Why histidine is found in the active site of enzymes

Basically, the enzyme's active site has an amino acid composition that when folded correctly, alters the local pH around the catalytic residues to favor catalysis. For example, in the enzyme acetylcholinesterase , the active site serine is rendered nucleophilic by being positioned next to a glutamate and a histidine, in an arrangement referred to as a catalytic triad.

The glutamate is an acidic residue, and its close proximity to the histidine means that it will stabilize the protonated form of the histidine. Energetically, this makes protonation of the histidine very favorable. This causes the histidine to take a proton from the active site serine. Now that serine's oxygen is deprotonated, it can act as a strong nucleophile. After the serine forms a covalent interaction with the substrate, the histidine will facilitate a similar nucleophilic attack by a water molecule, regenerating the enzyme and completing the catalytic cycle.

Something similar is seen with the beta-lactamase TEM In effect, the amino acid composition of the active site allows for the shuffling of protons needed for catalysis.

So to summarize, while physiological pH is widely regarded to be 7. In the latter case, the presence of acidic or basic residues can alter the protonation state of other acidic or basic residues, meaning the effective pKa of these residues or the effective pH around them is higher or lower than 7.

Sign up to join this community. The best answers are voted up and rise to the top. Stack Overflow for Teams — Collaborate and share knowledge with a private group. Create a free Team What is Teams? Learn more. Ask Question. Asked 3 years, 11 months ago. Active 3 years, 11 months ago. Viewed times. The proposal involves ring flipping of the imidazole function of the histidine side chain as a vehicle for proton transfer. It is suggested that the shape of histidine is as important as its p K a for its function at the active sites of enzymes.

This is a preview of subscription content, access via your institution. Rent this article via DeepDyve. Vedani, A. In press, and references therein. We thank Professor Gandour for a preprint of this manuscript.

Google Scholar. For a review see Venkatasubban, K. Sprang, S. Nature London , , , For alternate interpretations concerning the function of the carboxylate see Warshel, A. Biochemistry , , 25 , Gandour, R. Tsukuda, H.

Tsukada, H. For related suggestions involving the bidentate nature of carboxylates see Knowles, J. Histamine then binds to H2 receptors on parietal cells, triggering a release of gastric acids by activation of a proton pump.

The histidine metabolite carnosine beta-alanyl-L-histidine also combats intramuscular acidosis by maintaining intracellular and extracellular buffering in muscle tissue pH. 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 p K 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. Histidine is also a good chelator of metal ions like copper, zinc, manganese, and cobalt. 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. 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. 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.

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. 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.

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. 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.

Histidine deficiencies are related to anemia, as oxidative stress plays a role in the etiology of the disease. 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.

Though histidine is a contributor to anaphylaxis, it is most effectively treated not by antihistamines but with an injection of epinephrine. Unprotonated and protonated structures of histidine, including atom-numbering system at left. Contributed by Daniel Purich, Ph. This book is distributed under the terms of the Creative Commons Attribution 4.

Turn recording back on. National Center for Biotechnology Information , U. StatPearls [Internet]. Search term. Biochemistry, Histidine Aleeza T. Author Information Authors Aleeza T. Affiliations 1 University of Florida. Introduction Histidine is a nutritionally essential amino acid that is also a precursor for several hormones e.

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. Issues of Concern Appropriate dietary intake of histidine is crucial, both during development and throughout life.

Cellular Histidine has diverse roles in cellular function. Mechanism Though not synthesized in the body, histidine has an extensive metabolic pathway for breakdown and conversion to its various byproducts. 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.

Review Questions Access free multiple choice questions on this topic. Comment on this article. Figure Unprotonated and protonated structures of histidine, including atom-numbering system at left.

References 1.