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Biochemistry I > Chapter 24: Metabolism of Pyrimidine Nucleotides > Flashcards

Chapter 24: Metabolism of Pyrimidine Nucleotides Flashcards

1
Q

Principal nitrogenous pyrimidine bases

A
  • Uracil
  • Cytosine
  • Thymine
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2
Q

In pyrimidine nucleotide synthesis, the ring is synthesized

A
  • First

- Then the sugar ribose-5-phosphate is added

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3
Q

Addition of the sugar ribose-5-phosphate involves

A
  • Cytosolic and mitochondrial enzymes

- 3 ATPs

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4
Q

In purine nucleotide biosynthesis (cytoplasm), the ribose

A
  • Provides the scaffold

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

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5
Q

Origins of the atoms in the pyrimidine ring

A
  • Nitrogen
  • HCO3-
  • Glutamine amide
  • Aspartate
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6
Q

Pyrimidine nucleotide precursors

A
  • PRPP
  • Glutamine
  • HCO3-
  • Aspartate
  • Tetrahydrofolate (from dietary folic acid, required for thymine nucleotides)
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7
Q

De novo synthesis of UMP requires

A
  • ATP
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8
Q

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

A
  • 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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9
Q

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

A
  • 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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10
Q

Enzymes of pyrimidine nucleotide biosynthesis in eukaryotes are organized as

A
  • Cytosolic complexes
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11
Q

Key enzymes in pyrimidine nucleotide biosynthesis

A
  • Dihydroorotate synthetase

- Uridine monophosphate (UMP) synthase

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12
Q

Dihydroorotate synthetase catalyzes

A
  • First 3 steps
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13
Q

1st multicatalytic complex 3 steps enzymes

A
  • Carbomoyl phosphate synthetase II
  • Aspartate transcarbamoylase
  • Dihydroorotase
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14
Q

Uridine monophopshate (UMP) synthetase catalyzes

A
  • Final 2 steps
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15
Q

UMP synthetase is a bifunctional enzyme that is defective in

A
  • Orotic aciduria
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16
Q

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

A
  • Orotate phosphoribosyltransferase

- OMP decarboxylase

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17
Q

Dihydroorotate synthetase is a cytosolic

A
  • 220 kDa polypeptide
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18
Q

The transcarbamoyl phosphate synthetase II reaction is the

A
  • Committed step in animals
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19
Q

The transcarbamoyl phosphate synthetase II reaction is inhibited by

A
  • UTP

- UDP

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20
Q

The transcarbamoyl phosphate synthetase II reaction is activated by

A
  • PRPP

- ATP

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21
Q

Step 2 of pyrimidine nucleotide synthesis is the formation of

A
  • Carbamoyl aspartate from carbamoyl phosphate (catalyzed via ATCase)
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22
Q

OMP is formed by

A
  • De novo synthesis from N-carbamoyl aspartate
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23
Q

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

A
  • Uridine monophosphate (UMP)
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24
Q

The final step (UMP) is inhibited by

A
  • UMP

- CMP

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25
Q

UMP is converted to UTP by the process of

A
  • Sequential phosphorylation
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26
Q

UTP formed from UMP can be animated by

A
  • CTP synthetase

- Forms another pyrimidine nucleotide CTP

27
Q

The synthesis of CTP is from

A
  • UTP catalyzed by CTP synthetase
28
Q

Amination of UTP to CTP is catalyzed by

A
  • CTP synthetase
29
Q

Amino group donor for the conversion of UTP to CTP is

A
  • The amino group

- ATP is required for this reaction

30
Q

CTP synthetase exhibits

A
  • Allosteric control
  • Inhibition by CTP
  • Activation by GTP
31
Q

The remaining pyrimidine nucleotide in pyrimidine synthesis is

A
  • dTMP

- Required for DNA synthesis

32
Q

dTMP is formed from

A
  • CDP by reduction, dephosphorylation, deamination, and methylation steps
33
Q

Thymidylate synthase catalyzes

A
  • The final methylation step

- Uses folic acid derivatives ad a methyl group donor

34
Q

The final step in the synthesis of dTMP is catalyzed by

A
  • Thimydylate synthase
35
Q

Many chemotherapies target

A
  • The pathway of pyrimidine nucleotide biosynthesis
36
Q

Pyrimidine nucleotide biosynthesis is an ideal target for

A
  • Anti-cancer agents that focus on rapidly dividing cells
37
Q

Rapidly dividing tumor cells have

A
  • Increased pathway activity
38
Q

Thymidylate synthase is a particular target because it

A
  • Requires THF derivative
39
Q

THF levels are maintained by

A
  • Dihydrofolate reductase (which also becomes a target)
40
Q

Fluorouracil is converted in vivo into

A
  • Fluorodeoxyuridylate
41
Q

In vivo conversion of fluorouracil to fluorodeoxyuridylate forms a

A
  • Covalent complex with the enzyme irreversible inhibiting it
42
Q

In the regulation of pyrimidine nucleotide synthesis, both

A
  • Allosteric and induction/repression mechanisms participate
43
Q

Cytosolic carbamoyl phopshate synthetase II is inhibited by

A
  • UMP (product)

- CMP

44
Q

Aspartate transcarbamoylase is inhibited by _____ and activated by _____

A
  • CTP
  • ATP
  • Key regulatory step in E. Coli*
45
Q

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

A
  • Apparently coordinate repression and depression
46
Q

Key regulation step in mammals is allosteric control of

A
  • CPS-II and OMP decarboxylase
47
Q

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

A
  • PRPP levels that are connected to the activity of PRPP synthetase (which is also inhibited by ADP and GDP)
48
Q

Nucleotides can be regenerated from

A
  • Deoxyribonucleosides
  • Free bases
  • Neither require de novo synthesis
49
Q

Pyrimidine phosphoribosyl transferases (notably orotate phosphoribosyltransferase) salvages

A
  • Orotic acid by converting it to OMP
50
Q

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

A
  • Deoxycytidine kinase

- Forms the corresponding nucleotide

51
Q

Uridine monophosphate (UMP) synthase deficiency is called

A
  • Hereditary orotic aciduria
52
Q

UMP synthase also catalyzes

A
  • Orate phosphoribosyltransferase

- Orotidine-5’-monophosphate decarboxylase reactions

53
Q

With deficiency, orotic acid accumulates causing clinical manifestations of

A
  • Megaloblastic anemia
  • Orotic crystalluria and nephroathy
  • Cardiac malfunctions
  • Strabismus
  • Recurrent infections
54
Q

Clinical manifestations of megaloblastic anemia is a

A
  • Folate deficiency
55
Q

Strabismus is

A
  • Cross eyes
56
Q

Diagnosis of UMP synthase deficiency is by

A
  • Enzyme assay in a variety of tissues
57
Q

Treatment for UMP synthase deficiency is with

A
  • Oral uridine supplemation
58
Q

Pyrimidine nucleotide biosynthesis requires that

A
  • The ring structure of the base be synthesized initially

- Ribose-5-phosphate be added later (forming a nucleotide)

59
Q

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

A
  • Pyrimidine biosynthesis
60
Q

The pyrimidine biosynthesis pathway employs both

A
  • Cytosolic and mitochondrial enymes
61
Q

The cytosolic enzymes are organized into two multienzyme complexes

A
  • CAD

- Bifunctional UMP synthase

62
Q

Pyrimidine nucleotide biosynthesis is regulated by controlling the activity of

A
  • Allosteric enzymes ATCase in bacteria

- Carbamoyl phosphate synthetase II and OMP decarboxylase in animals

63
Q

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

A
  • DNA replication and are thus effective cancer chemotherapies
64
Q

Pyrimidine nucleotides can be salvaged or degraded to

A
  • Water-soluble products

Biochemistry I (34 decks)

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