- De novo synthesis from N-carbamoyl aspartate

Chapter 24: Metabolism of Pyrimidine Nucleotides Flashcards by Adam McAteer

Principal nitrogenous pyrimidine bases

Uracil
Cytosine
Thymine

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In pyrimidine nucleotide synthesis, the ring is synthesized

First

- Then the sugar ribose-5-phosphate is added

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Addition of the sugar ribose-5-phosphate involves

Cytosolic and mitochondrial enzymes

- 3 ATPs

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In purine nucleotide biosynthesis (cytoplasm), the ribose

Provides the scaffold

- Then then base is constructed around a N coming from gluatmine

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Origins of the atoms in the pyrimidine ring

Nitrogen
HCO3-
Glutamine amide
Aspartate

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Pyrimidine nucleotide precursors

PRPP
Glutamine
HCO3-
Aspartate
Tetrahydrofolate (from dietary folic acid, required for thymine nucleotides)

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De novo synthesis of UMP requires

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Step 1 of pyrimidine nucleotides (one of two key regulatory steps)

Condensation of glutamine
2 ATP and CO2 condense to form carbamoyl phosphate
Catalyzed by a cytosolic carbamoyl phospahte synthetase II
Committed step of pyrimidine nucleotide biosynthesis in animals

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Step 2 of pyrimidine nucleotide synthesis (second of two key regulatory steps)

Condensation of carbamoyl phosphate with aspartate to form carbamoyl aspartate
Catalyzed by aspartate transcarbamoylase (ATCase)
Committed step in bacteria (E. Coli)

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Enzymes of pyrimidine nucleotide biosynthesis in eukaryotes are organized as

Cytosolic complexes

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Key enzymes in pyrimidine nucleotide biosynthesis

Dihydroorotate synthetase

- Uridine monophosphate (UMP) synthase

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Dihydroorotate synthetase catalyzes

First 3 steps

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1st multicatalytic complex 3 steps enzymes

Carbomoyl phosphate synthetase II
Aspartate transcarbamoylase
Dihydroorotase

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Uridine monophopshate (UMP) synthetase catalyzes

Final 2 steps

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UMP synthetase is a bifunctional enzyme that is defective in

Orotic aciduria

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(2nd multicatalytic complex) UMP synthetase is a bifunctional enzyme that catalyzes the steps involving

Orotate phosphoribosyltransferase

- OMP decarboxylase

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Dihydroorotate synthetase is a cytosolic

220 kDa polypeptide

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The transcarbamoyl phosphate synthetase II reaction is the

Committed step in animals

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The transcarbamoyl phosphate synthetase II reaction is inhibited by

- UDP

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The transcarbamoyl phosphate synthetase II reaction is activated by

PRPP

- ATP

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Step 2 of pyrimidine nucleotide synthesis is the formation of

Carbamoyl aspartate from carbamoyl phosphate (catalyzed via ATCase)

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OMP is formed by

De novo synthesis from N-carbamoyl aspartate

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Step 6 (final step) of pyrimidine synthesis is the formation of

Uridine monophosphate (UMP)

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The final step (UMP) is inhibited by

- CMP

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UMP is converted to UTP by the process of

- Sequential phosphorylation

UTP formed from UMP can be animated by

- CTP synthetase | - Forms another pyrimidine nucleotide CTP

The synthesis of CTP is from

- UTP catalyzed by CTP synthetase

Amination of UTP to CTP is catalyzed by

- CTP synthetase

Amino group donor for the conversion of UTP to CTP is

- The amino group | - ATP is required for this reaction

CTP synthetase exhibits

- Allosteric control - Inhibition by CTP - Activation by GTP

The remaining pyrimidine nucleotide in pyrimidine synthesis is

- dTMP | - Required for DNA synthesis

dTMP is formed from

- CDP by reduction, dephosphorylation, deamination, and methylation steps

Thymidylate synthase catalyzes

- The final methylation step | - Uses folic acid derivatives ad a methyl group donor

The final step in the synthesis of dTMP is catalyzed by

- Thimydylate synthase

Many chemotherapies target

- The pathway of pyrimidine nucleotide biosynthesis

Pyrimidine nucleotide biosynthesis is an ideal target for

- Anti-cancer agents that focus on rapidly dividing cells

Rapidly dividing tumor cells have

- Increased pathway activity

Thymidylate synthase is a particular target because it

- Requires THF derivative

THF levels are maintained by

- Dihydrofolate reductase (which also becomes a target)

Fluorouracil is converted in vivo into

- Fluorodeoxyuridylate

In vivo conversion of fluorouracil to fluorodeoxyuridylate forms a

- Covalent complex with the enzyme irreversible inhibiting it

In the regulation of pyrimidine nucleotide synthesis, both

- Allosteric and induction/repression mechanisms participate

Cytosolic carbamoyl phopshate synthetase II is inhibited by

- UMP (product) | - CMP

Aspartate transcarbamoylase is inhibited by _____ and activated by _____

- CTP - ATP * Key regulatory step in E. Coli*

The first three and last two enzymes of the pathway are regulated at the genetic level by

- Apparently coordinate repression and depression

Key regulation step in mammals is allosteric control of

- CPS-II and OMP decarboxylase

In animals, the rate of OMP formation is also dependent on the

- PRPP levels that are connected to the activity of PRPP synthetase (which is also inhibited by ADP and GDP)

Nucleotides can be regenerated from

- Deoxyribonucleosides - Free bases - Neither require de novo synthesis

Pyrimidine phosphoribosyl transferases (notably orotate phosphoribosyltransferase) salvages

- Orotic acid by converting it to OMP

2'-deoxycytidine, deoxyguanosine, and deoxyadenosime are phosphorylated by

- Deoxycytidine kinase | - Forms the corresponding nucleotide

Uridine monophosphate (UMP) synthase deficiency is called

- Hereditary orotic aciduria

UMP synthase also catalyzes

- Orate phosphoribosyltransferase | - Orotidine-5'-monophosphate decarboxylase reactions

With deficiency, orotic acid accumulates causing clinical manifestations of

- Megaloblastic anemia - Orotic crystalluria and nephroathy - Cardiac malfunctions - Strabismus - Recurrent infections

Clinical manifestations of megaloblastic anemia is a

- Folate deficiency

Strabismus is

- Cross eyes

Diagnosis of UMP synthase deficiency is by

- Enzyme assay in a variety of tissues

Treatment for UMP synthase deficiency is with

- Oral uridine supplemation

Pyrimidine nucleotide biosynthesis requires that

- The ring structure of the base be synthesized initially | - Ribose-5-phosphate be added later (forming a nucleotide)

PRPP, glutamine, CO2, aspartate, and tetrahydrofolate derivatives are required for

- Pyrimidine biosynthesis

The pyrimidine biosynthesis pathway employs both

- Cytosolic and mitochondrial enymes

The cytosolic enzymes are organized into two multienzyme complexes

- CAD | - Bifunctional UMP synthase

Pyrimidine nucleotide biosynthesis is regulated by controlling the activity of

- Allosteric enzymes ATCase in bacteria | - Carbamoyl phosphate synthetase II and OMP decarboxylase in animals

Inhibition of thimydylate synthase (by FdUMP; 5-fluorouracil) or dihydrofolate reductase (by methotrexate, aminopterin, or trimethoprim) effectively blocks

- DNA replication and are thus effective cancer chemotherapies

Pyrimidine nucleotides can be salvaged or degraded to

- Water-soluble products