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Nonorthologous replacement of lysyl-tRNA synthetase prevents addition of lysine analogues to the genetic code.

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Insertion of lysine during protein synthesis depends on the enzyme lysyl-tRNA synthetase (LysRS), which exists in two unrelated forms, LysRS1 and LysRS2. LysRS1 has been found in most archaea and some bacteria, and LysRS2 has been found in eukarya, most bacteria, and a few archaea, but the two proteins are almost never found together in a single organism. Comparison of structures of LysRS1 and LysRS2 complexed with lysine suggested significant differences in their potential to bind lysine analogues with backbone replacements. One such naturally occurring compound, the metabolic intermediate S-(2-aminoethyl)-L-cysteine, is a bactericidal agent incorporated during protein synthesis via LysRS2. In vitro tests showed that S-(2-aminoethyl)-L-cysteine is a poor substrate for LysRS1, and that it inhibits LysRS1 200-fold less effectively than it inhibits LysRS2. In vivo inhibition by S-(2-aminoethyl)-L-cysteine was investigated by replacing the endogenous LysRS2 of Bacillus subtilis with LysRS1 from the
Lyme disease pathogen Borrelia burgdorferi. B. subtilis strains producing LysRS1 alone were relatively insensitive to growth inhibition by S-(2-aminoethyl)-L-cysteine, whereas a WT strain or merodiploid strains producing both LysRS1 and LysRS2 showed significant growth inhibition under the same conditions. These growth effects arising from differences in amino acid recognition could contribute to the distribution of LysRS1 and LysRS2 in different organisms. More broadly, these data demonstrate how diversity of the aminoacyl-tRNA synthetases prevents infiltration of the genetic code by noncanonical amino acids, thereby providing a natural reservoir of potential antibiotic resistance.

Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14351-6. Epub 2003 Nov 17. Comparative Study; Research Support, Non-U.S. Gov’t; Research Support, U.S. Gov’t, P.H.S.

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