biostudies-literatureHunter TNational Cancer InstituteNCI NIH HHSNIH2190-2200https://www.ebi.ac.uk/biostudies/studies/S-EPMC9219344biostudies-literatureUnknown82(12)Protein phosphorylation is a reversible post-translational modification. Nine of the 20 natural amino acids in proteins can be phosphorylated, but most of what we know about the roles of protein phosphorylation has come from studies of serine, threonine, and tyrosine phosphorylation. Much less is understood about the phosphorylation of histidine, lysine, arginine, cysteine, aspartate, and glutamate, so-called non-canonical phosphorylations. Phosphohistidine (pHis) was discovered 60 years ago as a mitochondrial enzyme intermediate; since then, evidence for the existence of histidine kinases and phosphohistidine phosphatases has emerged, together with examples where protein function is regulated by reversible histidine phosphorylation. pHis is chemically unstable and has thus been challenginMolecular cellA journey from phosphotyrosine to phosphohistidine and beyond.PMC9219344P30 CA014195CA242443R35 CA242443Hunter TfalseA journey from phosphotyrosine to phosphohistidine and beyond.Protein phosphorylation is a reversible post-translational modification. Nine of the 20 natural amino acids in proteins can be phosphorylated, but most of what we know about the roles of protein phosphorylation has come from studies of serine, threonine, and tyrosine phosphorylation. Much less is understood about the phosphorylation of histidine, lysine, arginine, cysteine, aspartate, and glutamate, so-called non-canonical phosphorylations. Phosphohistidine (pHis) was discovered 60 years ago as a mitochondrial enzyme intermediate; since then, evidence for the existence of histidine kinases and phosphohistidine phosphatases has emerged, together with examples where protein function is regulated by reversible histidine phosphorylation. pHis is chemically unstable and has thus been challengin2022-01-01T00:00:00Z2022 Jun2026-05-09T14:02:52.522Z2025-04-06T22:00:14.134ZS-EPMC92193443565404310.1016/j.molcel.2022.05.007