Review articles Mammalian histidine decarboxylase: from structure to function Aurelio A. Moya-Garcia, Miguel A´ ngel Medina, and Francisca Sa´ nchez-Jime´ nez* Summary a complete picture of histamine metabolism, contributions of Histamine is a multifunctional biogenic amine with different processes should be considered, including histamine relevant roles in intercellular communication, inflamma- synthesis, degradation, storage into vesicles, secretion from tory processes and highly prevalent pathologies. Hista- the histamine-producing cells and reception by the target mine biosynthesis depends on a single decarboxylation (2) step, carried out by a PLP-dependent histidine decarbox- cells. The latter is, by far, the best-characterized process. In ylase activity (EC 4.1.1.22), an enzyme that still remains to fact, nowadays, most of the anti-histaminic drugs interfere with be fully characterized. Nevertheless, during the last few reception systems.(12) years, important advances have been made in this field, Nevertheless, interest in the enzyme responsible for hista- including the generation and validation of the first three- mine synthesis, histidine decarboxylase (HDC, EC.4.1.1.22) dimensional model of the enzyme, which allows us to revisit previous results and conclusions. This essay has increased due to recent findings. HDC knockout animals provides a comprehensive review of the current knowl- exhibit altered mast cell development and increased bone edge of the structural and functional characteristics formation:loss ratio, among other symptoms.(6,13) In addition, BioEssays of mammalian histidine decarboxylase. new interesting relationships have been established between 27:57–63, 2005. ß 2004 Wiley Periodicals, Inc. HDC expression and growth of different carcinoma types and neuroendocrine tumours.(14–18) All of these recent results Introduction indicate that HDC can be a potential target for therapeutical Histamine plays important roles during immune responses,(1,2) intervention of many inflammatory diseases, some neurologi- modulates gastric acid secretion(3,4) and is considered as a cal and neuroendocrine diseases, osteoporosis and even neurotransmitter involved in memory, appetite and circadian several types of neoplasias. However, the full characterization rhythm regulation.(5–7) Histamine has also been described as of this enzyme has presented many problems, which have a modulator of cell growth.(8–10) Thus, impairment of histamine prevented the development of more efficient HDC inhibitors metabolism is related to highly prevalent pathologies such as that can be used pharmacologically. Up to now, substrate many inflammatory responses, peptic ulcer, schizophrenia analogues (the suicide inhibitor a-fluoromethylhistidine, and tumour progression, among others.(5–11) In order to have among others) have been useful for basic research on histamine physiology and molecular biology.(13,19–22) In mammals and Gram-negative bacteria, HDCs are PLP- dependent enzymes. Initially, it was deduced that the mam- Department of Molecular Biology and Biochemistry. Faculty of malian native enzyme should be a homodimer (53–54 kDa/ Sciences. University of Ma´laga, Spain (23–25) Funding agency: This work was supported by SAF2002-2586 (MCyT, subunit). When mammalian HDC cDNAs were se- Spain), and REMA (FIS-ISCIII, Spain), and is part of the activities of quenced, it was noticed that the messengers should encode the National Institute of Bioinformatics (GNV-5, Genoma-Espan˜a 74 kDa polypeptides, thus indicating the occurrence of Foundation). processing mechanisms.(26,27) Then, different active HDC *Correspondence to: Dr Francisca Sa´nchez-Jime´nez, Department of versions (53–74 kDa/subunit) have also been reported to Molecular Biology and Biochemistry. Faculty of Sciences. University of (28–32) Ma´laga. 29071 Ma´laga. E-mail: [email protected] occur in vivo. The first mammalian HDC gene (the (33) DOI 10.1002/bies.20174 human one) was reported in 1994. There is a unique Published online in Wiley InterScience (www.interscience.wiley.com). gene per haploid genome.(34) Alternative splicing of HDC gene transcripts has been reported; however, this does not seem to cause the different isoforms found in vivo, either.(35) Most of the studies on mammalian HDC transcriptional Abbreviations: HDC (histidine decarboxylase), DDC (dopa decar- 0 regulation were devoted to characterizing mechanisms boxylase or aromatic L-amino acid decarboxylase), PLP (pyridoxal 5 - phosphate), 3D (three-dimensional), C terminus (carboxy-terminus), operating in normal and neoplastic gastric cells under different N terminus (amino-terminus). stimuli and circumstances (gastrin, Helicobacter pilori infec- tion, oxidative stress, etc).(4,14,36,37) Nevertheless, important BioEssays 27:57–63, ß 2004 Wiley Periodicals, Inc. BioEssays 27.1 57 Review articles species- and cell-type specificities must exist to control the cofactor forms a Schiff’s base with the e-amino group of a mammalian HDC transcription, but little information is avail- lysine residue of the enzyme (internal aldimine, holoenzyme). able on them at the molecular level.(38) There is also evidence After substrate binding into the catalytic site, a transaldimina- of differential HDC expression depending on the differentia- tion reaction occurs (step I in Fig. 1), so that the cofactor tion/developmental stage.(6,39) Zhao and coworkers have changes to be bound to the alpha-amino group of the substrate reported that HDC can also be regulated at translational level (external aldimine). Then, after an irreversible decarboxylation in an important extent.(21) This work also claims the finding of (step II in Fig. 1) and the occurrence of different PLP-product a histamine auto-feedback inhibition on HDC in enterochro- intermediates, the internal aldimine is finally recovered by a maffin-like cells. new transaldimination reaction and the amine product is In the last few years, advances have been carried out to liberated (step III in Fig. 1). Nevertheless, the different L-amino understand structural, mechanistic and post-translational acid decarboxylases can differ in the major tautomeric aspects of mammalian HDC. This review, the first on forms of the reaction intermediates, in the rates of their structure–function relationships of this enzyme, summarizes sequential transformation and, of course, in the ligand(s) this information and gives insights into the control of both accepted as substrate(s). These properties can be deduced the activity and quantity of the protein responsible for the from changes in the spectral properties of the PLP adduct histamine synthesis in mammalian cells. along the reaction.(41–43) The kinetic properties of mammalian histidine decarbox- Characteristics of mammalian HDC activity ylase have been recently studied by different biophysical All known PLP-dependent L-amino acid decarboxylases approaches on a recombinant version of the rat enzyme.(44) follow a common reaction mechanism, extensively reviewed Its kinetic constants (Km and kcat) are very similar to those by Hayashi.(40) Fig. 1 shows a simplified scheme of the HDC reported for the mammalian enzyme isolated from natural reaction. In the absence of substrate, the aldehyde group of sources.(23–25,45) Mammalian HDCs, as well as PLP-dependent Figure 1. The mammalian histidine decarbox- ylase reaction. The structures of the internal aldimine and representative PLP-substrate and PLP-product adducts are specified. ‘‘T’’ indicates transaldimination reactions during steps I and III. 58 BioEssays 27.1 Review articles HDCs from Gram-negative bacteria, have affinity constants in DDC) was reported.(52) The first 480 residues of mammalian the 0.2–1.5 mM range. However, these two groups greatly HDC, more than 50% identical to those of pig DCC, are able to differ (2–3 order of magnitude) in their kcat values as well as in conform an active enzyme.(32) Consequently, a HDC 3D the major tautomeric form of the holoenzyme. model generated by comparative modeling techniques (using Mammalian HDC is also less efficient than the highly pig DDC as the template) should represent an active form of homologous mammalian DDC, a paralogous enzyme that is the enzyme.(53) The first 3D model of a rat HDC dimer also able to accept histamine as a low-affinity substrate. (fragment 5–479) has been generated and strongly supported Both enzymes show major aldimine tautomeric forms for the by experimental results.(22,54) A solvated version of this model respective holoenzymes and ketoenamine tautomeric forms is used here for Figs. 2 and 3. for the respective PLP substrate (external aldimine) com- In the holoenzyme, PLP should be located between plexes, suggesting changes in the polarities of the cofactor residues K308 and H197 and covalently bound to the former environment during reaction. However, in the case of mam- (Fig. 2A). The predicted quaternary structure of rat HDC dimer malian HDC, it has been observed that histidine entrance (step follows a two-fold axial symmetry pattern similar to that 1 in Fig. 1) involves an important rotation of the cofactor, which reported for the crystal structure of pig DDC (Fig. 2B), so two presents a diminished conjugation between the imine and the catalytic sites are conformed by the dimer interface. Each PLP pyridine ring in the external aldimine state as compared to the binding site mainly involves residues of one monomer (most other homologous enzymes mentioned above. This could of them located in the fragment 276–308); however, the explain the extremely