Histidine in Health and Disease: Metabolism, Physiological Importance, and Use as a Supplement

Abstract

L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease.

Keywords: Bretschneider’s solution; HTK solution; ammonia; beta-alanine; branched-chain amino acids; carnosine; glutamine; histidine supplementation.

Figure 1

Histidine structure: histidine (HIS) contains an α-amino group, a carboxylic acid group, and an imidazole side chain. Under physiological conditions, the amino group is protonated and the carboxylic group is deprotonated. The imidazole ring is responsible for the proton buffering, metal ion chelating, and antioxidant properties.

Figure 2

Main pathways of HIS metabolism. Most HIS metabolism is directed to protein turnover and catabolism to glutamate. The minor pathways, such as synthesis of carnosine (CAR), histamine, and HIS-rich proteins, make HIS unique among other amino acids.

Figure 3

HIS catabolism. 1, histidase; 2, urocanase, 3, imidazolone propionate hydrolase; 4, glutamate formimino transferase; 5, glutamate dehydrogenase; 6, alanine aminotransferase; 7, glutamine synthetase; 8, histidine aminotransferase. Ala, alanine; Asp, aspartic acid; FIGLU, formiminoglutamate; Gln; glutamine; Glu, glutamic acid; Gln, glutamine; Gly, glycine; HC, homocysteine; Met, methionine; Pyr, pyruvate; SAHC, S-adenosylhomocysteine; SAME, S-adenosylmethionine; Ser, serine; THF, tetrahydrofolate; TCAc, tricarboxylic acid cycle; UV, ultraviolet radiation; α-AA, α-amino acid; α-KA, α-keto acid; α-KG, α-ketoglutarate.

Figure 4

Synthesis and degradation of histamine: Histamine is formed by the decarboxylation of HIS by L-histidine decarboxylase (EC 4.1.1.22) found in many tissues. Released histamine is degraded to 1,4-methyl imidazoleacetic acid; the second pathway of histamine degradation is oxidation to imidazoleacetic acid. The metabolites are released in the urine or processed to other metabolites. 1, histidine decarboxylase; 2, histamine-N-methyltransferase; 3, monoamino oxidase; 4, aldehyde dehydrogenase; 5, diamino oxidase.

Figure 5

Methyl- and sulphur-containing derivatives of HIS.

Figure 6

Carnosine and homocarnosine.

Figure 7

Predicted effects and potential benefits of HIS-containing supplements.