Histidine decarboxylase

Histidine Decarboxylase
Cartoon depiction of C-truncated HDC dimer with PLP residing in active site.
Identifiers
EC no.	4.1.1.22
CAS no.	9024-61-7
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

The enzyme histidine decarboxylase (EC 4.1.1.22, HDC) 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.^[1][2] 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.^{[citation needed]} 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.^[3][4] Eukaryotes, as well as gram-negative bacteria share a common HDC, while gram-positive bacteria employ an evolutionarily unrelated pyruvoyl-dependent HDC.^[5] In humans, histidine decarboxylase is encoded by the HDC gene.^[2][6]

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.^[7][8] 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.^[7] HDC contains several regions that are sequentially and structurally similar to those in a number of other pyridoxal-dependent decarboxylases.^[9] This is particularly evident in the vicinity of the active site lysine 305.^[10]

HDC decarboxylates histidine through the use of a PLP cofactor initially bound in a Schiff base to lysine 305.^[11] Histidine initiates the reaction by displacing lysine 305 and forming an aldimine with PLP. Then, histidine's carboxyl group leaves the substrate, forming carbon dioxide. This is the rate-limiting step of the all process, requiring an activation energy of 17.6 kcal/mol ^[12] and fitting the experimental turnover of 1.73 ${\displaystyle {\ce {s^{-1}}}}$.^[13] 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.^[12] Finally, PLP re-forms its original Schiff base at lysine 305, and histamine is released. This mechanism is very similar to those employed by other pyridoxal-dependent decarboxylases. In particular, the aldimine intermediate is a common feature of all known PLP-dependent decarboxylases.^[14] HDC is highly specific for its histidine substrate.^[15]

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,^[16] 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.^[17] H₂ activation results in gastric acid secretion and smooth muscle relaxation.^[18][19] H₃ controls histamine turnover by feedback inhibition of histamine synthesis and release.^[20] Finally, H₄ plays roles in mast cell chemotaxis and cytokine production.^[17]

In humans, HDC is primarily expressed in mast cells and basophil granulocytes. Accordingly, these cells contain the body's highest concentrations of histamine granules. Non-mast cell histamine is also found in the brain, where it is used as a neurotransmitter.^[21]

HDC can be inhibited by α-fluoromethylhistidine and histidine methyl ester.^[22][23]

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.^[24] 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.^[25]

Mutations in the gene for Histidine decarboxylase have been observed in one family with Tourette syndrome (TS) and are not thought to account for most cases of TS.^[26]

• Aromatic L-amino acid decarboxylase
• Tyrosine decarboxylase
• Decarboxylation
• Histamine
• Antihistamine
• Pyridoxal 5'-phosphate
• Mast cell

• Histidine+Decarboxylase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.