Pyrimidine Synthesis Flashcards Preview

USMLE Biochemistry > Pyrimidine Synthesis > Flashcards

Flashcards in Pyrimidine Synthesis Deck (34)
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1
Q

Where does ribose phosphate come from?

A

HMP shunt

2
Q

What is the rate limiting step of pyrimidine synthesis?

A

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

  • ATP ->ADP
  • Co2
3
Q

What enzyme catalyses the conversion of Glutamine to Carbamoyl Phosphate?

A

Carbamoyl phosphate synthetase II

4
Q

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

A

Found in mitochondria

- Urea cycle

5
Q

What is Carbamoyl phosphate synthetase II inhibited by?

A

UMP

6
Q

What is formed first the ring or the ribose sugar?

A

Ring formed first then ribose sugar

- Purines is the opposite

7
Q

What is carbamoyl phosphate converted into?

A

Orotic acid (

8
Q

What 2 molecules are combined to make UMP?

A
  • Orotic acid (ring/base)
  • PRPP (Sugar + Phosphate)
    Enzyme: UMP synthase
9
Q

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

A

UMP synthase

10
Q

What molecules make up the pyrimidine ring?

A
  • Carbamoyl phosphate (1N, 1C)

- Aspartate (1N + 3C)

11
Q

What enzyme is defective in orotic aciduria?

A

UMP synthase

12
Q

How is orotic aciduria inherited?

A

Aut Recessive

13
Q

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

A

UMP

14
Q

What are the key findings/features in orotic aciduria

A
  • Orotic acid in urine
  • Loss of pyrimidines
  • Megaloblastic anemia
  • No B12/folate response
  • Growth retardation
15
Q

What is orotic aciduria treated with?

A
  • Uridine

As it bypasses UMP synthase

16
Q

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

A

Ornithine transcarbamylase deficiency

17
Q

How can you differentiate between OTC deficiency and orotic aciduria?

A

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

18
Q

What is the function of ornithine transcarbamylase?

A

Combines carbamoyl phosphate with ornithine to make citrulline

OTC deficiency causes therfore increased levels of substrates e.g

19
Q

What enzyme levels are increased in OTC deficiency?

A

Carbamoyl phosphate (not combined with ornithine to make citruline)

Increased carbamoyl phosphate will cause increased orotic acid

20
Q

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

A

ATP

21
Q

What chemotherapy drug may mimic cytidine?

A

Ara-C (Cytarabine or cytosine arabinoside)

  • Becomes AraCTP (3 phosphates added)
  • Mimics dCTP
  • Inhibits DNA polymerase
22
Q

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

A

deoxyuridine

23
Q

What is the 1st step in thymidine synthesis?

A

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

  • UDP to dUDP is catalysed by ribonucleotide reductase
24
Q

What enzyme does hydroxyurea inhibit?

A

Ribonucleotide reductase

25
Q

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

A
  • dUDP to dUMP
  • dUMP to dTMP (+N5, N10 THF, source of carbon)
    (thymidylate synthase)
26
Q

What do DHF and THF contain in comparison to folate?

A
  • DHF (2 Hs)

- THF (4 Hs)

27
Q

What molecule provides the Carbon to dUMP to create TMP?

A

N5, N10 Tetrahydrfolate

28
Q

What enzyme and reaction does leflunomide inhibit?

A

Enzyme: Dihydroorotate dehydrogenase

Carbamoyl phosphate -> (Aspartate) -> Orotic acid

29
Q

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

A

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

30
Q

What enzyme converts DHF to THF?

A

Dihydrofolate reductase

31
Q

What does 5-FU mimic?

A

Uracil

32
Q

How does 5-FU block dTMP synthesis?

A
  • 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)
33
Q

What does Methotrexate mimic and inhibit?

A
  • Mimics DHF
  • Inhibits dihydrofolate reductase
  • Blocks synthesis dTMP
34
Q

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

A

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