Flashcards in Purine and Pyrimidine Metabolism Deck (13)
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1
Where does the ribose 5P required for nucleotide synthesis come from?
ribose 5P required for nucleotide synthesis is derived from the hexose monophosphate shunt (HMP shunt)
2
Lesch-Nyhan disease
- missing hypoxanthine guanine phosphoribosyl pyrophosphate transferase (HPRT/HGPRT) (enzyme for purine salvage)
- hyperuricemia (bc purines can't be salvaged)
- orange crystals in diapers = needle-shaped sodium urate crystals
- have CNS deterioration, mental retardation
- spastic cerebral palsy associated with compulsive self-mutilation (hands, lips)
- bc cells in the basal ganglia of the brain (fine motor control) normally have very high HGPRT activity
- large amounts of urate cause crippling gouty arthritis and
- urate nephropathy (renal failure is usual COD)
- early death
- X-linked recessive
- w/o the salvage pathway, purines are shunted toward the excretion pathway
- compounded by lack of regulatory control of the PRPP amidotransferase in the purine synthesis pathway,
- results in EVEN more purine synthesis
- Tx: allopurinol to esa the amount of urate deposits formed
3
carbamoyl P synthetase-1 vs carbamoyl P synthetase-2
- carbamoyl P synthetase-1 is a liver mitochondrial enzyme involved in the urea cycle
- carbamoyl P synthetase-2 is a cytoplasmic enzyme involved in de novo pyrimidine synthesis
4
Orotic Aciduria
- AR
- defect in uridine monophosphate (UMP) synthase
- This enzyme has 2 activities:
1. orotate phosphoribosyltransferase and
2. orotidine decarboxylase
- The lack of pyrimidines impairs nucleic acid synthesis needed for hematopoiesis (causes megaloblastic anemia)
- orotic acid accumulates and spills into urine
- (orotic acid crystals can lead to orotic acid urinary obstruction)
- the presence of orotic acid in urine might suggest the defect could be OTC deficiency, but the lack of hyperammonemia rules out a defect in the urea cycle
- giving uridine relieves sx by bypassing the defect in the pyrimidine pathway
- uridine is salvaged to UMP, which feedback inhibits Carbamoyl phosphate synthase-2, preventing orotic acid formation
5
2 orotic acidurias
1. hyperammonemia
- no megaloblastic anemia
- pathway: urea cycle
- enzyme deficient: OTC
2. megaloblastic anemia
- no hyperammonemia
- pathway: pyrimidine synthesis
- enzyme deficient: UMP synthase
6
Ribonucleotide Reductase
- f(x)
- inhibited by what drug
- reduces all NDPs to dNDPs for DNA synthesis
- requires all 4 nucleotide substrates to be diphosphate (UDP, CDP, ADP, GDP)
- inhibited by hydroxyurea (S Phase)
7
Thymidylate synthase
- f(x)
- inhibited by what drug
- methylates dUMP to dTMP
- requires THF
- inhibited by 5-Fluorouracil (S Phase)
8
Dihydrofolate reductase (DHFR)
- f(x)
- inhibited by what drug
- inhibited by Methotrexate (eukaryotic S phase)
- inhibited by trimethoprim (prokaryotic)
- inhibited by pyrimethamine (protozoal, tx: toxoplasmosis)
9
Hyperammonemia with NO megaloblastic anemia
- pathway error:
- enzyme deficient:
Hyperammonemia with NO megaloblastic anemia
- pathway error: urea cycle
- enzyme deficient: OTC
10
Adenosine Deaminase (ADA) deficiency
- AR
- produces SCID
- lacking both B and T-cell function, children are multiply infected w many organisms (pneumocystis cairn, candida) and don't survive w/o treatment
- Need ERT (enzyme replacement therapy) and BM transplant
- high levels of dATP accumulate in RBC and inhibit ribonucleotide reductase, thereby inhibiting the production of other essential deoxynucleotide precursors for DNA synthesis
11
megaloblastic anemia with NO hyperammonemia
- pathway error:
- enzyme deficient:
megaloblastic anemia with NO hyperammonemia
- pathway error: pyrimidine synthesis
- enzyme deficient: UMP synthase
12
Allopurinol
inhibits xanthine oxidase and can reduce purine synthesis by inhibiting PRPP amidotransferase (provided HGPRT isa active)
13
