Purine and Pyrimidine Metabolism

Question 1

Where does the ribose 5P required for nucleotide synthesis come from?

Answer 1

ribose 5P required for nucleotide synthesis is derived from the hexose monophosphate shunt (HMP shunt)

Question 2

Lesch-Nyhan disease

Answer 2

• 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

Question 3

carbamoyl P synthetase-1 vs carbamoyl P synthetase-2

Answer 3

• 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

Question 4

Orotic Aciduria

Answer 4

• 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

Question 5

2 orotic acidurias

Answer 5

1. hyperammonemia
   - no megaloblastic anemia
   - pathway: urea cycle
   - enzyme deficient: OTC
2. megaloblastic anemia
   - no hyperammonemia
   - pathway: pyrimidine synthesis
   - enzyme deficient: UMP synthase

Question 6

Ribonucleotide Reductase

• f(x)
• inhibited by what drug

Answer 6

• 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)

Question 7

Thymidylate synthase

• f(x)
• inhibited by what drug

Answer 7

• methylates dUMP to dTMP
• requires THF
• inhibited by 5-Fluorouracil (S Phase)

Question 8

Dihydrofolate reductase (DHFR)

• f(x)
• inhibited by what drug

Answer 8

• inhibited by Methotrexate (eukaryotic S phase)
• inhibited by trimethoprim (prokaryotic)
• inhibited by pyrimethamine (protozoal, tx: toxoplasmosis)

Question 9

Hyperammonemia with NO megaloblastic anemia

• pathway error:
• enzyme deficient:

Answer 9

Hyperammonemia with NO megaloblastic anemia

• pathway error: urea cycle
• enzyme deficient: OTC

Question 10

Adenosine Deaminase (ADA) deficiency

Answer 10

• 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

Question 11

megaloblastic anemia with NO hyperammonemia

• pathway error:
• enzyme deficient:

Answer 11

megaloblastic anemia with NO hyperammonemia

• pathway error: pyrimidine synthesis
• enzyme deficient: UMP synthase

Question 12

Allopurinol

Answer 12

inhibits xanthine oxidase and can reduce purine synthesis by inhibiting PRPP amidotransferase (provided HGPRT isa active)

Question 13

Hyperuricemia and gout often accompany the following conditions:

Answer 13

• 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)