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The king of biocatalysis. This amino acid is the most costly when it comes to metabolic biosynthesis. Yet, it is worth the investments. The acid-base transition for the imidazole side chain occurs at the pH close to neutral values, and due to this fact, His residue is very common in catalytic triades. Proteases, lipases and many other enzymes require His for proton shuttling during the catalytic cycle.

Other important function of this side chain is ‘soft’ metal coordination, for instance, heme coordination usually involves either Met sulfur of His imidazole as an axial ligand, while the other axial position is available for catalysis. The metal coordination feature is also exploited in so-called histidine tags, a bunch of consecutive His residues for affinity chromatography on nickel (II) based stationary phase.

Interesting readings:

- Beiboer, S. H. W. et al. Incorporation of an unnatural amino acid in the active site of porcine pancreatic phospholipase A2. Substitution of histidine by l,2,4-triazole-3-alanine yields an enzyme with high activity at acidic pH. Protein Eng., 9, 1996, 345-352, doi: 10.1093/protein/9.4.345

The title speaks by itself. In comparison to imidazole, triazole has a different protonation profile, thus allowing the shift of the pH optimum to a different pH value in porcine pancreas phospholipase A2

- Xiao, H. et al. Genetic Incorporation of Histidine Derivatives Using an Engineered Pyrrolysyl-tRNA Synthetase. ACS Chem. Biol., 9, 2014, 1092-1096, doi: 10.1021/cb500032c

In this paper, they develop an orthogonal pair to incorporate various histidine derivatives into proteins.

- Green, A. P. et al. A Chemically Programmed Proximal Ligand Enhances the Catalytic Properties of a Heme Enzyme. J. Am. Chem. Soc., 138, 2016, 11344-11352, doi: 10.1021/jacs.6b07029

The paper is concerned with the reasons for the Asp-His placement below the heme cofactor in a peroxidase enzyme. The authors replaced the histidine with N-methyl histidine, and found that the enzyme performs even better than before. This spectacular finding is very well explained in the discussion section.