Record Information
Version1.0
Creation date2011-04-08 19:51:03 UTC
Update date2021-12-06 18:12:33 UTC
Primary IDFDB021798
Secondary Accession NumbersNot Available
Chemical Information
FooDB Name3-Methyl-L-histidine
Description3-Methyl-L-histidine, also known as 3-methylhistidine, 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 (PMID: 24137022 ). To help resolve this issue the IUPAC commission (PMID: 6743224 and IUPAC Compendium of Chemical Terminology, 2nd ed. (the "Gold Book"). Compiled by A. D. McNaught and A. Wilkinson. Blackwell Scientific Publications, Oxford (1997)) revised the nomenclature for histidine and introduced the terms pi (for prox or pros – near) and tau (for tele – far) to label the imidazole nitrogens in histidine. Therefore, the pi nitrogen is the nitrogen closest to the side chain beta carbon (atom #3 or N3) while the tau nitrogen is most distant from the side chain beta carbon (atom #1 or N1). IUPAC’s goal is for the global community to refer to the molecule depicted here is as “pi-methylhistidine” with the hope that the archaic term, 3-methylhistidine will eventually disappear. Unfortunately, this has not happened and confusion still persists. Older versions of the HMDB (prior to 2021) as well as current versions of PubChem, KEGG, UniProt and ChEBI indicate that an acceptable synonym for 3MH is tau-methylhistidine. This is incorrect and it continues to sow confusion. Indeed, a key paper that identified METTL18 as the enzyme responsible for tau-methylation of histidine incorrectly labelled the METTL18 product as 3MH (PMID: 33693809). Likewise, many members of the biochemical/nutrition community still incorrectly refer to 1MH as pi-methlyhistidine and 3MH as tau-methylhistidine. This has led to even more confusion. To maintain consistency for this compound description, all papers cited herein that incorrectly refer to 3MH as 1MH and vice versa, will have their conclusions re-stated and the citation will be marked with the phrase “3MH/1MH switch”. 3MH is a free amino acid arising from the proteolysis of 3MH-containing proteins and peptides. It is not synthesized on its own, nor can it be incorporated into proteins as an amino acid. However, it can be incorporated into certain dipeptides through the action of the enzyme known as Carnosine synthase I. 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 enzyme – METTL9. Recent discoveries have shown that 3MH is produced in essentially all vertebrates via the methyltransferase enzyme known as METTL9 (3MH/1MH switch - PMID: 33563959 ). 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. METTL9-catalyzed methylation requires a His-x-His (HxH) motif, where "x" is a small amino acid consisting of A, N, G, S or T. This H[ANGST]H or HxH motif is found in a number of abundant mammalian proteins such as ARMC6, S100A9, and NDUFB3 (PMID: 33563959 ). In addition to these pi-His-methylated proteins, a specialized dipeptide called anserine (called beta-alanyl-3-methyl-L-histidine) that consists of beta-alanine and 3MH is also known and particularly well studied (PMID: 24137022). This methylated analog of carnosine, which is naturally produced in the liver via the enzyme Carnosine synthase I (PMID: 20097752), is especially abundant in the skeletal muscles and brains of mammals, birds and fish (PMID: 24137022 ). Anserine, like its homologs ophidine and carnosine, is believed to act as a pH buffer (for lactic acid generated by muscles), an antiglycating agent and an antioxidant. Neither ophidine nor anserine are produced in humans, with humans being the only vertebrate not producing methylated histidine versions of carnosine (PMID: 24137022 ). 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 (PMID: 21527577 ). 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 (PMID: 30018457 ). The consumption of fish, especially salmon and cod, has also been shown to increase the levels of 3MH in serum and urine (3MH/1MH switch PMID: 31401679 ). As a general rule, urinary 3MH is associated with white meat intake (p< 0.001), whereas urinary 1MH is associated with red meat intake (p< 0.001) (3MH/1MH switch - PMID: 34091671).
CAS Number368-16-1
Structure
Thumb
Synonyms
SynonymSource
3-Methyl-DL-histidineChEBI
2-amino-3-(3-Methylimidazol-4-yl)propanoateGenerator
(2S)-2-amino-3-(1-Methyl-1H-imidazol-5-yl)propanoateGenerator
(2S)-2-amino-3-(1-Methyl-1H-imidazol-5-yl)propanoic acidChEBI
3-MethylhistidineChEBI
3-N-Methyl-L-histidineHMDB
L-3-MethylhistidineHMDB
N-pros-Methyl-L-histidineChEBI
N(Pai)-methyl-L-histidineChEBI
N(pros)-Methyl-L-histidineHMDB
N3-Methyl-L-histidineHMDB
Pi-methyl-L-histidineHMDB
Tau-methyl-L-histidineHMDB
Tau-methylhistidineHMDB
Predicted Properties
PropertyValueSource
Water Solubility6.93 g/LALOGPS
logP-2.9ALOGPS
logP-3.4ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)1.96ChemAxon
pKa (Strongest Basic)9.43ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area81.14 ŲChemAxon
Rotatable Bond Count3ChemAxon
Refractivity42.96 m³·mol⁻¹ChemAxon
Polarizability16.75 ųChemAxon
Number of Rings1ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Chemical FormulaC7H11N3O2
IUPAC name2-amino-3-(1-methyl-1H-imidazol-5-yl)propanoic acid
InChI IdentifierInChI=1S/C7H11N3O2/c1-10-4-9-3-5(10)2-6(8)7(11)12/h3-4,6H,2,8H2,1H3,(H,11,12)
InChI KeyJDHILDINMRGULE-UHFFFAOYSA-N
Isomeric SMILESCN1C=NC=C1CC(N)C(O)=O
Average Molecular Weight169.1811
Monoisotopic Molecular Weight169.085126611
Classification
Description Belongs to the class of organic compounds known as histidine and derivatives. Histidine and derivatives are compounds containing cysteine or a derivative thereof resulting from reaction of cysteine at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.
KingdomOrganic compounds
Super ClassOrganic acids and derivatives
ClassCarboxylic acids and derivatives
Sub ClassAmino acids, peptides, and analogues
Direct ParentHistidine and derivatives
Alternative Parents
Substituents
  • Histidine or derivatives
  • Alpha-amino acid
  • Imidazolyl carboxylic acid derivative
  • Aralkylamine
  • N-substituted imidazole
  • Azole
  • Imidazole
  • Heteroaromatic compound
  • Amino acid
  • Carboxylic acid
  • Azacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Organic nitrogen compound
  • Organonitrogen compound
  • Organooxygen compound
  • Primary amine
  • Primary aliphatic amine
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Carbonyl group
  • Organic oxygen compound
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Ontology
OntologyNo ontology term
Physico-Chemical Properties - Experimental
Physico-Chemical Properties - Experimental
PropertyValueReference
Physical stateSolid
Physical DescriptionNot Available
Mass CompositionNot Available
Melting PointNot Available
Boiling PointNot Available
Experimental Water SolubilityNot Available
Experimental logPNot Available
Experimental pKaNot Available
Isoelectric pointNot Available
ChargeNot Available
Optical RotationNot Available
Spectroscopic UV DataNot Available
DensityNot Available
Refractive IndexNot Available
Spectra
Spectra
EI-MS/GC-MS
TypeDescriptionSplash KeyView
Predicted GC-MS3-Methyl-L-histidine, non-derivatized, Predicted GC-MS Spectrum - 70eV, Positivesplash10-00dm-9700000000-8ce4a0cee2650fb60b66Spectrum
MS/MS
TypeDescriptionSplash KeyView
Predicted MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-00di-0900000000-bd361de840da1605d6fcSpectrum
Predicted MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-00di-2900000000-25de15c2f0684098ed12Spectrum
Predicted MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-014j-9100000000-714e5609aba4cc3f38b3Spectrum
Predicted MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-0900000000-c1cc6cca72965c95fe8cSpectrum
Predicted MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0gi0-3900000000-02c7e8836e9e4717cc8aSpectrum
Predicted MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-05di-9300000000-6096897a72b87396d2d3Spectrum
NMRNot Available
ChemSpider ID58494
ChEMBL IDNot Available
KEGG Compound IDC01152
Pubchem Compound ID64969
Pubchem Substance IDNot Available
ChEBI IDNot Available
Phenol-Explorer IDNot Available
DrugBank IDNot Available
HMDB IDHMDB00479
CRC / DFC (Dictionary of Food Compounds) IDBDH94-R:BDH95-S
EAFUS IDNot Available
Dr. Duke IDNot Available
BIGG IDNot Available
KNApSAcK IDNot Available
HET IDMHS
Food Biomarker OntologyNot Available
VMH IDNot Available
Flavornet IDNot Available
GoodScent IDNot Available
SuperScent IDNot Available
Wikipedia IDNot Available
Phenol-Explorer Metabolite IDNot Available
Duplicate IDSNot Available
Old DFC IDSNot Available
Associated Foods
FoodContent Range AverageReference
FoodReference
Biological Effects and Interactions
Health Effects / BioactivitiesNot Available
EnzymesNot Available
PathwaysNot Available
MetabolismNot Available
BiosynthesisNot Available
Organoleptic Properties
FlavoursNot Available
Files
MSDSshow
References
Synthesis ReferenceNot Available
General ReferenceNot Available
Content Reference