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Pyrimidine Metabolism, Biosynthesis and catabolism
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- 2. PYRIMIDINE INTRODUCTION • Aheterocyclic aromatic compound that presents as a pyrimidine ring, and servesas a component of nucleic acids (e.g.DNA and RNA), certain proteins, starches, etc. • Pyrimidine is a heterocyclic aromatic organic compound.It has a single ring (called a pyrimidine ring) with alternating carbon and nitrogen atoms. The molar mass of pyrimidine is 80.088g/mol and its melting point is at 20-22 °C. • Cytosine, thymine, and uracil are pyrimidine nucleobases. • Cytosine has a chemical formulaof C4H5N3O. • Thymine has a chemical formula of C5H6N2O2. • Uracil is similar to thymine in terms of structure except for the methyl group at position 5 in the heterocyclic aromatic ring present in thymine. It has a chemical formula of C4H4N2O2
- 3. NUCLEOTIDE BIOSYNTHESIS Pathways forthe biosynthesis of nucleotides Nucleotidebiosynthesis in the cell can be groupedinto two broad classes. 1. De novo synthesis 2. Salvage pathways De novo synthesis(synthesis from scratch): it is a biochemical pathway in which nucleotides are synthesized new from simple precursor molecules. Salvage pathways: used to recover bases and nucleosidesformed during the degradation of RNA and DNA.
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- 5. DE NOVO SYNTHESYSOF PYRIMIDINES • Biosynthesisof pyrimidines is simple than that of purines. • Unlike purine synthesis, pyrimidines are synthesizedas bases and later it is added to ribose sugar, i.e.,the ring is completed before being it is linked to ribose-5- phosphate. • Following diagram shows the source of different atoms in a pyrimidine skeletonidentified by radio labelling studies. • N1, C6, C5 AND C4 are derived from aspartate. • N3 is derivedfrom glutamine. • C2 is derived from HCO3-(bicarbonate)
- 6. DE NOVO SYNTHESYSOF UMP UMPIS SYNTHESIZED IN A SERIESOF6 STEPS.
- 7. DE NOVO SYNTHESYSOF UMP Step 1: synthesis of carbamoyl phosphate: With the hydrolysisof two ATPs, bicarbonate and amide nitrogen of glutamine combine to form carbamoyl phosphate.
- 8. DE NOVO SYNTHESYSOF UMP Step 2: synthesis of carbamoyl aspartate: Carbamoyl phosphate reacts with aspartate to yield carbamoyl aspartate.
- 9. DE NOVO SYNTHESYSOF UMP Step 3: Ring closureand dihydroorotate formation: By the elimination reaction, the carbamoyl aspartate is converted to a ring compound dihydroorotate. One moleculeof water is eliminated in this step
- 10. DE NOVO SYNTHESYSOF UMP Step 4: Oxidation of dihydroorotate: Dihydroorotate is dehydrogenatedto form orotate.
- 11. DE NOVO SYNTHESYSOF UMP Step 5: Acquisition of the ribose phosphate moiety: Orotate reacts with PRPP to produce orotidine-5’- monophosphate(OMP)
- 12. DE NOVO SYNTHESYSOF UMP Step 6: Decarboxylation to form UMP: OMP undergoes decarboxylation to form UMP
- 13. DE NOVO SYNTHESYSOF PYRIMIDINES Synthesis of UTP from UMP UMP is converted to UTP in two step kinase reaction with 2 moleculesof ATP. Synthesis of CTP CTP is synthesized by the amination of UTP by the enzyme CTP synthase. In animals amino group is donated by glutamine whereas in bacteria, the amino group is donated directly by ammonia
- 14. DE NOVO SYNTHESYSOF PYRIMIDINES Synthesis of deoxyribonucleotide. Deoxyribonucleotidesare synthesizedfrom their corresponding ribonucleotidesby the reduction of ribose sugar at position C2. enzymesinvolvedin the formation of deoxyribonucleotidesby the reduction of the corresponding ribonucleotidesare called ribonucleotide reductases (RNRs). There are three classes of RNRs so far describedin the living world and they all differ in their prosthetic groups.All of them replace the c2-OH group of ribose with –H via free radical mechanism.
- 15. DE NOVO SYNTHESYSOF PYRIMIDINES Synthesis of dTTP from dUMP • The dUMP is added with CH3 (methyl group) to form dTMP catalysed by the enzyme thymidylate synthetase. • The dTMP is then phosphorylatedin two step reaction forming dTDP and finally dTTP catalysed by kinase enzymeshydrolysingtwo ATPs,
- 16. DE NOVO SYNTHESYSOF PYRIMIDINES Regulation of Pyrimidine synthesis • In bacteria, aspartate transcarbamoylase (ATCase) catalyses a committed step in pyrimidine biosynthesis.ATCase is a good example of an enzyme controlled by feedbackmechanism by the end product of CTP. In certain bacteria, UTP also inhibits ATCase. ATP, however, stimulates ATCase activity. • The second enzyme CTP synthetase is activated by GTP while inhibited by CTP.
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- 18. SALVAGE SYNTHESIS OFPYRIMIDINES
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- 20. DEGRADATION OF PYRIMIDINES •The pyrimidine nucleotides undergo similar reactions (dephosphorylation,deamination and cleavage of glycosidic bond) like that of purine nucleotides to liberate the nitrogenous bases- cytosine, uracil and thymine. • The bases are then degraded to highly solubleproducts- beta alanine and beta aminoisobutyrate. • These are the amino acids which undergo transamination and other reaction to finally produce acetyl CoA and succinyl CoA.
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