Protein methionine and histidine residues

Protein methionine and histidine residues are specific amino acid side chains that play vital roles in protein structure, catalysis, and regulation. Methionine is a sulfur-containing amino acid that acts as a potent antioxidant by undergoing reversible oxidation to methionine sulfoxide, a process regulated by methionine sulfoxide reductases (MSRs) and involved in redox signaling (Vogt, 1995, Free Radic Biol Med; nih.gov). Histidine contains an imidazole side chain that is frequently found in enzyme active sites, where it participates in acid-base catalysis and coordinates essential metal ions such as zinc and copper (Che and Jones, 2022, RSC Med. Chem.). While these residues are not individual therapeutic targets, they serve as critical sites for the action of various drugs, including metal-based chemotherapeutics like cisplatin, which forms coordination complexes with both methionine and histidine (ResearchGate). Additionally, emerging covalent drug discovery efforts utilize electrophilic warheads to selectively target these residues in specific protein pockets to achieve irreversible inhibition (ACS Publications, 2026). For example, fumagillin and its derivatives target a specific histidine residue in methionine aminopeptidase 2 (MetAP2) to inhibit angiogenesis (ResearchGate). The broad distribution of these residues across the proteome poses significant challenges for drug selectivity and can lead to off-target toxicities (Levine et al., 1996, NIH).

Other names

Methionine and histidine side chainsMet and His residuesProtein-bound methionine and histidine

Covalent modification or coordination complex formation with the thioether group of methionine or the imidazole ring of histidine residues to modulate protein function or facilitate drug transport.