Pyrimidine biosyn

Question 1

What is the first step in pyrimidine biosynthesis?

Answer 1

Glutamine + HCO3 + 2 ATP produces carbamoyl phosphate, via carbamoyl phosphate synthetase II (CPS 2)

CPS 2 is the rate limiting enzyme / step!

Question 2

What is the second step in pyrimidine biosynthesis?

Answer 2

Normally, ornithine + carbamoyl phosphate produces citrulline (urea cycle) via ornithine transcarbamoylase (OTC)

When OTC is defective, carbamoyl phosphate accumulates and becomes orotate (which then becomes pyrimidines and urine

Question 3

Overall pathway of pyrimidine biosynthesis?

Answer 3

Carbamoyl phosphate -> carbamoyl aspartate -> dihydroorotate -> orotate -> OMP -> UMP -> UDP -> UTP -> CTP

Question 4

Which steps of the biosyn occur in the cytosol?

Answer 4

Carbamoyl phosphate formation -> carbamoyl aspartate -> dihydroorotate

Question 5

Which steps of the biosyn occur in the mitochondria?

Answer 5

Dihydroorotate -> orotate -> OMP -> UMP

Question 6

Ribonucleotide reductase (OH to H) is activated by which molecule? (dATP or ATP?)

Answer 6

Activated by ATP! Inhibited by dATP!

Question 7

What does dTTP do? dGTP? dATP?

Answer 7

dTTP: helps convert GDP to dGTP and inhibits purine synthesis (T and C)

dGTP: helps convert ADP to dADP and inhibits its own synthesis

dATP: helps convert CDP to dCDP and inhibits all of them

Question 8

Role of hydroxyurea? Role of 5-Fluorouracil?

Answer 8

Hydroxyurea: inhibits ribonucleotide reductase (UDP, then, does NOT go to dUDP)

5-FU: inhibits thymidylate synthase (dUTP does NOT go to dTMP)

Question 9

Synthesis of dTMP? (Thymidalate)

Answer 9

dCDP -> dCTP -> dUTP -> dUMP

dUMP -> dTMP, via thymidalate synthase (TS)

TS is inhibited by fluorouracil

Question 10

What are the pyrimidine salvage pathways?

Answer 10

Both uridine and uracil can be salvaged to UMP

Uridine: via UK
Uracil: via phosphoribosyltransferase

Question 11

Hereditary Orotic Aciduria characteristics

Answer 11

Arises due to deficiencies of bifxnal enzyme of the last 2 steps of UMP synthesis

Results in pyrimidine starvation; overproduction of pyrimidine precursor is seen (orotic acid)

Orotic acid accumulates and forms crystals

RBCs are abnormally shaped

Question 12

Tx of hereditary OA

Answer 12

Treat with uridine, because increasing uridine will increase UMP production

UMP (as UTP and also CTP) then inhibits CPS II, reducing the rate of production of orotic acid