The role of arylamine N-acetyltransferase 1 (NAT1) in the clinical therapy of tuberculosis

Abstract

Despite attempts to develop new drugs to reduce the worldwide mortality rate attributable to tuberculosis (TB), the illness remains a threat. Isoniazid (INH) has been used as a frontline drug for decades. However, several resistant strains of the organism - Mycobacterium tuberculosis (M. tuberculosis) - still emerge. The drug is mainly metabolised by a family of enzymes, arylamine N-acetyltransferases (NAT). The three human NAT genes - NAT1, NAT2 and the pseudogene, NATP - are found on chromosome 18p22. NAT1 and NAT2 are isoenzymes which differ at certain amino acid positions. Subsequently, the differences affect substrate specificity. NAT1 shows specificity to p-aminobenzoic acid (PABA) and paminosalicylate (PAS). Previously, computer algorithms were used to predict the efficacy of the enzyme with regard to the acetylation phenotype it confers. The two which were focused on, Sorting Intolerant From Tolerant (SIFT) program and Polymorphism phenotyping version 2 program (PolyPhen-2), showed conflicting results for the effect of SNPs on the acetylation rate and subsequent enzyme function. Further structural prediction methods were used to test the effect of V231G on the structure and consequent function of the native protein, NAT1.