Pyrimidine Synthesis Flashcards
Where does ribose phosphate come from?
HMP shunt
What is the rate limiting step of pyrimidine synthesis?
Glutamine into Carbamoyl Phosphate (enzyme: carbamoyl phosphate synthetase II)
- ATP ->ADP
- Co2
What enzyme catalyses the conversion of Glutamine to Carbamoyl Phosphate?
Carbamoyl phosphate synthetase II
Where is carbamoyl phosphate I found (what is it involved in)?
Found in mitochondria
- Urea cycle
What is Carbamoyl phosphate synthetase II inhibited by?
UMP
What is formed first the ring or the ribose sugar?
Ring formed first then ribose sugar
- Purines is the opposite
What is carbamoyl phosphate converted into?
Orotic acid (
What 2 molecules are combined to make UMP?
- Orotic acid (ring/base)
- PRPP (Sugar + Phosphate)
Enzyme: UMP synthase
What is the bifunctional (catalyses 2 steps) enzyme that convertes Orotic acid and PRPP to UMP?
UMP synthase
What molecules make up the pyrimidine ring?
- Carbamoyl phosphate (1N, 1C)
- Aspartate (1N + 3C)
What enzyme is defective in orotic aciduria?
UMP synthase
How is orotic aciduria inherited?
Aut Recessive
What nucleotide is made first (what are the 2 derived from)?
UMP
What are the key findings/features in orotic aciduria
- Orotic acid in urine
- Loss of pyrimidines
- Megaloblastic anemia
- No B12/folate response
- Growth retardation
What is orotic aciduria treated with?
- Uridine
As it bypasses UMP synthase
What is the other condition that causes orotic acid in the urine?
Ornithine transcarbamylase deficiency
How can you differentiate between OTC deficiency and orotic aciduria?
OTC deficiency causes increases ammonia levels (urea cycle dysfunction)
- Associated symptoms of incr ammonia
What is the function of ornithine transcarbamylase?
Combines carbamoyl phosphate with ornithine to make citrulline
OTC deficiency causes therfore increased levels of substrates e.g
What enzyme levels are increased in OTC deficiency?
Carbamoyl phosphate (not combined with ornithine to make citruline)
Increased carbamoyl phosphate will cause increased orotic acid
What molecule can add phosphates (e.g UMP to UTP)
ATP
What chemotherapy drug may mimic cytidine?
Ara-C (Cytarabine or cytosine arabinoside)
- Becomes AraCTP (3 phosphates added)
- Mimics dCTP
- Inhibits DNA polymerase
What is Thymidine (deoxythymidine as it is only required for DNA) synthesised from?
deoxyuridine
What is the 1st step in thymidine synthesis?
UMP to UDP and then to deoxyuridine-DP (dUDP)
- UDP to dUDP is catalysed by ribonucleotide reductase
What enzyme does hydroxyurea inhibit?
Ribonucleotide reductase
What are the 2nd and 3rd steps of thymidine synthesis?
- dUDP to dUMP
- dUMP to dTMP (+N5, N10 THF, source of carbon)
(thymidylate synthase)
What do DHF and THF contain in comparison to folate?
- DHF (2 Hs)
- THF (4 Hs)
What molecule provides the Carbon to dUMP to create TMP?
N5, N10 Tetrahydrfolate
What enzyme and reaction does leflunomide inhibit?
Enzyme: Dihydroorotate dehydrogenase
Carbamoyl phosphate -> (Aspartate) -> Orotic acid
What is Ribose 5-Phosphate converted to and what by?
PRPP by PRPP (phosphoribosyl pyrophosphate) synthetase (has sugar and phosphates)
What enzyme converts DHF to THF?
Dihydrofolate reductase
What does 5-FU mimic?
Uracil
How does 5-FU block dTMP synthesis?
- Converted to 5-FdUMP (abnormal dUMP)
- Covalently binds N5, N10 TFH and thymidylate synthase
- Results in the inhibition of thymidylate synthase
- Blocks dTMP synthesis (thymineless death)
What does Methotrexate mimic and inhibit?
- Mimics DHF
- Inhibits dihydrofolate reductase
- Blocks synthesis dTMP
What is the mechanism of action of leucovorin (folinic acid)?
Used in patients w. bone marrow suppression alongside methotrexate therapy
- Converted into THF (thus bypassing Dihydrofolate reductase which is inhibited by MTX)
