Purine and Pyrimidine Metabolism Flashcards Preview

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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

Hyperuricemia and gout often accompany the following conditions:

- lesch-nyhan syndrome (no purine salvage)
- partial deficiency of HGPRT
- alcoholism (lactate and urate compete for the same transport system in the kidney)
- glucose 6 phosphatase deficiency
- hereditary fructose intolerance*
- galactose 1-P uridyl transferase deficiency* (galactosemia)
* in galactose 1PUTD and HFI: (phosphorylated sugars accumulate, decreasing available Pi and increasing AMP (which can't be phosphorylated to ADP and ATP). The excess AMP is converted to uric acid)