3-Methylhistidine, also known as 3-MHis, 3MH, pi-methylhistidine or pros-methylhistidine, belongs to the class of organic compounds known as histidine and derivatives. 3MH is also classified as a methylamino acid. Methylamino acids are primarily proteogenic amino acids (found in proteins) which have been methylated (in situ) on their side chains by various methyltransferase enzymes. Histidine can be methylated at either the N1 or N3 position of its imidazole ring, yielding the isomers 1-methylhistidine (1MH; also referred to as tau-methylhistidine, according to IUPAC) or 3-methylhistidine (3MH; pi-methylhistidine, according to IUPAC), respectively. There is considerable confusion with regard to the nomenclature of the methylated nitrogen atoms on the imidazole ring of histidine in histidine-containing proteins (such as actin and myosin) as well as histidine-containing peptides (such as anserine and ophidine/balenine). In particular, older literature (mostly prior to the year 2000) as well as most biochemists and nutrition scientists incorrectly number the imidazole nitrogen atom most proximal to the side chain beta-carbon as 1 or N1, while organic chemists correctly designate it as 3 or N3. As a result, biochemists and nutrition scientists historically designated anserine (Npi-methylated) as beta-alanyl-N1-methylhistidine (or beta-alanyl-1-methylhistidine), whereas according to standard IUPAC nomenclature, anserine is correctly named as beta-alanyl-N3-methylhistidine. As a result, for several decades, many papers incorrectly identified 1MH as a specific marker for dietary consumption or various pathophysiological effects when they really are referring to 3MH – and vice versa. 3MH can only be generated from histidine residues through the action of methyltransferases as a protein post-translational modification event. Histidine methylation on the 3- or pi site of histidine-containing proteins is mediated by only one known enzyme – METTL9. Recent discoveries have shown that 3MH is produced in essentially all vertebrates via the methyltransferase enzyme known as METTL9. METTL9 is a broad-specificity S-adenosylmethionine-mediated methyltransferase that mediates the formation of the majority of 3MH present in mammalian and other vertebrate proteomes. Because of its abundance in some muscle-related proteins but especially because of the high abundance of anserine found in poultry and fish, 3MH has been found to be a good biomarker for the consumption of meat. Dietary studies have shown that general poultry consumption (p-trend = 0.0006) and especially chicken consumption (p-trend = 0.0003) are associated with increased levels of 3MH in human plasma. 3‐MH is synthesized only in the muscle by the methylation of one histidine residue in actin and in varying amounts in myosin depending on the type of muscle. Thus, muscle protein degradation is the only endogenous source of 3‐MH in human plasma. 3‐MH might be a helpful biomarker in the assessment of muscle protein turnover, which is important in the diagnosis of frailty and sarcopenia.

Metabolism and Physiological Effects of 3-Methylhistidine References