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Synthesis of Purine Ribonucleotides

Introduction
Nucleotides play a variety of important roles in all cells. They are the activated precursors of DNA and RNA. ATP, an adenine nucleotide, is a universal currency of energy in biological systems. GTP is an essential carrier of chemical energy. Adenine nucleotides are components of the coenzymes NAD+, NADP+, FMN, FAD and Coenzyme A. UDP-Glucose in Glycogen synthesis and CDP-diacylglycerol in Phosphoglyceride synthesis are the nucleotide derivatives that act as activated intermediates. Cyclic AMP is a ubiquitous mediator for the action of many hormones. All cells can synthesize nucleotides from simple building blocks (de novo synthesis) or by the recycling of pre-formed bases (Salvage pathway). Nucleotides are phosphate esters of pentoses in which a nitrogenous base is linked to C1’ of the sugar residue. A nucleotide without the phosphate group is known as a nucleoside. The major purine components of nucleic acids are adenine and guanine residues. The major pyrimidine residues are those of Cytosine, Uracil and Thymine. Pyrimidines are bound to ribose through N 1 atoms.

Synthesis of Pyrimidine Ribonucleotides

Formation of deoxyribonucleotides
Ribonucleotide reductase catalyzes the synthesis of deoxyribonucleotide. The reductant is NADPH. Thioredoxin transfers electrons from NADPH for reduction of 2’-OH of ribose. dTMP is formed by thymidylate synthase by methylation of deoxy uridine monophosphate.

There are 4 purines and 4pyrimidines that are of concern to us.

We can both synthesize them de novo andsalvage and reuse those we already have.

Relatively low levels ofnucleotides result in decreased inhibition of de novo synthesis, resulting infurther overload of the non-functioning salvage pathway and increased uric acidproduction.

Carbamoyl phosphate utilizedin pyrimidine nucleotide synthesis differs from that synthesized in the ureacycle; it is synthesized from glutamine instead of ammonia and is synthesizedin the cytosol.

synthesis of purines is most active in liver.

Pyrimidine synthesis occursin a variety of tissues.

In the next step, the first reaction unique to purine biosynthesis, the enzyme phosphoribosyl pyrophosphate amidotransferase (Ppat) replaces the pyrophosphate moiety of PRPP with the amide nitrogen of glutamine, purine N9, to form PRA.

Synthesis of purine ribonucleotides
IMP is synthesized from ribose 5-phosphate. There are 11 reactions in the formation of IMP. IMP is converted to GMP and AMP with the help of ATP and GTP respectively. Nucleoside monophosphates are converted to nucleoside diphosphates by base specific monophosphate kinases. Purine nucleotide synthesis is regulated by feedback inhibitor – AMP, GMP and IMP. An important regulatory factor is the availability of PRPP. Salvage pathway for purines is observed in RBC and the brain. Free purines are salvaged by APRTase and HGPRTase enzymes

Synthesis of pyrimidine ribonucleotides
Pyrimidine ring is synthesized as free pyrimidine and then it is incorporated into the nucleotide. 6 reactions are involved in the synthesis of UMP. UDP and UTP are synthesized from UMP with the help of ATP. CTP is formed by adding an amino group from glutamine. Pyrimidine can also be salvaged using PRPP. In orotic aciduria, excretion of large amount of orotic acid is observed. It results from the deficiency of either orotate phospho ribosyl transferase or OMP decarboxylase.

We end with a discussion of chemotherapeuticagentsthat affect nucleotide synthesis.
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Purine and Pyrimidine Metabolism - EHSL

The names of purine nucleosides end in -osineand the names of pyrimidine nucleosides end in -idine. Theconvention is to number the ring atoms of the base normally and to use l', etc.

The Synthesis and Degradation of Nucleotides

Catabolism of purinesand pyrimidines occurs in a less useful fashion than did the catabolism ofamino acids in that we do not derive any significant amount of energy from thecatabolism of purines and pyrimidines.

BIOCHEM-- Purines and Pyrimidines Flashcards | Quizlet

Pyrimidine catabolism, however, doesproduce beta-alanine, and the endproduct of purine catabolism, which is uricacid in man, may serve as a scavenger of reactive oxygen species.

BIOCHEM-- Purines and Pyrimidines

Hypoxanthine andxanthine are not incorporated into the nucleic acids as they are beingsynthesized but are important intermediates in the synthesis and degradation ofthe purine nucleotides.

start of the purine synthesis pathway ..

Indeed, the ability to salvage nucleotides fromsources within the body alleviates any nutritional requirement for nucleotides,thus the purine and pyrimidine bases are not required in the diet.

De novo and salvage pathway of purines - SlideShare

For purines, especially, non-hepatic tissues relyheavily on preformed bases - those salvaged from their own intracellularturnover supplemented by bases synthesized in the liver and delivered totissues via the blood.

de novo and salvage pathway of purines ..

First, thereis evidence, especially in the de novo purine pathway, that the enzymes arepresent as large, multienzyme complexes in the cell, a recurring theme in ourdiscussion of metabolism.

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