Histidine decarboxylase

The enzyme histidine decarboxylase is transcribed on chromosome 15, region q21.1-21.2, and catalyzes the decarboxylation of histidine to form histamine. In mammals, histamine is an important biogenic amine with regulatory roles in neurotransmission, gastric acid secretion and immune response. Histidine decarboxylase is the sole member of the histamine synthesis pathway, producing histamine in a one-step reaction. Histamine cannot be generated by any other known enzyme. HDC is therefore the primary source of histamine in most mammals and eukaryotes. The enzyme employs a pyridoxal 5'-phosphate (PLP) cofactor, in similarity to many amino acid decarboxylases. Eukaryotes, as well as gram-negative bacteria share a common HDC, while gram-positive bacteria employ an evolutionarily unrelated pyruvoyl-dependent HDC. In humans, histidine decarboxylase is encoded by the HDC gene.

Structure

is normally covalently bound to HDC at lysine 305. It is also held in place with hydrogen bonds to other nearby amino acids. Here, the active site is shown with PLP bound to histidine methyl ester, which was necessary for crystallization. Generated from 4E1O.|left Histidine decarboxylase is a group II pyridoxal-dependent decarboxylase, along with aromatic-L-amino-acid decarboxylase, and tyrosine decarboxylase. HDC is expressed as a 74 kDa polypeptide which is not enzymatically functional. Only after post-translational processing does the enzyme become active. This processing consists of truncating much of the protein's C-terminal chain, reducing the peptide molecular weight to 54 kDa. Histidine decarboxylase exists as a homodimer, with several amino acids from the respective opposing chain stabilizing the HDC active site. In HDC's resting state, PLP is covalently bound in a Schiff base to lysine 305, and stabilized by several hydrogen bonds to nearby amino acids aspartate 273, serine 151 and the opposing chain's serine 354. This is particularly evident in the vicinity of the active site lysine 305. == Mechanism ==

Mechanism

co-factor. This mechanism is similar to many other PLP-dependent carboxylases.|thumbHDC decarboxylates histidine through the use of a PLP cofactor initially bound in a Schiff base to lysine 305. and fitting the experimental turnover of 1.73 s^{-1}. After the decarboxylation takes place, the PLP intermediate is protonated by tyrosine 334 from the second subunit. The protonation is mediated by a water molecule and it is very fast and also very exergonic. HDC is highly specific for its histidine substrate. == Biological relevance ==

Biological relevance

Histidine decarboxylase is the primary biological source of histamine. Histamine is an important biogenic amine that moderates numerous physiologic processes. There are four different histamine receptors, H1, H2, H3, and H4, each of which carries a different biological significance. H1 modulates several functions of the central and peripheral nervous system, including circadian rhythm, body temperature and appetite. H2 activation results in gastric acid secretion and smooth muscle relaxation. H3 controls histamine turnover by feedback inhibition of histamine synthesis and release. Finally, H4 plays roles in mast cell chemotaxis and cytokine production. ==Inhibition==

Inhibition

HDC can be inhibited by α-fluoromethylhistidine and histidine methyl ester. == Clinical significance ==

Clinical significance

Antihistamines are a class of medications designed to reduce unwanted effects of histamine in the body. Typical antihistamines block specific histamine receptors, depending on what physiological purpose they serve. For example, diphenhydramine (Benadryl™), targets and inhibits the H1 histamine receptor to relieve symptoms of allergic reactions. Inhibitors of histidine decarboxylase can conceivably be used as atypical antihistamines. Tritoqualine, as well as various catechins, such as epigallocatechin-3-gallate, a major component of green tea, have been shown to target HDC and histamine-producing cells, reducing histamine levels and providing anti-inflammatory, anti-tumoral, and anti-angiogenic effects. Mutations in the gene for histidine decarboxylase have been observed in one family with Tourette syndrome and are not thought to account for most cases of it. == See also ==

Source: Wikipedia ↗

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