M. Sassanfar et al., A EUBACTERIAL MYCOBACTERIUM-TUBERCULOSIS TRANSFER-RNA SYNTHETASE IS EUKARYOTE-LIKE AND RESISTANT TO A EUBACTERIAL-SPECIFIC ANTISYNTHETASE DRUG, Biochemistry, 35(31), 1996, pp. 9995-10003
We report here the cloning and primary structure of Mycobacterium tube
rculosis isoleucyl-tRNA synthetase. The predicted 1035-amino acid prot
ein is significantly more similar in sequence to eukaryote cytoplasmic
than to other eubacterial isoleucyl-tRNA synthetases. This similarity
correlates with the enzyme being resistant to pseudomonic acid A, a p
otent inhibitor of Escherichia coli and other eubacterial isoleucyl-tR
NA synthetases, but not of eukaryote cytoplasmic enzymes. Consistent w
ith its eukaryote-like features, and unlike E. coli isoleucyl-tRNA syn
thetase, the M. tuberculosis enzyme charged yeast isoleucine tRNA. In
spite of these eukaryote-like features, M. tuberculosis isoleucyl-tRNA
synthetase exhibited highly specific cross-species aminoacylation, as
demonstrated by its ability to complement isoleucyl-tRNA synthetase-d
eficient mutants of E. coli. When introduced into a pseudomonic acid-s
ensitive wild-type strain of E. coli, the M. tuberculosis enzyme confe
rred trans-dominant resistance to the drug. The results demonstrate th
at the sequence of a tRNA synthetase could have predictive value with
respect to the interaction of that synthetase with a specific inhibito
r. The results also demonstrate that mobilization of a pathogen's gene
for a drug-resistant protein target can spread resistance to other, n
ormally drug-sensitive pathogens infecting the same host.