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FoundSci Unit 6 > Nucleotide Metabolism II > Flashcards

Nucleotide Metabolism II Flashcards

1
Q

How are pyrimidines made?

A

Synthesized as free bases and then transferred to ribose

First three steps catalyzed by multifunctional protein CAD

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2
Q

What is the first pyrimidine synthesized?

A

UMP

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3
Q

What are the first three steps of pyrimidine synthesis?

A

Glutamine and HCO3- and 2 ATP are converted to carbamoyl phosphate by carbamoyl phosphate synthetase II

Carbamoyl phosphate is converted to N-carbamoyl aspartate by aspartate transcarbamoylase

N-carbamoyl aspartate is converted to dihydroorotate by dihydroorotase

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4
Q

How is UMP synthesized?

A

Dihydroorotate is converted to orotate by dihydroorotate dehydrogenase

Orotate with PRPP is converted to orotidine 5’-monophosphate (OMP) by orotate phosphoribosyltransferase

Orotidine 5’-monophosphate is converted to Uridine 5’-monophosphate (UMP) by OMP decarboxylase

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5
Q

Where is dihydroorotate dehydrogenase found?

A

In mitochondria

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6
Q

Where are orotate phosphoribosyltransferase and OMP decarboxylase activites carried on?

A

Multifunctional protein UMP synthase (cytoplasm and nucleus)

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7
Q

What converts UMP to UTP?

A

Nucleoside 5’-monophosphate kinases and nucleoside diphosphate kinases

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8
Q

What converts UTP to CTP?

A

CTP synthase

Glutamine provides amino group

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9
Q

What does carbamoyl phosphate synthetase II do and how is it regulated?

A

Converts CO2, glutamine, and 2 ATP to carbamoyl phosphate

Inhibited by UTP - first step of pyrimidine synthesis inhibited by high levels of pyrimidine nucleotides

Activated by PRPP - high levels of precursor stimulates pyrimidine synthesis

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10
Q

What does CTP synthase do and how is it regulated?

A

CTP synthase converts UTP to CTP

Inhibited by CTP

Activated by UTP

Self regulating system

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11
Q

What do we need more of when cells divide?

A

Deoxyribonucleotides

Via Ribonucleotide reductase which converts nucleoside 5’-diphosphates to 2’-deoxyribonucleoside 5’-diphosphates

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12
Q

How is ribonucleotide reductase regulated?

A

Transcriptional control - both induction and repression

Allosteric modulators - NTPs and dNTPS function as activators and inhibitors. dATP inhibits reduction of ADP, CDP, GDP, and UDP

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13
Q

What targets ribonucleotide reductase?

A

Antineoplastic agent hydroxyurea

Inhibits ribonucleotide reductase

Prevents dNTP synthesis

Blocks cell division

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14
Q

What are deoxyribonucleotides of thymine?

A

dTMP, dTDP, dTTP

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15
Q

How is dTMP made?

A

dUMP is converted to dTMP by thymidylate synthase

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16
Q

How does 5-flourouracil inhibit thymidylate synthase?

A

5-fluourouracil converts to F-flurouridine monophosphate (FUMP)

FUMP becomes FUDP

FUDP becomes FdUDP

FdUDP them becomes FdUMP which irreversibly inhibits thymidylate synthase

17
Q

What does degradation of pyrimidine nucleotides yield?

A

Beta-amino acids

UMP, CMP, and dCMP - metabolized to acetyl-CoA

dTMP catabolyzed to Beta-aminoisobutyrate which is metabolized to succinyl-CoA

These are readily soluble and some eliminated in the urine

18
Q

What is unique to pyrimidine metabolism?

A

the production of Beta-aminoisobutyrate

Found in urine of cancer patients undergoing radiation or chemotherapy

19
Q

What are the salvage pathways?

A

Conversion of free bases and nucleosides to nucleotides

20
Q

What are the sources of free bases and nucelosides?

A

Purine and pyrimidine nucleotide degradation and diet.

21
Q

What is the path of ingested DNA and RNA to red blood cells?

A

Ingested DNA and RNA is converted to free nucleotides by pancreatic nucleases

Free nucleotides are converted to free nucleosides by phosphatases

Free nucleosides are taken up by intestinal epithelial cells and are mostly metabolized

Some free bases and nucleosides released in to circulation where they are trafficked to red blood cells

22
Q

What are the enzymes associated with purine base salvage pathway? What do they do?

A

Hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) - converts Hypoxanthine and PRPP to IMP and PPi and is reversed

Adenine phosphoribosyltransferase (APRTase) - converts Guanine and PRPP to GMP and PPi (reverse rxn too). Also converts Adenine and PRPP to AMP and PPi (reverse rxn too)

23
Q

How does the salvage of purine bases affects the synthesis of purines?

A

Reduces the rate of de novo synthesis

PRPP consumed by HGPRTase and APRTase so less PRPP available for amidophophoribosyltransferase. Less PRA formed

24
Q

What can be directly phosphorylated to its corresponding nucleotide?

A

Adenosine

Adenosine kinase converts adenosine to AMP

25
Q

What is the path of the salvage of pyrimidine bases?

A

Free uracil (and orotate) salvaged by pyrimidine phosphoribosyltransferase which converts Pyrimidine and PRPP to Pyrimidine nuceloside 5’monophosphate and PPi

26
Q

What is the outcome of the salvage of pyrimidine bases?

A

Consumes PRPP

Less PRPP available for stimulation of carbamoyl phosphate synthetase II

Less PRPP for orotate phosphoribosyltransferase

Impacts de novo pyrimidine synthesis

27
Q

How are pyrimidine nucleosides converted to nucleotides?

A

Specific kinases

Uridine-Cytidine kinase converts Uridine to UMP and Cytidine to CMP

Thymidine kinase converts thymidine to dTMP

FoundSci Unit 6 (14 decks)

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