Histidyl-tRNA synthetase

Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histid yl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes. A compilation of currently known primary structures of HisRS shows that the subunits of these homodimeric enzymes consist of 420-550 amino acid residu es. This represents a relatively short chain length among aminoacyl-tRNA sy nthetases (aaRS), whose peptide chain sizes range from about 300 to 1100 am ino acid residues. The crystal structures of HisRS from two organisms and their complexes with histidine, histidyl-adenylate and histidinol with ATP have been solved. Hi sRS from Escherichia coli and Thermus thermophilus are very similar dimeric enzymes consisting of three domains: the N-terminal catalytic domain conta ining the six-stranded antiparallel beta-sheet and the three motifs charact eristic of class II aaRS, a HisRS-specific helical domain inserted between motifs 2 and 3 that may contact the acceptor stem of the tRNA, and a C-term inal alpha/beta domain that may be involved in the recognition of the antic odon stem and loop of tRNA(His). The aminoacylation reaction follows the standard two-step mechanism. HisRS also belongs to the group of aaRS that can rapidly synthesize diadenosine t etraphosphate, a compound that is suspected to be involved in several regul atory mechanisms of cell metabolism. Many analogs of histidine have been te sted for their properties as substrates or inhibitors of HisRS, leading to the elucidation of structure-activity relationships concerning configuratio n, importance of the carboxy and amino group, and the nature of the side ch ain. HisRS has been found to act as a particularly important antigen in autoimmu ne diseases such as rheumatic arthritis or myositis. Successful attempts ha ve been made to identify epitopes responsible for the complexation with suc h auto-antibodies.