Pyrimidine Synthesis

Question 1

Where does ribose phosphate come from?

Answer 1

HMP shunt

Question 2

What is the rate limiting step of pyrimidine synthesis?

Answer 2

Glutamine into Carbamoyl Phosphate (enzyme: carbamoyl phosphate synthetase II)

• ATP ->ADP
• Co2

Question 3

What enzyme catalyses the conversion of Glutamine to Carbamoyl Phosphate?

Answer 3

Carbamoyl phosphate synthetase II

Question 4

Where is carbamoyl phosphate I found (what is it involved in)?

Answer 4

Found in mitochondria

- Urea cycle

Question 5

What is Carbamoyl phosphate synthetase II inhibited by?

Answer 5

UMP

Question 6

What is formed first the ring or the ribose sugar?

Answer 6

Ring formed first then ribose sugar

- Purines is the opposite

Question 7

What is carbamoyl phosphate converted into?

Answer 7

Orotic acid (

Question 8

What 2 molecules are combined to make UMP?

Answer 8

• Orotic acid (ring/base)
• PRPP (Sugar + Phosphate)
  Enzyme: UMP synthase

Question 9

What is the bifunctional (catalyses 2 steps) enzyme that convertes Orotic acid and PRPP to UMP?

Answer 9

UMP synthase

Question 10

What molecules make up the pyrimidine ring?

Answer 10

• Carbamoyl phosphate (1N, 1C)

- Aspartate (1N + 3C)

Question 11

What enzyme is defective in orotic aciduria?

Answer 11

UMP synthase

Question 12

How is orotic aciduria inherited?

Answer 12

Aut Recessive

Question 13

What nucleotide is made first (what are the 2 derived from)?

Answer 13

UMP

Question 14

What are the key findings/features in orotic aciduria

Answer 14

• Orotic acid in urine
• Loss of pyrimidines
• Megaloblastic anemia
• No B12/folate response
• Growth retardation

Question 15

What is orotic aciduria treated with?

Answer 15

• Uridine

As it bypasses UMP synthase

Question 16

What is the other condition that causes orotic acid in the urine?

Answer 16

Ornithine transcarbamylase deficiency

Question 17

How can you differentiate between OTC deficiency and orotic aciduria?

Answer 17

OTC deficiency causes increases ammonia levels (urea cycle dysfunction)
- Associated symptoms of incr ammonia

Question 18

What is the function of ornithine transcarbamylase?

Answer 18

Combines carbamoyl phosphate with ornithine to make citrulline

OTC deficiency causes therfore increased levels of substrates e.g

Question 19

What enzyme levels are increased in OTC deficiency?

Answer 19

Carbamoyl phosphate (not combined with ornithine to make citruline)

Increased carbamoyl phosphate will cause increased orotic acid

Question 20

What molecule can add phosphates (e.g UMP to UTP)

Answer 20

ATP

Question 21

What chemotherapy drug may mimic cytidine?

Answer 21

Ara-C (Cytarabine or cytosine arabinoside)

• Becomes AraCTP (3 phosphates added)
• Mimics dCTP
• Inhibits DNA polymerase

Question 22

What is Thymidine (deoxythymidine as it is only required for DNA) synthesised from?

Answer 22

deoxyuridine

Question 23

What is the 1st step in thymidine synthesis?

Answer 23

UMP to UDP and then to deoxyuridine-DP (dUDP)

• UDP to dUDP is catalysed by ribonucleotide reductase

Question 24

What enzyme does hydroxyurea inhibit?

Answer 24

Ribonucleotide reductase

Question 25

What are the 2nd and 3rd steps of thymidine synthesis?

Answer 25

- dUDP to dUMP - dUMP to dTMP (+N5, N10 THF, source of carbon) (thymidylate synthase)

Question 26

What do DHF and THF contain in comparison to folate?

Answer 26

- DHF (2 Hs) | - THF (4 Hs)

Question 27

What molecule provides the Carbon to dUMP to create TMP?

Answer 27

N5, N10 Tetrahydrfolate

Question 28

What enzyme and reaction does leflunomide inhibit?

Answer 28

Enzyme: Dihydroorotate dehydrogenase Carbamoyl phosphate -> (Aspartate) -> Orotic acid

Question 29

What is Ribose 5-Phosphate converted to and what by?

Answer 29

PRPP by PRPP (phosphoribosyl pyrophosphate) synthetase (has sugar and phosphates)

Question 30

What enzyme converts DHF to THF?

Answer 30

Dihydrofolate reductase

Question 31

What does 5-FU mimic?

Answer 31

Uracil

Question 32

How does 5-FU block dTMP synthesis?

Answer 32

- 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)

Question 33

What does Methotrexate mimic and inhibit?

Answer 33

- Mimics DHF - Inhibits dihydrofolate reductase - Blocks synthesis dTMP

Question 34

What is the mechanism of action of leucovorin (folinic acid)?

Answer 34

Used in patients w. bone marrow suppression alongside methotrexate therapy - Converted into THF (thus bypassing Dihydrofolate reductase which is inhibited by MTX)