Lecture Notes on Nucleotide Metabolism, Lecture notes of Chemistry

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Nucleotide Metabolism

Contents

 Introduction

 Bases, nucleosides and nucleotides

 Metabolism

 Processes involved in nucleotides biosynthesis

 Biosynthesis of purine nucleotides

 Biosynthesis of pyrimidine nucleotides

 Catabolism of Purines

 Catabolism of Pyrimidines

 Conclusions

Bases, Nucleosides and Nucleotides

Bases, Nucleosides and Nucleotides

• Ingested nucleic acids and nucleotides, which are dietarily nonessential, are degraded in the intestinal tract to mononucleotides, which may be absorbed or converted to purine and pyrimidine bases.

Process involved in nucleotides biosynthesis

These are, in order of decreasing importance

(1) Synthesis from amphibolic intermediates (synthesis de novo).

(2) Phosphoribosylation of purines (3) Phosphorylation of purine nucleosides.

Biosynthesis of purine nucleotides

 Conversion of purines, their ribonucleosides, and their deoxyribonucleosides to mononucleotides involves so called “salvage reaction.

 Liver is the major site for purine nucleotide synthesis.

 Erythrocytes, polymorphonuclear leukocytes and brain cannot produce purines.  Folic acid is essential for the synthesis of purine nucleotides. Folic (methotrexate) are employed to control cancer.

Biosynthesis Of Pyrimidine Nucleotides

 The catalyst for the initial reaction is cytosolic carbamoyl phosphate synthase II, a different enzyme from the mitochondrial carbamoyl phosphate synthase I of urea synthesis.

 Compartmentation thus provides two independent pools of carbamoyl phosphate. PRPP, an early participant in purine nucleotide synthesis, is a much later participant in pyrimidine biosynthesis.

 Mammalian cells reutilize few free pyrimidines, “salvage reactions” convert the ribonucleosides uridine and cytidine and the deoxyribonucleosides thymidine and deoxycytidine to their respective nucleotides.

 ATP dependent phosphoryltransferases (kinases) catalyze the phosphorylation of the nucleoside diphosphates 2′-deoxycytidine, 2′-deoxyguanosine, and 2′- deoxyadenosine to their corresponding nucleoside triphosphates.

 In addition, orotate phosphoribosyltransferase, an enzyme of pyrimidine nucleotide synthesis, salvages orotic acid by converting it to orotidine monophosphate (OMP).

 Antifolate drugs and glutamine analogs inhibit purine biosynthesis.

Catabolism of purines

Humans convert adenosine and guanosine to uric acid.

Adenosine is first converted to inosine by adenosine deaminase.

In mammals other than higher primates, uricase converts uric acid to the watersoluble product allantoin.

Since humans lack uricase, the end product of purine catabolism in humans is uric acid.

Degradation of uric acid in animals other

than man

Conclusions

 Coordinated regulation of purine and pyrimidine nucleotide biosynthesis ensures their presence in proportions appropriate for nucleic acid biosynthesis and other metabolic needs.

 Pyrimidine nucleotides are synthesized from the precursors aspartate, glutamine and CO 2 , besides ribose 5-phosphate.

 Pyrimidines are degraded to amino acids, nomely β alanine and β aminoisobutyrote which are then metabolized