Nucleotide metabolism

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Nucleotide metabolism
2011-01-28 16:10:47

nucleotide metabolism and disorders associated
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  1. Roles of nucleotides
    • monomeric units of nucleic acids
    • energy currency (ATP), activated intermediates
    • regulation - adenosine controls coronary blood flow, cAMP&cGMP signal, allosteric regulators
    • coenzyme components (NAD+, FAD, CoA)
  2. Purine metabolism
    • synthesized on PRPP
    • first nucleotide: IMP
    • required energy
    • degraded to uric acid
    • salvaged thru base
  3. Pyrimidine metabolism
    • synthesized then added to PRPP
    • first nucleotide: UMP
    • requires energy
    • degraded to aa, NH3, CO2
    • salvaged thru nucleoside
  4. pyrimidine salvage
    • while ingested purines are degraded to uric acid, pyrimidines are absorbed as nucleosides
    • de novo synthesis is obligatory for Toxo, P. falciparum and HIV
  5. PRPP
    • Phosphoribosylpyrophosphate - used for purine and pyrimidine synthesis
    • Ribose-5-P + ATP -PRPP synthetase-> PRPP
    • regulated step
  6. de novo synthesis pathway
    • dietary supply inadequate
    • LIVER (other cells too)
    • Purine ring built on PRPP
    • Pyrimidine built then added to PRPP
  7. Purine de novo biosynthesis committed step
    • PRPP + Gln -amidophosphoribosyl transferase-> 5-phosphoribosylamine + Glu + PPi
    • cancer cells love Gln - this is why
    • regulated by final product/feedback inhibition
  8. How are ribose v. deoxyribose nucleotides made?
    • ribose made first - IMP -> GMP or AMP -> GDP or ADP -> deoxy forms
    • in other words, the diphosphate form of ribose is converted into deoxyribose
    • remember aa synth is directly tied to nucleotide synth
  9. GOUT
    • primary: familial, overactivity of PRPP synthetase, Lesch-Nyhan
    • secondary: meds, incr. cell death (chemo), chronic kidney failure
    • hyperuricemia
    • arthritis: usually occurs in one joint at a time - common in big toe
    • urinary tract stones
    • tophi - visible crystals
  10. Prevention and treatment of gout
    • avoid foods rich in purines: seafood, gravy, red meat, EtOH
    • NSAIDs, corticosteroids - prevent inflammation
    • allopurinol - blocks xanthine oxidase, decrease uric acid formation, buildup of xanthine ok b/c soluble
    • colchicine - microtubule inhibition, decreases inflammation
  11. Pseudogout
    • Deposition of calcium pyrophosphate crystals
    • Caused by excessive Ca2+ in blood - overactive thyroid gland, hemochromatosis
    • treat with colchicine, NSAIDs, corticosteroids (not allopurinol!)
  12. Lesch-Nyhan syndrome
    • HGPRT deficiency: no purine salvage
    • uric crystals, gout-like
    • neuro defects (HGPRT expressed in brain)
    • aggressive behavior, compulsive self-mutilation
  13. HGPRT
    • purine salvage
    • hypoxanthine or guanine + PRPP -hypoxanthine phosphoribosyl transferase-> IMP or GMP
    • deficiency - Lesch-Nyhan, gout-like symptoms due to uric acid buildup
  14. SCID
    • severe combined immunodeficiency
    • B and T cell defects due to lack of ADA (adenosine deaminase)
    • d-adenosine can't be converted to d-inosine, dATP builds up and inhibits synth of DNA
    • treatment: BMT, stem cell
  15. UMPS
    • pyrimidine de novo synth
    • UMP synthetase
    • activates 5-FU, chemo agent, and allows it to inhibit DNA synth
  16. Oroticaciduria
    • orotate + PRPP -> UMP
    • UMPS deficiency
    • orotate accumulates, very rare
    • anemia, retarded growth, immunodeficiency
    • treatment: uridine (uracil doesn't help b/c defective enz would be needed to attach ribose)
  17. PNP
    • purine nucleoside phosphorylase
    • deficiency leads to incr. levels of dGTP
    • inhibits RNR, toxic to immune system
    • not as severe as SCID/ADA deficiency
  18. RNR
    • ribonucleotide reductase
    • converts NDPs -> dNDPs
    • NADPH is e- source - comes from pentose phosphate shunt
    • lack of any dNTP = lethal
    • excess of dNTP = mis-incorporation
  19. essential aa's
  20. non-essential aa synthesis
    • transamination of alpha-ketoacids
    • most use B6 as a cofactor
  21. positive and negative nitrogen balance
    • positive: intake > excretion => growth, pregnancy, tissue repair
    • negative: excretion > intake => starvation, malnutrition, illness, surgery, burns
  22. Thymine
    • dUMP + CH3 -thymidylate synthase-> dTMP
    • THF = source of methyl, oxidized to DHF
    • need to minimize [dUTP] in cell b/c DNA pol doesn't efficiently differentiate between dUTP and dTTP
  23. thymidylate synthase
    • dUMP->dTMP
    • blocked by FdUMP (5FU activated by UMPS), suicide inhibitor
    • cancer cells will upregulate this pathway, be more affected
  24. DHFR
    • dihydrofolate reductase
    • DHF -> THF (uses NADPH)
    • blocked by antifolates: methotrexate, aminopterin, trimethoprim
    • latter 2 are antibiotics that bind to bacterial DHFR best
  25. Metabolic roles of folate
    • One-carbon unit metabolism
    • Purine (formyl-THF) and pyrimidine synthesis (methylene-THF)
    • Synthesis of the methyl donor S-adenosylmethionine (SAM)
    • Needed for the conversion of homocysteine to methionine (N5-methyl-THF)
  26. PABA
    • bacteria can synthesize folic acid using para-amino benzoic acid (PABA)
    • sulfonamide is an analog that inhibits folic acid synth = antibiotic
  27. Only rxn in humans that requires THF and vit B12
    • methionine synthase
    • homocysteine -> methionine
    • vit B12 deficiency: megaloblastic anemia; pernicious anemia; paresthesias; peripheral neuropathy; irritability; dementia; depression; psychosis
  28. 6-Mercaptopurine (6-MP)
    • inhibits amidophosphoribosyltransferase
    • 6MP + PRPP -HGPRT-> 6MP-ribose-P +PPi
    • (converted to the nucleotide by HGPRT)
    • childhood leukemia
    • other derivs are immunosuppressants
  29. Cytosine Arabinose (araC)
    • analog of CTP
    • incorporates into DNA, inhibits chain elongation
  30. AZT
    • azido-3-deoxythymidine
    • pyrimidine analog
    • viral pol more error prone and sensitive than host DNA pol
  31. Acyclovir
    • only activated by viral thymidine kinase
    • acts as analog, stops replication