Histamine Metabolism

Edited by Holger Stark Chapter 3 Histamine Metabolism H.G. Schwelberger1, F. Ahrens2, W.A. Fogel3, F. Sánchez-Jiménez4 1Molecular Biology Laboratory, Department of Visceral, Transplantation and Thoracic Surgery, Medical University Innsbruck, Austria, e-mail: [email protected] 2Department of Veterinary Science, Institute of Animal Physiology, Ludwig-Maximilians University Munich, Germany 3Department of Hormone Biochemistry, Medical University of Lodz, Poland 4Department of Molecular Biology and Biochemistry, University of Malaga, Spain Abstract Histamine is formed by decarboxylation of the amino acid L-histidine, a process catalyzed by histidine decarboxylase (HDC) and can be inactivated either by methylation of the imidazole ring, catalyzed by histamine N-methyltransferase (HMT) or by oxidative deamination of the primary amino group, catalyzed by diamine oxidase (DAO). This chapter describes the enzymatic reactions and the properties of the enzymes involved, including their structures, their cellular localization, their genes, expression and regulation, and the determination of their enzymatic activities. It also addresses cellular histamine transport, storage and release. Further, it discusses alterations in histamine metabolism associated with human diseases and how this might affect histamine receptor signaling. 3.1. Introduction Histamine [2-(1H-Imidazol-4-yl)ethanamine] is an important mediator of many biological processes including inflammation, gastric acid secretion, neuromodulation, and regulation of immune function (Falus et al., 2004). Due to its potent pharmacological activity even at very low concentrations, the synthesis, transport, storage, release, and degradation of histamine have to be carefully Chapter 3 6 3 Histamine H4 Receptor: A Novel Drug Target in Immunoregulation and Inflammation regulated to avoid undesirable reactions. Histamine may also be generated by microbiological action in the course of food processing and spoilage and may therefore be present in substantial amounts in many fermented foodstuffs and beverages (Sarkadi, 2004). Histamine is formed by decarboxylation of the amino acid L-histidine in a reaction catalyzed by the enzyme histidine decarboxylase (HDC) (Darvas and Falus, 2004). The major routes of histamine inactivation in mammals are methylation of the imidazole ring, catalyzed by histamine N-methyltransferase (HMT) (Schwelberger, 2004a), and oxidative deamination of the primary amino group, catalyzed by diamine oxidase (DAO) (Schwelberger, 2004b) (Figure 3.1 and Figure 3.2). The primary histamine inactivation products are inactive at the histamine receptors and are further metabolized for transport and secretion. Although the principles of histamine formation and degradation have been known for several decades, the details of the individual reactions and the enzymes involved have only been investigated recently. Cloning of genes and cDNAs encoding histamine metabolizing enzymes were crucial for clarifying the identity of the proteins involved in this pathway and for studying their regulation, expression and processing. The determination of the three- dimensional structures of the proteins facilitated the understanding of the reaction mechanisms. Despite these advances, several key issues remain to be addressed in the future including the regulation of tissue-specific gene Figure 3.1 Formation and inactivation of histamine. Histamine is formed by decarboxylation of L-histidine, catalyzed by histidine decarboxylase (HDC), and can be inactivated either by methylation of the imidazole ring, catalyzed by histamine N-methyltransferase (HMT), or by oxidative deamination of the primary amino group, catalyzed by diamine oxidase (DAO). 6 4 Chapter 3 Edited by Holger Stark Figure 3.2 Details of the reactions leading to the formation and inactivation of histamine. The reactions catalyzed by (A) histidine decarboxylase (HDC), (B) histamine N-methyltransferase (HMT), and (C) diamine oxidase (DAO) are depicted with all co-substrates and co-products. expression and both the cellular and subcellular localization, especially of the human enzymes. In the sections below we summarize the current knowledge of the proteins involved in histamine metabolism and transport and discuss their potential involvement in human diseases. 3.2. Histamine Formation 3.2.1. Histidine Decarboxylase Reaction Mechanism Histamine is synthetized by decarboxylation of the amino acid L-histidine. In Gram positive bacteria, the reaction catalyst is a pyruvoyl-containing enzyme (Snell and Guirard, 1986; Gallager et al., 1989); however, in Gram negative Chapter 3 6 5 Histamine H4 Receptor: A Novel Drug Target in Immunoregulation and Inflammation bacteria and Metazoa, including humans, the histidine decarboxylase (HDC) reaction (EC 4.1.1.22) is assisted by the cofactor pyridoxal 5’-phosphate (PLP), a vitamin B6 derivative acting as a universal ligand to the alpha-amino group of α-amino acids in different catalytic processes (racemases, amino transferases, α and β-decarboxylases, synthases, transferases, and lyases) (Hayashi, 1995; Hayashi et al., 1990 and 2010; Mehta and Christen, 2000). The reaction mechanism of the PLP-dependent enzyme proceeds as shown in Figure 3.3. It has been extensively described in previous references (Olmo et al., 2002; Rodriguez-Caso et al., 2003; Moya-García et al., 2008; Pino-Ángeles et al., 2010). Briefly, in the free form of the enzyme, the carbonyl group of PLP forms a Schiff’s base (internal aldimine) with the ε-amino group of a specific lysine group of the polypeptide. When the substrate L-histidine enters the catalytic center, its α-amino group acts as a nucleophilic group towards the Schiff’s base. Therefore, the L-histidine α-amino group displaces the lysine group of the protein forming the external aldimine (transaldimination). Then a Figure 3.3 Reaction mechanism of mammalian HDC. Reaction mechanism of mammalian HDC as experimentally deduced from rat HDC (Olmo et al., 2002). (A) Major enolimine tautomeric form of the PLP-enzyme complex (internal aldimine). (B) Major ketoenamine form of the PLP- substrate intermediate (external aldimine). (C) instable carbanionic intermediate produced during decarboxylation. 6 6 Chapter 3 Edited by Holger Stark carbanionic intermediate is generated by deprotononation which is most likely stabilized by the extended π system of the PLP pyridine ring (Eliot and Kirsch, 2004; Hayashi, 1995; John, 1995). This intermediate is named as the quinonoid intermediate due to its quinone-like structure. These steps are common to all PLP dependent enzymes. The way to proceed after the quinonoid formation determines the Cα that will be broken, that is to say the type of catalysis carried out by the PLP-dependent enzyme. In the case of HDC, it is the Cα-COO-bond (decarboxylation reaction). In rat HDC, it is the limitant step of the reaction as demonstrated by Olmo et al. (2002). In fact, this step is extremely slow leading -1 to very low catalytic constants (Kcat in the range of 0.1 s ) for the mouse and rat enzymes. However, a recent publication on the catalytic properties of the human enzyme describes it as two orders of magnitude more efficient one (similar affinity as the rodent enzyme but highercat K ) (Komori et al., 2012). Once L-histidine is decarboxylated, a reverse transaldimination occurs, so the polypeptidic ε-amine group (K308 in rat HDC and K305 in human HDC) recovers its bond to PLP, and histamine is released. The mentioned PLP-adducts can present enol-keto tautomeric forms. Thus enolimine forms are more stable in a hydrophobic environment and ketoenamine forms are the major forms in a polar environment. These characteristics are useful to study PLP-dependent reactions, as the cofactor derivatives change their absorption properties (300-500 nm) depending on their bonds and even the major tautomeric forms occurring during a PLP-dependent reaction, giving valuable information on both the chemical properties and dynamics of the intermediates along the catalytic process. This strategy has been used to characterize many PLP-dependent enzymes from many different sources (Hayashi, 1995), including mammalian HDCs (Olmo et al., 2002; Rodríguez-Caso et al., 2003a), as well as HDC inhibitors affecting PLP-derivative status (Bertoldi et al. 2002; Rodríguez-Caso et al., 2003a and b). At present only a few HDC inhibitors have been described, none of which are currently used for human therapies. Some substrate analogs are used as inhibitors for research purposes, such as histidine-methylester (HME), a competitive inhibitor able to form an external aldimine that cannot be further solved, and α-fluoromethyl histidine (FMH) that acts as a suicide substrate (Rodriguez-Caso et al., 2003a). These inhibitors are common for both PLP-dependent enzymes, the bacterial and the mammalian HDCs (Kubota et al., 1984; Hayashi et al., 1986). More recently, Wu and Gehring described new mammalian HDC inhibitors that mimic the transition state of the reaction, i.e. a pyridoxyl-histidine methyl ester conjugate (Wu and Gehring, 2008). Its development was facilitated by the information provided by the 3D model of rat HDC (Moya-García et al., 2005). In addition, it has been found that tea polyphenols such as epigallocatechin 3-gallate (EGCG) are able to inhibit both HDC and its homologous DDC (Bertoldi et al., 2002; Rodríguez-Caso et al., 2003b). A molecular dynamics study predicts Chapter 3 6 7 Histamine H4 Receptor: A Novel Drug Target in Immunoregulation and Inflammation that the

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