Though not synthesized in the body, histidine has an extensive metabolic pathway for breakdown and conversion to its various byproducts. The biosynthesis of histamine from histidine occurs via vitamin B-dependent decarboxylation reaction by histidine decarboxylase that occurs in multiple types of cells located throughout the body, particularly in the brain and stomach. Histamine synthesis is continuous and, once made, is stored in granules, awaiting activation signals for release.[13] Another major pathway in histidine metabolism involves its deamination to produce urocanic acid and ammonia done by the enzyme histidine ammonia lyase (histidase), followed by urocanase.

Histidine is a significant catalytic residue in the enzymes of many classes of biological reactions. Its efficiency at shuttling protons greatly enhances catalysis. Histidine is particularly important in acid-base catalysis due to its amphoteric properties. Another type of reaction catalysis histidine residues participates in are elimination-addition reactions in the body, as well as hemolytic and redox reaction.[14]

One excellent example of histidine’s involvement as a catalytic residue is provided by serine esterases, such as trypsin, chymotrypsin, acetylcholinesterase, and the various enzymes in the blood-clotting cascade. In these cases, histidine lies between a catalytic aspartate (which serves as a specific base), pulling a proton from the imidazole group, thereby making the imidazole group a better base to abstract/polarize the hydrogen ion from the active-site serine hydroxyl.

Histidinemia

Histidinemia is a metabolic disorder in which a lack of the enzyme histidase causes elevated levels of histidine and its byproducts in the blood and urine and decreased concentrations of urocanic acid in the skin and blood.[15] It is inherited as an autosomal recessive disorder and has incidence rates similar to those of phenylketonuria.[16][17] In most cases, it is considered a metabolic variant and can be benign, but in very rare cases it can correlate with neurological deficits and speech delays. While treatable with a low-histidine diet to prevent the higher levels of histidine and its metabolites, dietary management does not affect the elimination the neurological symptoms.[16]

Chronic Kidney Disease

Patients with chronic kidney disease (CKD) tend to have marked changes in their urinary amino acid concentrations. CKD can correlate with low levels of histidine, which contributes to the disruption of histidine metabolism and irregularity in the concentrations of its important byproducts like histamine.[18]  Research shows that low levels of plasma histidine are related to oxidative stress and protein-energy wasting as well as inflammation.[19] CKD patients have been shown to have higher levels of plasma histamine, which can damage the glomerular capillaries. This damage affects filtration ability and contributes to the abnormal plasma and urinary concentrations of metabolites. Other effects of elevated histamine levels include impairment to renal and arterial endothelium as well as being associated with pruritus.[18][20]

 Anemia

Histidine deficiencies are related to anemia, as oxidative stress plays a role in the etiology of the disease.[21] Histidine is important for erythropoiesis and globin synthesis.[22] It also works to protect cells already in circulation as its presence reduces the generation of reactive oxidative species that participate indirectly in red blood cell destruction.[21] A histidine-deficient diet promotes anemia particularly in CKD patients, but can also be associated with the anemia in otherwise healthy subjects as well.[22] In particular, a lack of folate may play a role in depleting histidine levels through increased urinary output in anemic patients.[23]

Allergic Reactions

Histamine, a significant byproduct of histidine, is found in elevated levels in the tissue and plasma during allergic reactions. Histamine is released from basophils and mast cells and causes an inflammatory response by the immune system, leading to common visible allergic symptoms like itching and swelling, as well as smooth muscle constriction, increased vascular permeability, and mucus secretion. Histamine receptors function in the characteristic mediation of allergic diseases such as urticaria, asthma, and allergic rhinitis, which are treatable with antihistamine drugs.[9] A significant concern posed by histamine release is anaphylaxis, which can cause fatal complications. Though histidine is a contributor to anaphylaxis, it is most effectively treated not by antihistamines but with an injection of epinephrine.[24]