Histidine (His, H)
Histidine is an aromatic amino acid with an imidazole side chain that can switch between neutral and positively charged near physiological pH. It binds metals and is central to many catalytic and receptor-recognition sites.
Structure and properties
Histidine carries an imidazole ring, a five-membered aromatic heterocycle with two nitrogens. Its protonation state changes close to physiological pH, so histidine can act as either a proton donor or acceptor and can switch charge in response to small pH changes. This property makes it a key residue in enzyme active sites and in pH-sensitive peptides. The imidazole nitrogens are also excellent ligands for transition metals including copper, zinc and nickel, the basis of polyhistidine affinity tags. Histidine exists as two neutral tautomers depending on which ring nitrogen carries the hydrogen, which influences how it binds metals.
Role in peptides
Histidine is the first residue of native GLP-1 and of semaglutide, and the N-terminal region is required for receptor activation. In GHK-Cu, the histidine imidazole and adjacent backbone nitrogens coordinate copper. Histidine forms part of the His-Phe-Arg-Trp melanocortin core in Melanotan II and PT-141, and appears in Semax. Growth hormone secretagogues such as GHRP-6 and ipamorelin also contain histidine. Histidine-rich antimicrobial peptides use pH-dependent charge to interact with membranes, becoming more active under mildly acidic conditions in vitro.
Stability and analysis
Histidine racemises more readily than most residues during coupling, because the imidazole can catalyse removal of the alpha proton; side-chain protection and careful activation are needed, and chiral purity should be considered for His-containing peptides. Histidine is susceptible to metal-catalysed oxidation, forming 2-oxo-histidine and related products, and to photo-oxidation. Trace metals in buffers can bind histidine and alter HPLC behaviour. For copper complexes, the metal content should be measured separately from the peptide.
In PeptideWiki compounds
Compounds whose sequence contains histidine, with the number of occurrences.
- Abaloparatide (3)
- Teriparatide (3)
- Afamelanotide (1)
- Calcitonin (salmon) (1)
- Exenatide (1)
- GHK-Cu (1)
- GHRP-6 (1)
- Gonadorelin (1)
- Ipamorelin (1)
- Melanotan II (1)
- PT-141 (bremelanotide) (1)
- Pramlintide (1)
- Semax (1)
- Setmelanotide (1)
- Triptorelin (1)
- VIP (vasoactive intestinal peptide) (1)
Frequently asked questions
Why is histidine charge pH-dependent?
The imidazole ring gains or loses a proton at a pH close to that of cells and blood. Small shifts in pH, such as those in endosomes or inflamed tissue, therefore change whether histidine is mostly neutral or positively charged. Peptides and proteins exploit this for catalysis, pH-triggered membrane interaction and pH-dependent binding. The exact protonation point varies with local environment, so it differs between positions in a peptide.
How does histidine bind copper in GHK-Cu?
In GHK-Cu, copper is held by the imidazole nitrogen of histidine together with the free N-terminal amine of glycine and a deprotonated backbone amide nitrogen between them. Additional ligands, such as from a second peptide or solvent, can complete the coordination sphere. The binding is strong enough that GHK forms a defined complex, but the copper-to-peptide ratio should still be verified analytically.
Cite this page