Nucleic Acid Metabolism

The first part of this chapter reviews the biosynthesis, salvage, and interconversion of purine and pyrimidine ribonucleotides; the biosynthesis of deoxyribonucleotides; and the biosynthesis and function of (p)ppGpp in Mycobacterium tuberculosis. The second part reviews the processes of DNA replication, repair, and mutagenesis in the context of the mechanisms of genome evolution, pathogenesis, and the development of drug resistance in Mycobacterium tuberculosis. The genome sequence of M. tuberculosis confirmed that the de novo synthesis of purines is mediated by the same highly conserved pathways seen in other bacteria. Purine nucleotide phosphorylase catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and deoxynucleosides. Ribonucleotide reductase (RNR), the two-subunit enzyme that catalyzes the reduction of nucleoside diphosphates to deoxynucleoside diphosphates, is responsible for the first committed step in DNA synthesis. This step is the rate-limiting step for replicating the genome and thus is an ideal candidate for drug targeting. All drug resistance in M. tuberculosis is mediated by the introduction of mutations in chromosomal genes, a significant proportion of which correspond to base substitution and frameshift mutations. Whole-genome expression profiling has provided exciting insights into the global response of M. tuberculosis to DNA damage. The development of increasingly powerful technologies for exploring protein function, structure, and expression in M. tuberculosis has led to a quantum leap in understanding nucleic acid metabolism in this organism.