Pyrimidine Synthesis

What makes up the Pyrimidine ring?

1. Glutamine

2. Aspartate

3. HCO3-

What are the major pyrimidines?

• Cytosine

• Thymine

• Uracil

How many steps are in the pyrimidine synthesis pathway?

6 steps

What enzyme catalyzes steps 1-3 of Pyrimidine Synthesis?

Dihydroorotate Synthase

What enzyme catalyzes steps 4-6 of Pyrimidine Synthesis?

UMP Synthase

What is step 1 of UMP/pyrimidine synthesis?

Glutamine + HCO3- + 2ATP + H2O → Carbamoyl Phosphate + Glutamate + 2ADP + Pi

What enzyme catalyzes the first step of UMP/Pyrimidine Synthesis?

Carbamoyl Phosphate Synthetase II (CPSII)

Location of UMP/pyrimidine synthesis

Cytosol

What is step 2 of UMP/ pyrimidine synthesis?

Carbamoyl Phosphate + Asparate → Carbamoyl asparata + Pi

What enzyme is used to catalyze step 2 of UMP/pyrimidine synthesis?

Asparate transcarbamoylase (ATCase)

What is the final product of UMP/pyrimidine Synthesis?

Uridine 5’-monophosphate (UMP)

What is the nitrogen source for CPS-I?

NH3

What is the nitrogen source for CPS-II?

Glutamine

What are CPS-II’s activators?

• PRPP

• IMP

What are CPS-II’s inhibitors?

• several pyrimidines

What enzyme catalyzes the first commited step for UMP synthesis, in prokaryotes?

Aspartate transcarbamoylase (ATCase)

What activates Aspartate transcarbamoylase (ATCase)?

• ATP

What inhibits Aspartate transcarbamoylase (ATCase)?

• CTP

• CTP + UTP

How many steps does it take to synthesize CTP from UMP?

3 steps

What is step 1 of CTP → UMP?

UMP → UDP

• x1 ATP

What is step 2 of CTP → UMP?

UDP → UTP

• x1 ATP

What is step 3 of CTP → UMP?

UTP + Glutamine + H2O + ATP → CTP + Glutamate + ADP + Pi

What enzyme is used to catalyze UTP → CTP?

CTP synthetase

What activates CTP synthetase?

• GTP

What inhibits CTP synthetase?

• CTP

What is the function of ribonucleotide diphosphate reductase (RDR)?

Converts ribonucleoside diphosphates (NDPs) → deoxyribonucleoside diphosphates (dNDPs)

Reduced Ribonucleotide reductase

Active

Oxidized Ribonucleotide reductase

Inactive

How many steps are in dTMP synthesis?

4 steps

What are the steps for dTMP synthesis?

UMP → UDP → dUDP → dUMP → dTMP

Enzyme used to convert doexy thymidine → dTMP

Thymidine kinase

What does 5-Fluorouracil inhibit?

Thymidylate Synthase

What does Methotrexate inhibit?

DHFR = dihydrofolate reductase

What does Tomudex inhibit?

Thymidylate Synthase

What is Uracil catabiolized (broken down) into?

Acetyl CoA

What is Thymine catabiolized (broken down) into?

Succinyl CoA

CO2 + Glutamine + ATP

Carbamoyl phosphate Synthetase-2 (CPS-II)

Carbamoyl Phosphate

Orotic Acid

Orotic Aciduria

UMP Synthase

UMP → UDP

dUDP → dUMP

CTP

Ribonucleotide reductase

Hydroxyurea

dTMP

What does trimethoprim inhibit?

DHFR = dihydrofolate reductase

What does pyrimethamine inhibit?

DHFR = dihydrofolate reductase

Aspartate

• PRPP

• CO2

What happens when OTC decreases?

Carbamoyl Phosphate increases