Staphylococcus aureus isoleucyl-tRNA synthetase (IleRS) (IleRS)

Staphylococcus aureus isoleucyl-tRNA synthetase (IleRS) is an essential enzyme belonging to the Class I aminoacyl-tRNA synthetase family, responsible for catalyzing the attachment of L-isoleucine to its corresponding tRNA (UniProt: P0A024). This two-step reaction involves the formation of an isoleucyl-adenylate intermediate followed by the transfer of the isoleucyl moiety to the 2'- or 3'-hydroxyl group of the tRNA, a process vital for bacterial protein translation (PubMed: 12142450). As an essential gene for bacterial viability, IleRS serves as a critical target for the antibiotic mupirocin, which is primarily used for the topical treatment of skin infections and the eradication of nasal colonization by methicillin-resistant Staphylococcus aureus (MRSA) (StatPearls: NBK538201). Mupirocin functions as a competitive inhibitor, binding to the enzyme's active site and mimicking the isoleucyl-adenylate intermediate, thereby halting protein synthesis and leading to bacteriostatic or bactericidal effects depending on concentration (PubChem: CID 446596). However, the therapeutic efficacy of targeting IleRS is increasingly threatened by the development of resistance, characterized by either point mutations in the native ileS gene or the acquisition of plasmid-borne mupA or mupB genes encoding alternative, resistant versions of the enzyme (PubMed: 24563512).

Other names

Isoleucine--tRNA ligaseIleSIRSIsoleucyl-tRNA synthetase

Mupirocin competitively inhibits the enzyme by binding to the Rossmann fold active site, mimicking the isoleucyl-adenylate intermediate and preventing the ligation of isoleucine to tRNA, which halts bacterial protein synthesis (PubMed: 19157513).