Histidine decarboxylase

Structure

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

Mechanism

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.

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.

Inhibition

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

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 (TS) and are not thought to account for most cases of TS.

References

References

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