Introduction

Histidine is a nutritionally essential amino acid that is also a precursor for several hormones (e.g., thyrotropin-releasing hormone), and critical metabolites affecting renal function, neurotransmission, gastric secretion, and the immune system. Its unique acid/base properties make it a versatile catalytic residue in many enzymes, as well as for those proteins and enzymes that coordinate metal ions.[1]

Fundamentals

Histidine is one of the nine essential amino acids humans must get from their diet and is present in most protein-rich foods such as meat, fish, eggs, soy, whole grains, beans, and nuts. Histidine’s imidazole side chain is unique amongst amino acids, giving rise to its aromaticity and amphoteric properties at physiologic pH. This property makes it a key catalytic residue in many enzymes.[2][3] It also performs important anti-inflammatory, anti-oxidant, and anti-secretory functions within the body.[4]

Issues of Concern

Appropriate dietary intake of histidine is crucial, both during development and throughout life. Deficiencies in histidine, as well as genetic defects in histidine metabolism, can pose problems across various systems of the body. Noteworthy metabolic byproducts are histamine, urocanic acid, and muscle dipeptides such as carnosine and anserine.[4] As a neurotransmitter, histamine is crucial to modulating inflammatory response as well as gastric acid regulation. Urocanic acid (urocanate) is vital to epidermal barrier formation in the skin.[5] It also has links to UV light absorption and immunosuppression. Finally, muscle dipeptides, like carnosine and anserine, play roles as homeostatic regulators that protect tissues.[6]

Cellular

Histidine has diverse roles in cellular function. In addition to playing a structural and catalytic role in many enzymes, histidine residues can undergo enzyme-catalyzed methylation (using S-adenosyl methionine as the methyl donor), as illustrated by the key role of 3-methylhistidine in the ATP binding site of actin.[7] Histidine residues are also key to the maintenance of the myelin sheath as they participate in the hydroxylation of the galactosylceramide, which is responsible for the compaction of the myelin.[8]

Histamine is released by mast cells to bind histamine (H1) receptors during allergic reactions.  This binding can trigger allergy symptoms like itching, prostaglandin production, smooth muscle contraction, increased vascular permeability, and tachycardia.[9] Histamine also acts as a paracrine element that plays a crucial role in gastric acid secretion and regulation. The hormone gastrin is released by food intake to trigger secretion of histamine by enterochromaffin-like (ECL) cells. Histamine then binds to H2 receptors on parietal cells, triggering a release of gastric acids by activation of a proton pump.[10]

The histidine metabolite carnosine (beta-alanyl-L-histidine) also combats intramuscular acidosis by maintaining intracellular and extracellular buffering in muscle tissue pH.[11]

Molecular

Histidine’s importance to the human body derives from the properties determined by its distinctive structure. Its side-chain is composed of an imidazole ring that is heterocyclic and contains nitrogen atoms at position 1 (pi) and 3 (tau). It is ionizable and exists both in neutral and protonated forms in the body, which gives histidine a pK one pH-unit below neutrality, allowing it to be both acid and base at physiologic pH. The imidazole ring of histidine is aromatic, which confers stability and makes it apolar at physiologic pH.[2]

Histidine is also a good chelator of metal ions like copper, zinc, manganese, and cobalt.[1] This ability comes from the imidazole nitrogen atoms which can act as either electron donors or acceptors in different cases. The importance of this is exemplified by the consideration of histidine-rich motifs in DNA transcription factors which participate in the connection of proteins and nucleic acids by Zn-fingers.[12] Zinc is also found coordinated to the active-site imidazole in carbonic anhydrase, where it acts as a Lewis acid.

Mechanism

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.

Clinical Significance

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]