Term
Purines and Pyrimidines
di- and triphosphate formation |
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Definition
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Step 1 formation of ATP.
Adenylate kinase generates ADP from ATP and AMP.
AMP + ATP ↔ 2 ADP
ADP is phosphorylated to ATP in glycolysis and ETC.
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Term
Purines and Pyrimidines
di- and triphosphate formation
(Step 2) |
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Definition
Step 2: Use of ATP to form nucleoside diphosphates.
Nucleoside monophosphate kinases are base specific
and use ATP as a phosphate donor.
NMP + ATP ↔
NDP + ADP
Nucleoside monophosphate kinases act on NMP and dNMPs, i.e. not sugar specific.
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Term
Purines and Pyrimidines
di- and triphosphate formation
(Step 3) |
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Definition
Step 3: Formation of triphosphates.
Nucleoside diphosphate kinase is promiscuous.
Base non-specific for donor or acceptor.
NTPDonor + NDPacceptor ↔ NDPDonor + NTPacceptor
-Reaction is determined by relative concentrations of the di- and
triphosphate forms of the nucleotides available.
-Thus, ATP is the most common donor in vivo.
Nucleoside diphosphate kinases act on NDP and dNDPs, i.e. not sugar specific.
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Term
Deoxyribonucleotides
Ribonucleotide Reductase Regulation |
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Definition
-A single enzyme is responsible for the formation of all dNTPs.
-Thus, ribonucleotide reductase must be regulated in 2-ways.
-Overall activity (primary regulation site) binds ATP and dATP.
Controls the overall activity of the enzyme.
-Substrate specificity site allostericly controls substrate selection.
This site controls relative levels of each dNTP formed.
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Term
Chemotherapeutics
Inhibitor of Ribonucleotide Reductase |
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Definition
Hydroxyurea- has many effects on DNA metabolism.
-Remember sickle cell anemia.
-Hydroxyurea is also an inhibitor of ribonucleotide reductase.
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Term
Deoxyribonucleotides
thymidylate synthesis |
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Definition
-dTMP is synthesized from dCTP or dUTP.
-This enzyme reaction has been an argument for the evolution of DNA from RNA.
-Assuming that there was time when thymidylate did not exist.
-dUTPase prevents incorporation of uracil into DNA.
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Term
Deoxyribonucleotides
thymidylate synthetase |
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Definition
-Thymidylate is formed by the
methylation of deoxyuridylate.
-The carbon source is THF which becomes
oxidized in the reaction.
-THF is then regenerated through the
action of dihydrofolate reductase (DHFR).
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Term
Thymidylate synthesis
Drug Target |
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Definition
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1.Fluorouracil is a suicide inhibitor of thymidylate synthetase.
-(blocks conversion of dUMP to dTMP.
Used in cancer treatment.)
2.Methotrexate inhibits dihydrofolate reductase (DHFR).
(Methotrexate binds dihydrofolate reductase with 100X greater affinity than dihydrofolate.)
-Inhibits thymidylate synthesis.
Used in cancer treatment.
3.Sulfonamides target folate synthesis in bacteria.
Sulfonamides- analogues of PABA, inhibitors of folate biosynthesis.
Absence of folate = absence of THF = absence of nucleotide synthesis
Used clinically as antimicrobial. Humans obtain folate from diet.
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