Functional consequence of SNPs on the Tuberculosis drug metabolising enzyme, human arylamine N-acetyltransferase 1

The human arylamine N-acetyltransferase 1 (NAT1) plays a vital role in determining the duration of action and pharmacokinetics of amine-containing drugs such as para-aminosalicylic acid used in clinical therapy, as well as influencing the balance between detoxification and metabolic activation of these drugs. Single nucleotide polymorphisms (SNPs) in this enzyme are continuously being detected and show inter-ethnic and inter-individual variation. Administrating tuberculosis (TB) treatment in the absence of genotypic information for drug metabolizing enzymes can limit the successful eradication of the disease from a patient. Recent studies have shown that loss of H-bonds affects protein function.

Results: In this study, the eects of 11 novel non-synonymous SNPs (nsSNPs) on the structure and function of NAT1 was tested computationally using SIFT and POLYPHEN-2 algorithms and structural analyses methods including loss of hydrogen-bonding, stability calculation, solvent accessibility and sequence conservation. Four out of 11 nsSNPs (Q210P, D229H, V231G and V235A) were predicted to aect protein function using both algorithms. Two of these four SNPs showed a loss of 2-4 hydrogen bonds and in most cases a destabilized protein structure. Another two SNPs (F202V, N245I) were predicted to aect protein function using both algorithms but without any loss of hydrogen-bonds. Three additional nsSNPs (T240S, S259R, T193S) were predicted to b