<p>The aminoacyl-tRNA synthetases (<db_xref db="EC" dbkey="6.1.1."/>) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction. These proteins differ widely in size and oligomeric state, and have limited sequence homology [<cite idref="PUB00007191"/>]. The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric [<cite idref="PUB00006477"/>]. Class II aminoacyl-tRNA synthetases share an anti-parallel beta-sheet fold flanked by alpha-helices [<cite idref="PUB00000386"/>], and are mostly dimeric or multimeric, containing at least three conserved regions [<cite idref="PUB00000723"/>, <cite idref="PUB00005365"/>, <cite idref="PUB00004391"/>]. However, tRNA binding involves an alpha-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan and valine belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, lysine, phenylalanine, proline, serine, and threonine belong to class-II synthetases [<cite idref="PUB00015156"/>]. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c.</p><p>Histidyl-tRNA synthetase (<db_xref db="EC" dbkey="6.1.1.21"/>) is an alpha2 dimer that belongs to class IIa. Every completed genome includes a histidyl-tRNA synthetase. Apparent second copies from <taxon tax_id="1423">Bacillus subtilis</taxon>, <taxon tax_id="1148">Synechocystis sp.</taxon> (strain PCC 6803), and <taxon tax_id="63363">Aquifex aeolicus</taxon> are slightly shorter, more closely related to each other than to other hisS proteins, and not demonstrated to act as histidyl-tRNA synthetases (see <db_xref db="INTERPRO" dbkey="IPR004517"/>). Theregulatory protein kinase GCN2 of <taxon tax_id="4932">Saccharomyces cerevisiae</taxon> (YDR283c), and related proteins from other species designated eIF-2 alpha kinase, have a domain closely related to histidyl-tRNA synthetase that may serve to detect and respond to uncharged tRNA(his), an indicator of amino acid starvation, but these regulatory proteins are not orthologous.</p>