Purine and Pyrimidine Metabolism

Question 1

Which drug can cause a depletion of DHF?

Answer 1

5-fluorouracil

Question 2

What kind of block does methotrexate do to DHF reductase? Effects on kinetics

Answer 2

• competitive inhibition

- ⬆️ Km, same Vmax

Question 3

Different between orotic aciduria from pyrimidine synthesis and from urea cycle?

Answer 3

• pyrimidine synthesis: megaloblastic anemia, no hyperammonemia, normal BUN. ⬇️ UMP synthase
• urea cycle: hyperammonemia, no megaloblastic anemia, ⬇️ BUN, ⬇️ ornithine transcarbamoylase (OTC)

Question 4

What is the different between carbamoyl phosphate synthase 1 and 2? What pathway involves? Localization in cell and substrates.

Answer 4

• carbamoyl phosphate synthase-1: mitochondria, urea cycle, substrates: 2 ATP, HCO3, NH4+
• carbamoyl phosphate synthase-2: cytoplasm, pyrimidine synthesis, substrates: CO2, glutamine, ATP

Question 5

How can you treat an infant with orotic aciduria by defect in pyrimidine synthesis?

Answer 5

Formula with uridine ▶️ salvaged to UMP and ▶️ feedback (-) carbamoyl phosphate synthase-2 ▶️▶️ ⬇️ orotic acid

Question 6

What is the consequence of ADA deficiency? Why does it occur?

Answer 6

Severe combined immunodeficiency (SCID)

- ⬇️ ADA ▶️ ⬆️⬆️ dATP ▶️ (-) ribonucleotide reductase ▶️ ⬇️ DNA synthesis (unknown why the target are B and T cells)

Question 7

Why the exercise and alcoholism can elevate the Uric acid?

Answer 7

⬆️⬆️ lactic acid ▶️ compete by urinary excretion with Uric acid ▶️ ⬆️⬆️ Uric acid

Question 8

Treatment for ADA deficiency

Answer 8

Enzyme replacement therapy and bone marrow transplantation

Question 9

Treatment for chronic hyperuricemia because underexcretion?

Answer 9

• uricosuric drug: probenecid

Question 10

Symptoms of lesch-nyhan syndrome, what is the cause earliest sign?

Answer 10

• “less” - mental retardation, cerebral spastic palsy, “hand” - compulsive biting hands and lips.
• appearance of orange crystals in diapers (needle-shape sodium urate crystals)
• HGPRT deficiency

Question 11

Why Von Gierke disease, hereditary fructose intolerance and galactosemia are associated with hyperuricemia?

Answer 11

• phosphorylated sugars accumulated (galactosemia and hereditary fructose intolerance) ▶️ ⬇️⬇️ Pi free availability (all) ▶️ ⬆️⬆️ AMP (can’t be phosphorylated to ADP, ATP) excess AMP ▶️ Uric acid

Question 12

Why purines production in lesch-nyhan syndrome is even more? Not just the deviation to the excretion pathway because the deficiency is the cause of hyperuricemia

Answer 12

• No feedback to PRPP amidotransferase ▶️ continue production of purines

Question 13

Treatment lesch-nyhan syndrome

Answer 13

Allopurinol

Question 14

List the possible causes and conditions of hyperuricemia, and which are their general mechanism?

Answer 14

• radiation and chemotherapy regimens
• excessive cell death
• lesch-nyhan syndrome
• glucose 6-phosphatase deficiency (Von Gierke)
• hereditary fructose intolerance
• galactosemia
• excessive dietary nucleic acid
• alcoholism, exercise (not necessarily hyperuricemia)