Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase

Abstract

Background: HDC catalyzes the rate-limiting step in histamine biosynthesis. Results: A mutation based on the crystal structure of HDC changed the substrate selectivity from L-histidine to L-DOPA. Conclusion: The molecular basis for substrate specificity and recognition of group II PLP-dependent decarboxylases were clarified. Significance: Knowledge of the HDC tertiary structure now makes it possible to design novel drugs that prevent histamine biosynthesis.

Discovery and Characterization of Gut Microbiota Decarboxylases that Can Produce the Neurotransmitter Tryptamine

“…Second, no apparent rules were found in the sequence alignment of the decarboxylases with aromatic amino acids as substrates that could explain their specificities or promiscuities for the aromatic amino acids; therefore, it is likely that the aromatic amino acid substrate specificity is governed by differences in the active site structures and/or orientations of the substrates. Even the serine residue at position 356 (354 in the original sequence) that was found to determine the histidine specificity of the human histidine decarboxylase (Komori et al, 2012) is found in other decarboxylases with no observed histidine activity (data not shown). Third, the binding sites of decarboxylases with aromatic amino acid substrates are rich in proline residues, suggesting that the specificity for different aromatic amino acid substrates could also be driven by active sites whose shapes match more rigidly those of the substrates.…”

Biochemical Evaluation of the Decarboxylation and Decarboxylation-Deamination Activities of Plant Aromatic Amino Acid Decarboxylases

“…Analysis of a recently released mammalian HDC (the only type II PLP decarboxylase with electron density for the catalytic loop) enables speculation on the interactions between the substrate ␣-carbon and the catalytic loop tyrosine (16). Careful examination of the HDC active site confirmation revealed that although its Tyr-344 from monomer B (the equivalent active site tyrosine in plant AAAD and mammalian DDC) is quite close to the ␣-carbon of the external aldimine complex (7.50 Å), its side chain hydroxyl group is actually much closer to the imidazole amine (⑀-amine group) (4.42 Å) of monomer A His-194.…”

“…Next, analyses of published crystal structures were preformed to identify putative activity differentiating residues within plant AAAD and AAS enzymes. Several structures were analyzed, but due to the strong plant AAAD homology, the conservation of active site residues, and substantial electron density of an active site proximal catalytic loop (absent from other AAAD structures), the Human histidine decarboxylase (huHDC) structure was chosen as the primary model (16). Investigation of the Human HDC (PDB code 4E1O) crystal structure identified residues located within 6 Å of the pyridoxal 5Ј-phosphate inhibitor adduct.…”

Knockout of histidine decarboxylase decreases bile duct ligation-induced biliary hyperplasia via downregulation of the histidine decarboxylase/VEGF axis through PKA-ERK1/2 signaling

“…We have observed that histamine also regulates biliary repair and regeneration in the liver (19). Histamine is formed from the one-step decarboxylation reaction of the amino acid histidine by L-histidine decarboxylase (HDC) and, following release, is either stored or degraded by histamine-N-methyltransferase and monoamine oxidase B (15,21,32). Histamine exerts its effects through interaction with one of four G protein-coupled receptors, H1-H4 histamine receptor (HR).…”