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PYRIMIDINE SYNTHESIS

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The document summarizes the de novo synthesis of pyrimidine nucleotides in three steps. First, carbamoyl phosphate and aspartate condense to form carbamoyl aspartate. Second, the pyrimidine ring forms and is further modified through a series of reactions to eventually form orotidine monophosphate. Third, OMP undergoes reactions to form the pyrimidine nucleotides UMP, UDP, UTP, CTP, and through additional steps, dUMP and dTMP. Key enzymes involved include carbamoyl phosphate synthetase, aspartate transcarbamoylase, and OMP decarboxylase. Feedback inhibition regulates the process.

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PYRIMIDINE SYNTHESIS
 Cytosine  Thymine  Uracil
 The pyrimidine ring is synthesized as free pyrimidine & it is incorporated into the nucleotide.  Aspartate, glutamine (amide group) & CO2 contribute to atoms in the formation of pyrimidine ring.
 The reaction occurs in cytoplasm.  Glutamine transfers its amido nitrogen to CO2 to produce carbamoyl phosphate.  This reaction is catalyzed by ATP dependent enzyme carbamoyl phosphate synthetase II (CPS II).  CPS-I is involved in urea cycle.
 Carbamoyl phosphate condenses with aspartate to form carbamoyl aspartate.  This reaction is catalysed by aspartate transcarbamoylase.  The atoms C2 & N3 are derived from carbamoyl phosphate & the rest are from aspartate.
 Dihydroorotase catalyses the pyrimidine ring closure with a loss of H2O.  Step 4: Oxidation  NAD+ dependent dehydrogenation, leading to the formation of orotate.  The enzyme is dihydro orotate dehydrogenase (DHODH).
 Ribose 5-phosphate is now added to orotate to produce orotidine monophosphate (OMP).  This reaction is catalysed by orotate phosphoribosyltransferase.  PRPP is the donor of ribose 5-phosphate.
 OMP undergoes decarboxylation to uridine mono-phosphate (UMP).  The enzyme is OMP decarboxylase (OMPDC).  This is the first pyrimidine that is synthesized.  6-aza-uridine inhibits this step & used as an anticancer drug.
 Orotate phosphoribosyl transferase & OMP decarboxylase are domains of a single protein.  A defect in this bifunctional enzyme causes orotic aciduria.
 By an ATP-dependent UMP kinase reaction, UMP is converted to UDP which serves as a precursor for the synthesis of dUMP, dTMP, UTP & CTP.  UDP is phosphorylated to UTP (uridine triphosphate) with the help of ATP.  The enzyme is nucleoside diphosphate kinase.
 Ribonucleotide reductase converts UDP to dUDP by a thioredoxin-dependent reaction.  Thymidylate synthetase catalyses the transfer of a methyl group from N5, N10 - methylene tetrahydrofolate to produce deoxythymidine monophosphate (dTMP).
 Cytidine triphosphate (CTP) is synthesized from UTP by amination.  CTP synthetase is the enzyme & glutamine provides the nitrogen.  CTP synthetase needs ATP.
PYRIMIDINE SYNTHESIS
PYRIMIDINE SYNTHESIS
UDP dUDP dUMP dTMP UTP CTP UMP ATP ADP UMP Kinase Thioredoxin (2SH) Thioredoxin (-S-S-) Ribonucleotide reductase N5, N10 Methylene THF THF Glutamine + ATP + H2O Glutamate + ADP + Pi CTP synthetase Nucleoside diphosphate Kinase ATP ADP
 In bacteria, aspartate transcarbamoylase (ATCase) catalyses a committed step in pyrimidine biosynthesis.  ATCase is a good example of an enzyme controlled by feedback mechanism by the end product CTP.
 Carbamoyl phosphate synthetase II (CPS II) is the regulatory enzyme of pyrimidine synthesis in animals.  It is activated by PRPP and ATP & inhibited by UDP & UTP.  OMP decarboxylase, inhibited by UMP & CMP, also controls pyrimidine formation.
 Textbook of Biochemistry-U Satyanarayana  Textbook of Biochemistry-DM Vasudevan
PYRIMIDINE SYNTHESIS

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PYRIMIDINE SYNTHESIS

  • 3.  The pyrimidine ring is synthesized as free pyrimidine & it is incorporated into the nucleotide.  Aspartate, glutamine (amide group) & CO2 contribute to atoms in the formation of pyrimidine ring.
  • 4.  The reaction occurs in cytoplasm.  Glutamine transfers its amido nitrogen to CO2 to produce carbamoyl phosphate.  This reaction is catalyzed by ATP dependent enzyme carbamoyl phosphate synthetase II (CPS II).  CPS-I is involved in urea cycle.
  • 5.  Carbamoyl phosphate condenses with aspartate to form carbamoyl aspartate.  This reaction is catalysed by aspartate transcarbamoylase.  The atoms C2 & N3 are derived from carbamoyl phosphate & the rest are from aspartate.
  • 6.  Dihydroorotase catalyses the pyrimidine ring closure with a loss of H2O.  Step 4: Oxidation  NAD+ dependent dehydrogenation, leading to the formation of orotate.  The enzyme is dihydro orotate dehydrogenase (DHODH).
  • 7.  Ribose 5-phosphate is now added to orotate to produce orotidine monophosphate (OMP).  This reaction is catalysed by orotate phosphoribosyltransferase.  PRPP is the donor of ribose 5-phosphate.
  • 8.  OMP undergoes decarboxylation to uridine mono-phosphate (UMP).  The enzyme is OMP decarboxylase (OMPDC).  This is the first pyrimidine that is synthesized.  6-aza-uridine inhibits this step & used as an anticancer drug.
  • 9.  Orotate phosphoribosyl transferase & OMP decarboxylase are domains of a single protein.  A defect in this bifunctional enzyme causes orotic aciduria.
  • 10.  By an ATP-dependent UMP kinase reaction, UMP is converted to UDP which serves as a precursor for the synthesis of dUMP, dTMP, UTP & CTP.  UDP is phosphorylated to UTP (uridine triphosphate) with the help of ATP.  The enzyme is nucleoside diphosphate kinase.
  • 11.  Ribonucleotide reductase converts UDP to dUDP by a thioredoxin-dependent reaction.  Thymidylate synthetase catalyses the transfer of a methyl group from N5, N10 - methylene tetrahydrofolate to produce deoxythymidine monophosphate (dTMP).
  • 12.  Cytidine triphosphate (CTP) is synthesized from UTP by amination.  CTP synthetase is the enzyme & glutamine provides the nitrogen.  CTP synthetase needs ATP.
  • 15. UDP dUDP dUMP dTMP UTP CTP UMP ATP ADP UMP Kinase Thioredoxin (2SH) Thioredoxin (-S-S-) Ribonucleotide reductase N5, N10 Methylene THF THF Glutamine + ATP + H2O Glutamate + ADP + Pi CTP synthetase Nucleoside diphosphate Kinase ATP ADP
  • 16.  In bacteria, aspartate transcarbamoylase (ATCase) catalyses a committed step in pyrimidine biosynthesis.  ATCase is a good example of an enzyme controlled by feedback mechanism by the end product CTP.
  • 17.  Carbamoyl phosphate synthetase II (CPS II) is the regulatory enzyme of pyrimidine synthesis in animals.  It is activated by PRPP and ATP & inhibited by UDP & UTP.  OMP decarboxylase, inhibited by UMP & CMP, also controls pyrimidine formation.
  • 18.  Textbook of Biochemistry-U Satyanarayana  Textbook of Biochemistry-DM Vasudevan