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Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ 07103
3To whom correspondence should be addressed. E-mail: jakubows{at}umdnj.edu
Aminoacyl-tRNA synthetases establish the rules of the genetic code by matching amino acids (AA) with their cognate tRNA. When differences in binding energies of AA to an aminoacyl-tRNA synthetase are inadequate, editing is used as a major determinant of the enzyme selectivity. Metabolic conversion of the nonprotein AA homocysteine (Hcy) to the thioester Hcy thiolactone by methionyl-, isoleucyl-, and leucyl-tRNA synthetases in vivo shows that continuous editing of incorrect AA is part of the process of tRNA aminoacylation in living organisms, including humans. Reversible S-nitrosylation of Hcy prevents its editing by methionyl-tRNA synthetase and allows incorporation of Hcy into proteins at positions specified by methionine codons. This illustrates how the genetic code can be expanded by invasion of the metionine-coding pathway by Hcy. Translational (nitric oxide-mediated) and post-translational (thiolactone-mediated) incorporation of Hcy into protein provide plausible chemical mechanisms by which elevated levels of Hcy may contribute to the pathology of human cardiovascular diseases.
KEY WORDS: translational editing S-nitroso-homocysteine homocysteine thiolactonase protein N-homocysteinylation atherosclerosis
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