. hypoxanthine and guanine converted to xanthine
  2. xanthine oxidase converts it to uric acid
  3. excreted via kidneys
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14
Q

hyperuricemia

A

excess uric acid in blood
from reduced excretion (renal insufficiency, metabolic acidosis)
OR
inc production (inc nucleotide turnover aka sickle cell, G6DP deficiency, chemo, or purine rich diet)

alcohol does both

treat w/ allopurinol

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15
Q

gout

A

crystals of sodium urate deposit in joints of extremities (esp first toe)

bc uric acid is relatively insoluble and close to limit of solubility normally

treat with allopurinol

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16
Q

kidney stones

A

high concentrations of uric acid in urine lead to deposition of stones in kidney aka urolithiasis

10-25% ppl with gout also have stones

17
Q

allopurinol

A

effective treatment for hyperuricemia
metabolizes to oxypurinol that competitively inhibits xanthine oxidase
=more hypoxanthine and xanthine that are more soluble than uric acid so excreted easier

18
Q

de novo synthesis

pyrimidines-basic

A

start as synthesis of free bases then get transferred to ribose

19
Q

synthesis of UMP

first pyrimidine made

A
  1. syn carbamoyl phosphate w/ glutamine + bicarb
  2. carbamoyl aspartate by adding aspartate
  3. cyclization = dihydroorotate
  4. dehydrogenation = orotate
  5. syn OMP w/ PRPP
  6. decarboxylate = UMP
20
Q

CAD

A

single multifunctional protein w/ 3 distinct active sites for steps 1/2/3 of pryrimidine syn

Carbamoyl phosphate synthetase II
Aspartate transcarbamoylase
Dihydroorotase

21
Q

UMP synthase

A

single multifunctional protein for last two steps of pyrimidine syn

orotate phosphoribosyltransferase
OMP decarboxylase

22
Q

orotic aciduria

A

defect in UMP synthase so orotic acid accumlates in urine

symptoms of megaloblastic anemia and maybe cellular immunity

treat w/ pyrimidine supplement (uridine)

23
Q

synthesis of CMP

A
  1. UMP to UTP w/NMP
  2. UTP to CTP w/CTP synthase and glutamine
24
Q

regulation of pryimidine

A
  1. carbamoyl phosphate synthetase II
    -inhibited by UTP
    -activated by PRPP
  2. CTP synthase
    -inhibited by CTP
    -activated by UTP
25
Q

deoxyribonucleotide synthesis

A

triggered by cell division bc require DNA

NDP to dNDP via ribonucleotide reductase and thioredoxin oxidation

regulated by allosteric effectors
-specific NTP or dNTP for reduction of a NDP= positive effector
-some dNTPs potent negative effectors aka dTNP

NTP and dNTPs regulate ribonucleotide reductase and dATP key inhibitor

26
Q

hydroxyurea

A

pharmacological inhibitor of ribonucleotide reductase

blocks activity so no dNTP synthesis so no cell division

chemotherapy

27
Q

SCID

severe combined immuodeficiency

A

mutations in adenosine deaminase (purine degradation) = build up adenine metabolites aka dATP
ribonucleotide reductase activity inhibited so all purine/pyrimidine conversion to dNDPs blocked
immune response requires cell proliferation so inhibited from lack of dNTPs

adenine metabolites toxic for immune system

28
Q

synthesis of dTMPs

A

must come from dUMP via thymidylate synthase = dTMP
-uses N5N10-methylene THF

dTMP kinase converts to dTDP

29
Q

cytotoxic therapy

A

inhibit thymidylate synthase = prevent cell proliferation bc dec dTTP available

5-fluorouracil>FUMP>FUDP>FUTP or FdUDP>FdUMP = irreversible inhibition

lack of dTTP = dUTP and FdUTP in DNA instead = strand breakage and death

30
Q

pyrimidine degradation

A

UMP, CMP, dCMP > beta-alanine (>acteyl CoA)
dTMP > beta-aminoisobutyrate (>succinyl CoA)

both betas water soluble so eliminated in urine OR further metabolized

beta-amino unique to thymine degradation so measures DNA turnover

31
Q

salvage pathways

liver

A

converts nucleotides to nucleosides and free bases > enter blood > tissues via RBCs

32
Q

salvage pathways

diet

A
  1. nucleic acids DNA/RNa in food digested by pancreatic nucleases = free nucleotide
  2. convert to nucleosides via phosphatases and taken up by intestinal epithelial cells

nucleosides and free basees precursors for nucleotide synthesis

33
Q

salvage of purines

A

requires
1. HGPRTase for hyposxanthine and guanine
2. APRTase for adenine

plus PRPP = IMP (hypox) or GMP (guanine and adenine)

product inhibition

only adenosine only nucleoside directly phos to nucleotide AMP

34
Q

lesch-nyhan syndrome

A

hyperuricemia, uric acid stones, intellectual diability, self-injurious/destructive biting of fingers and lips

severe or complete deficiency of HGPRTase activity

35
Q

salvage of pyrimidines

A

pyrimidine phosphoribosyltransferase

uracil + PRPP = UMP
orotate + PRPP = OMP

conversion to nucleotides via uridine-cytidine kinase

Fall-Foundational Sciences Year 1 (33 decks)

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