Pyrimidine Metabolism

Synthesis
1. glutamine
  1. carbamoyl phosphate
    1. urea cycle
    2. committed step
    3. N-carbamoylaspartate
      1. dihydroorotate
        orotate
        + PRPP
        orotidylate
        UMPS
        OPRT
        ODC
        UMP
        UTP
        CTP
        CTP synthetase
        + ATP
        + ATP
        NAD+ --> NADH
      2. dehydration
    4. + aspartate
      1. aspartate transcarbamoylase
  2. CPS II
    1. cytosol
    2. 2 ATP
2. salvage pathway
  1. thymidine kinase
    1. thymidine + ATP
      1. TMP + ADP
    2. deoxyuridine + ATP
      1. dUMP + ADP
  2. uridine phosphorylase/uridine kinase
    1. uracil + ribose-1-p
      1. uridine + Pi
    2. uridine + ATP
      1. UMP + ADP
  3. deoxycytidine kinase
    1. deoxycytidine + ATP
      1. dCMP + ADP
Deoxyribonucleotides
1. NDP
  1. dNDP
  2. ribonucleotide reductase
    1. thioredoxin
      1. NADPH reduces
    2. (-) hydroxyurea
    3. (+) ATP, (-) dATP
      1. metabolic state
    4. allosteric
      1. dTTP, dGTP, dATP
2. dUMP
  1. dTMP
    1. + dihydrofolate
  2. thymidylate synthase
  3. + N5,N10-methylenetetrahydrofolate
    1. donates CH3
Regulation of Synthesis
1. cytoplasmic CPSII
2. inhibition
  1. UTP
  2. CTP
3. stimulation
  1. ATP
  2. PRPP
Catabolism
1. ultimate products
  1. B-alanine
    1. CMP or UMP
  2. B-aminoisobutyrate
    1. dTMP
  3. CO2
  4. NH3
2. alanine
  1. malonyl-CoA
    1. FA synthesis
3. aminoisobutyrate
  1. methyl malonyl-CoA
    1. succinyl-CoA
      1. TCA cycle
4. DPD
  1. initial/RLS
    1. reduction of U or T
    2. also degrades
      1. 5-fluorouracil
      2. tegafururacil
Functions of Nucleotides
1. precursors for DNA/RNA
2. metabolism
  1. ATP/GTP
  2. SAM, UDP sugar, CDP choline
  3. cAMP/cGMP
3. coenzymes
  1. NADH
  2. FAD
  3. CoA
Disorders
1. UMP synthase deficiency
  1. hereditary orotic aciduria
  2. function
    1. catalyze decarbox rxn
      1. orotate phosphoribosyltransferase
      2. orotidine-5'-monophosphate decarboxylase
  3. orotic acid accumulates
    1. megablastic anemia
    2. orotic crystalluria
    3. nephropathy
    4. cardiac malformations
    5. strabismus
    6. recurrent infections
  4. autosomal
    1. recessive
  5. dagnosis
    1. enzyme assay
      1. various tissues
  6. treatment
    1. oral uridine
2. DPD deficiency
  1. autosomal
    1. recessive
  2. function
    1. metabolism of uracil/thymine
  3. develop severe toxicity
    1. when exposed to 5-FU
      1. chemotherapy drug
      2. also Xeloda
Drugs
1. cancer treatment
  1. thymidine analog
    1. inhibition
      1. thymidylate synthase
    2. F replace CH3
    3. prevent DNA replication
2. HIV
  1. derivatives of nucleosides
    1. AZT
      1. chronic use
        compromised mitos
    2. ddC, 3TC, ddI, d4T
    3. cellular kinase
      1. triphosphate
      2. metabolism
        inhibition
        HIV reverse transcriptase
        chain termination
        incorporate AZT or DDC
        growing 3' end
        truncate DNA chain

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Pyrimidine Metabolism

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	Erstellt von hardinbc vor fast 12 Jahre