pncB1 and
pncB2 are two putative nicotinic acid phosphoribosyltransferases, playing a role in cofactor salvage and drug resistance in
Mycobacterium tuberculosis. Mutations have been reported in first- and second-line drug targets, causing resistance. However,
pncB1 and
pncB2 mutational data are not available,
[...] Read more.
pncB1 and
pncB2 are two putative nicotinic acid phosphoribosyltransferases, playing a role in cofactor salvage and drug resistance in
Mycobacterium tuberculosis. Mutations have been reported in first- and second-line drug targets, causing resistance. However,
pncB1 and
pncB2 mutational data are not available, and neither of their mutation effects have been investigated in protein structures. The current study has been designed to investigate mutations and also their effects on
pncB1 and
pncB2 structures. A total of 287 whole-genome sequenced data of drug-resistant
Mycobacterium tuberculosis isolates from Khyber Pakhtunkhwa of Pakistan were retrieved (BioSample PRJEB32684, ERR2510337-ERR2510445, ERR2510546-ERR2510645) from NCBI. The genomic data were analyzed for
pncB1 and
pncB2 mutations using PhyResSE. All the samples harbored numerous synonymous and non-synonymous mutations in
pncB1 and
pncB2 except one. Mutations Pro447Ser, Arg286Arg, Gly127Ser, and delTCAGGCCG1499213>1499220 in
pncB1 are novel and have not been reported in literature and TB databases. The most common non-synonymous mutations exhibited stabilizing effects on the
pncB1 structure. Moreover, 36 out of 287 samples harbored two non-synonymous and 34 synonymous mutations in
pncB2 among which the most common was Phe204Phe (TTT/TTC), present in 8 samples, which may have an important effect on the usage of specific codons that may increase the gene expression level or protein folding effect. Mutations Ser120Leu and Pro447Ser, which are present in the loop region, exhibited a gain in flexibility in the surrounding residues while Gly429Ala and Gly127Ser also demonstrated stabilizing effects on the protein structure. Inhibitors designed based on the most common
pncB1 and
pncB2 mutants may be a more useful strategy in high-burden countries. More studies are needed to elucidate the effect of synonymous mutations on organism phenotype.
Full article