Nucleic acid metabolism

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Nucleic acid metabolism includes all the processes by which nucleotides are synthesized and degraded.

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Synthesis

Purine ribonucleotides

By using a variety of isotopically labeled compounds it was demonstrated that N1 of purines arises from the amine group of Asp; C2 and C8 originate from formate; N3 and N9 are contributed by the amide group of Gln; C4, C5 and N7 are derived from Gly; and C6 comes from HCO3- (CO2).

The de novo synthesis of purine nucleotides by which these precursors are incorporated into the purine ring, proceeds by a 10 step pathway to the branch point intermediate IMP, the nucleotide of the base hypoxanthine. AMP and GMP are subsequently synthesized from this intermediate via separate, two step each, pathways. Thus purine moieties are initially formed as part of the ribonucleotides rather than as free bases. Six enzymes take part in IMP synthesis. Three of them are multifunctional - GART (reactions 2, 3, and 5), PAICS (reactions 6, and 7) and ATIC (reactions 9, and 10).

Reaction 1. The pathway starts with the formation of PRPP. PRPS1 is the enzyme that activates R5P, which is primarily formed by the pentose phosphate pathway, to PRPP by reacting it with ATP. The reaction is unusual in that a pyrophosphoryl group is directly transferred from ATP to C1 of R5P and that the product has the α configuration about C1. This reaction is also shared with the pathways for the synthesis of the pyrimidine nucleotides, Trp, and His. As a result of being on (a) such (a) major metabolic crossroad and the use of energy, this reaction is highly regulated.

Reaction 2. In the first reaction unique to purine nucleotide biosynthesis, PPAT catalyzes the displacement of PRPP's pyrophosphate group (PPi) by Gln's amide nitrogen. The reaction occurs with the inversion of configuration about ribose C1, thereby forming β-5-phosphorybosylamine (5-PRA) and establishsing the anomeric form of the future nucleotide. This reaction which is driven to completion by the subsequent hydrolysis of the released PPi, is the pathway's flux generating step and is therefore regulated too.

Reaction 3.


Pyrimidine ribonucleotides