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Home , Decarboxylation, Histidine decarboxylase, Histidine methyl ester

Review articles

Mammalian decarboxylase: from structure to function Aurelio A. Moya-Garcia, Miguel A´ ngel Medina, and Francisca Sa´ nchez-Jime´ nez*

Summary a complete picture of , contributions of Histamine is a multifunctional biogenic 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 depends on a single (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 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, (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 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 secretion(3,4) and is considered as a cal and neuroendocrine diseases, osteoporosis and even involved in memory, 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 .(13,19–22) In and Gram-negative bacteria, HDCs are PLP- dependent . Initially, it was deduced that the mam- Department of Molecular Biology and . 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 (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- 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 forms a Schiff’s base with the e-amino group of a mammalian HDC transcription, but little information is avail- 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 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.

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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 and the catalytic sites are conformed by the dimer interface. Each PLP pyridine ring in the external aldimine state as compared to the 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 low rate of the mammalian enzyme substrate-binding sites bring together residues from both action in the subsequent catalytic steps.(40,43,44) monomers. Models showing residues involved in the catalytic In addition, mammalian histidine decarboxylase holoen- sites have been published and validated.(22,54) zyme seems to have a highly restrictive and hydrophobic However, local changes have been shown to be induced by catalytic site. It is only able to bind histidine or imidazol- substrate (or substrate analogue) entrance into the catalytic containing analogues, such as the inhibitors a-fluoromethyl- site, affecting the global conformation of the enzyme, so histidine and .(43,44) Nevertheless, it has reducing its Stokes radius.(22) It is likely that the flexible loop recently been reported that the natural polyphenol epigallo- (331–349) of rat HDC (Fig. 2) has a relevant role in the global -3-gallate acts as an inhibitor of both mammalian conformational change of the enzyme. The loop is located in HDC and DDC, by inducing a similar conformation change of the catalytic site entrance and overlaps the in the the enzyme-bound PLP, so reinforcing the idea of important dimer (Fig. 2B and the left panel of Fig. 3). A conformational similarities between the two catalytic sites.(46,47) change of the loop after substrate binding has also been In order to confirm that mammalian HDC is a putative experimentally proven; two essential residues, Y337 and Y83 target for anti-histamine pharmacology, it is essential to fully (from different monomers), could mediate these conforma- characterize the molecular bases of any functional differences tional changes during reaction.(54) It is noteworthy that with respect to other homologous enzymes, since other L- structure and location of the homologous loop of pig DDC amino acid decarboxylases can coincide in the same cell type have not been solved yet. Nevertheless, a local conforma- and/or system, and their products also play a very important tional change of the DDC flexible loop is also required during role in mammalian physiology/pathology. Since functional transaldimination,(55) and both Y residues are conserved in properties are consequences of structural features, the this enzyme. It has been shown that a Y/F substitution at structural characterization of mammalian HDC should be position 332 of pig DDC (homologous to Y337 of rat HDC) considered a priority to allow more meaningful discussions converts DDC into a decarboxylation-dependent oxidative and further applications of the present knowledge. deaminase.(56) Whether a similar mutant of HDC could also carry out an oxidative deamination of histidine is not yet known. Mammalian HDC structural data Four evolutionary origins are distinguished for PLP-dependent Mammalian HDC polypeptide stability decarboxylases.(48) PLP-dependent HDCs together with DDCs and glutamate decarboxylases belong to group II.(49–51) Processing Mammalian HDCs are experimentally proven to conform as It is generally accepted that processing provides an addi- dimers.(22,25) However, some bacteria PLP-dependent homo- tional regulation mechanism of mammalian HDC activation logous HDCs have been described as tetramers.(45) As far as in vivo,(21,29,30,32) and must involve the C terminus of the we know, there is no solved crystal structure for any PLP- 74 kDa full-length monomer.(57–63) Very recent data demon- dependent HDC. This is largely due to its high instability strate that these full-length monomers can form dimers, but especially in highly purified preparations.(24,44) Recently, an they lack the capability to react with substrate analogues.(64) alternative way of approaching mammalian HDC 3D structure Fragment 617–633 was identified as responsible for such a func- arose when the first crystal structure of a mammalian DDC (pig tional inhibition. In any case, involvement of other C-terminal

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Figure 2. Three-dimensional models of monomeric and dimeric forms of rat HDC 5-479. The model was built as the one reported previously,(22) but adding a 4,000-molecule water environment (http://www.mpibpc.gwdg.de/abteilungen/071/solvate/docu.html). Further energy minimization calculations were performed with the program XPLOR(71) in a SGI Altix 3000 under GNU/Linux RedHat 7.2. Secondary structure was calculated with the DSSP program.(72) A: A monomer is depicted by the secondary structure of its fragments. N and C indicate the amino and carboxy termini of the polypeptide, respectively. Positions of some residues are indicated by their numbers. Atoms of both K308 and H197 are depicted. B: Homodimeric form represented by its surfaces. Positions of N and Ctermini, and those of residues 175 of both the light-grey monomer (A) and the black one (B) are also indicated. The dashed arrow indicates that the N terminus of monomer B is located behind the image. Monomer A is shown at the same position as in panel A. The rectangle on the N terminus of monomer A frames the surface of its PEST region, and the rectangle on the right hand of the image frames the surface of the flexible loop 331–349 of monomer B. PDB files of the solvated and minimized HDC structures can be obtained from the authors upon request. fragments in the optimum conformation cannot be ruled out, its contribution to the enzyme regulation in vivo are still open since isoforms with molecular masses from 70 to 58 kDa topics with multiple uncertainties and even contradictory exhibit gradually increasing specific activities. Further efforts results in literature.(28,59,66) are necessary to clarify whether the different processed bands observed in vivo(29–31) are sequentially or alternatively Degradation derived from their precursor, and whether cell-/species- Mammalian HDC has been shown to be a short-lived protein in specific differences exist. At least in Cos-7-transfected cells, vivo, half-life values ranging approximately 50–100 minutes several HDC immunoreactive bands ranging from 63–36 kDa under different circunstances.(21,29,30) Consequently, degra- are generated from the full-length open reading frame.(64) dation is an important contributor to short-term regulation of It would be interesting to know the minimum fragment able to the intracellular levels of this mammalian enzyme. PEST be active in vivo. The limit for this C-terminal processing is regions are usual motifs in short-lived proteins that target them known to be between residues 472 and 477.(32) However, the for proteolysis. In 1994, we reported the presence of PEST limit for its N terminus is still unknown. N-terminus-truncated regions at both N and Ctermini of mammalian HDCs.(67) versions that still have activity in vitro have also been Taking into account the structural requirements proposed for reported.(58,62) functional PEST regions,(68) the ones located in the N termini Finally, intracellular location of the different isoforms could of mammalian HDC (Fig. 2A and the right panel of Fig. 3) would also provide important information that needs to be taken into accomplish each of them: in addition to the presence of P, S/T account for any inhibitory strategy. In rat histamine-producing and acidic residues, they are located at the surface and cells, the full-length polypeptide has been located associated conformed as very flexible structures. In the case of the rat to membranes. A putative endoplasmic-reticulum-targeting HDC N-terminal PEST region, it has been proven to be signal has been reported in the C terminus (fragment 588–607 involved in stability of the enzyme both in vitro and in vivo.(57,62) of the mouse polypeptide).(65) Nevertheless, HDC sorting and The relevance of the N-terminal domain for both mammalian

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Figure 3. Two different views of mammalian histidine decarboxylase showing potential sites for regulation (and intervention) of its activity and turnover. Monomer surfaces are represented in red and green to differentiate them. Molecular graphics were carried out using PyMo.(73) Left Panel, a view from the right of the image shown in Fig. 2B; it shows the catalytic site entrance, representing the 331–349 flexible loop by its secondary structure and the colour of its monomer. Residues K308 and H197 of the red monomer are coloured in blue. Residues Y337 (green monomer) and Y83 (red monomer) are depicted by their atoms in lighter green and orange, respectively. Right panel, a view from the top of the image shown in Fig. 2B; N-terminal PEST regions are represented by their secondary structures and the colour of their respective monomers. Residue numbers at both the beginning and the end of each PEST region, and the amino (N) and carboxy termini (C) of both monomers, are also indicated.

HDC dimerization (Fig. 2B and the right panel of Fig. 3) and to post-translational characteristics of the enzyme, sum- degradation(57,62) suggests that the N terminus of the protein marizes efforts for its mechanistic and structural characteriza- may play regulatory roles on both activity and stability. tion, which have advanced insights into the putative targets for In any case, mammalian HDC degradation and processing histamine synthesis intervention. They can be summarized as seem to be complex processes. The proteasomal pathway follows: has been shown to play a critical role in inflammation and in the immune system, in general,(69) and in mammalian HDC 1. The reaction mechanism. The catalytic site conformation turnover, in particular.(63) In addition, m-calpain is able to and, consequently, the reaction mechanism, is similar but efficiently degrade both the full-length polypeptide and the not identical to those of mammalian DDC and Gram- carboxy-truncated active forms of the enzyme.(70) This is an negative bacteria PLP-dependent HDCs. These facts interesting result, since calcium is clearly involved in histamine could provide a target for selective intervention. secretion.(2) It has also been suggested that cytosolic 2. The dimerization of the holoenzyme. Differences have histamine could regulate HDC half-life.(21) been detected in the overall quaternary structure with respect to Gram-negative bacteria PLP-dependent HDCs. Concluding remarks Since the substrate-binding site is conformed by both Key proteins of inducible responses are frequently minority monomers, interference with the dimerization process proteins that present a rapid turnover and a complex tran- provides a promising possibility for selective inhibition not scriptional and post-transcriptional regulation. Mammalian explored so far. In addition, it has been demonstrated that HDC is no exception to this rule. The present level of changes in the dimer conformation occur at different steps knowledge about this enzyme has taken more than 20 years of the HDC reaction, and some residues involved in these to achieve and the efforts of different research groups. changes have been located. Blockade/alteration of any of However, important questions remain on the molecular these conformations could also lead to the blockade/ mechanisms operating in vivo. This review, mainly devoted alteration of the reaction.

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3. The processing/degradation. The present information human melanoma cells in immunodeficient mice. Cell Biol Int 26:833– indicates that both termini of the polypeptide modulate 836. 10. Diks SH, Hardwick JC, Diab RM, van Santen MM, Versteeg HH, et al. both activity and stability of the enzyme; so their with- 2003. Activation of the canonical beta-catenin pathway by histamine. drawals are more than simple activation/inactivation J Biol Chem 278:52491–52496. mechanisms. These findings underscore the importance 11. Nathan C. 2002. Points of control of inflammation. Nature 420:846–852. 12. Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, et al. of a full characterization of the proteolytic events and 1997, International Union of Pharmacology. XIII. Classification of their locations inside histamine-producing cells, since this histamine receptors. Pharmacol Rev 49:253–278. knowledge can clearly have an applied interest. With 13. 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