http://www.paper.edu.cn REVIEW Bioactive S-alk(en)yl cysteine sulfoxide metabolites in the genus www.rsc.org/npr Allium: the chemistry of potential therapeutic agents NPR Peter Rose,*a Matt Whiteman,a Philip K. Mooreb and Yi Zhun Zhu*b a Department of Biochemistry, National University of Singapore, 8 Medical Drive, Singapore, 117597. E-mail: [email protected]; Fax: (65)-6779-1453; Tel: (65)-6874-4996 b Department of Pharmacology, National University of Singapore, 18 Medical Drive, Singapore, 117597. E-mail: [email protected]; Fax: (65)-6773-7690; Tel: (65)-6874-3676 Received (in Cambridge, UK) 30th March 2005 First published as an Advance Article on the web 10th May 2005 Covering: 1892 to 2004 S-Alk(en)yl cysteine sulfoxides are odourless, non-protein sulfur amino acids typically found in members of the family Alliaceae and are the precursors to the lachrymatory and flavour compounds found in the agronomically important genus Allium. Traditionally, Allium species, particularly the onion (Allium cepa) and garlic (A. sativum), have been used for centuries in European, Asian and American folk medicines for the treatment of numerous human pathologies, however it is only recently that any significant progress has been made in determining their mechanisms of action. Indeed, our understanding of the role of Allium species in human health undoubtedly comes from the combination of several academic disciplines including botany, biochemistry and nutrition. During tissue damage, S-alk(en)yl cysteine sulfoxides are converted to their respective thiosulfinates or propanethial-S-oxide by the action of the enzyme alliinase (EC 4.4.1.4). Depending on the Allium species, and under differing conditions, thiosulfinates can decompose to form additional sulfur constituents including diallyl, methyl allyl, and diethyl mono-, di-, tri-, tetra-, penta-, and hexasulfides, the vinyldithiins and (E)- and (Z)-ajoene. Recent reports have shown onion and garlic extracts, along with several principal sulfur constituents, can induce phase II detoxification enzymes like glutathione-S-transferases (EC 2.5.1.18) and quinone reductase (QR) NAD(P)H: (quinine acceptor) oxidoreductase (EC 1.6.99.2) in mammalian tissues, as well as also influencing cell cycle arrest and apoptosis in numerous in vitro cancer cell models. Moreover, studies are also beginning to highlight a role of Allium-derived sulfur compounds in cardiovascular protection. In this review, we discuss the chemical diversity of S-alk(en)yl cysteine sulfoxide metabolites in the context of their biochemical and pharmacological mechanisms. Peter Rose is a research fellow in the Department of Biochemistry, National University of Singapore. He obtained his BSc in Botany at the University of Nottingham prior to obtaining his PhD at the Institute of Food Research and the John Innes Centre, UK. His research focuses on signaling cascades mediated by natural products. Matt Whiteman is an Assistant Professor in the Department of Biochemistry, National University of Singapore. He obtained his PhD in Medical Biochemistry in 1997 in the Department of Pharmacology, King’s College, University of London. He moved to Singapore in 2000 after completing 3 years’ post-doctoral work at the Centre for Age-Related Diseases, King’s College. His research interests focus on reactive nitrogen and chlorine species in cellular behaviour. Philip Moore is a Professor and Head of the Department of Pharmacology at National University of Singapore. He obtained his PhD from King’s College in London, and has been actively involved in research into the mechanisms underlying inflammatory and cardiovascular disease for over 25 years. Yi Zhun Zhu is a senior research fellow at the Department of Pharmacology, National University of Singapore and Professor of Pharmacology at Fudan University, Shanghai. He obtained his undergraduate medical training in Shanghai and did doctorate and post-doctoral training in Heidelberg and Kiel. His research is focusing on cardioprotective effects of ischemic heart disease using Western drugs and/or extracts from natural products. :10.1039/b417639c Peter Rose Matt Whiteman Philip Moore Yi Zhun Zhu DOI This journal is © The Royal Society of Chemistry 2005 Nat. Prod. Rep., 2005, 22, 351–368 351 转载 中国科技论文在线 http://www.paper.edu.cn 1 Introduction Allium species arose from non-volatile precursor substances. It 2 Sulfur storage compounds was in the laboratory of Stroll and Seebrook in 1948 that the 2.1 S-Alk(en)yl cysteine sulfoxides in Allium species first stable precursor compound, (+)-S-allyl-L-cysteine sulfoxide 2.1.1 Alliinase (ACSO), commonly known as alliin, was identified.3 Alliin is the 2.2 Organosulfur compounds in Allium species parental sulfur compound that is responsible for the majority of 2.2.1 Thiosulfinates the odorous volatiles produced from crushed or cut garlic. Three 2.2.2 Decomposition products additional sulfoxides present in the tissues of onions were later 2.2.3 Novel thiosulfinate-derived sulfur compounds identified in the laboratory of Virtanen and Matikkala, these 3 Allium vegetables and human health being (+)-S-methyl-L-cysteine sulfoxide (methiin; MCSO), (+)- 3.1 Anticarcinogenic properties S-propyl-L-cysteine sulfoxide (propiin; PCSO) and (+)-S-trans- 3.1.1 Enzymatic inhibition 1-propenyl-L-cysteine sulfoxide or isoalliin (TPCSO). Isoalliin 3.1.2 Enzymatic induction is the major sulfoxide present within intact onion tissues and is 3.1.3 Apoptosis the source of the A. cepa lachrymatory factor.4,5 With regards 3.2 Anti-inflammatory properties to chemical distribution, (+)-S-methyl-L-cysteine sulfoxide is 3.3 Antioxidant properties by far the most ubiquitous, being found in varying amounts 3.4 Antimicrobial properties in the intact tissues of A. sativum, A. cepa, A. porrum,andA. 3.5 Antifungal and antiparasitic properties ursinum L.(Table 1). 3.6 Cardiovascular disease To date, only the L-(+)-isomers have been described in nature.6 3.7 Metabolism of Allium sulfur compounds A variety of methods have now been established to allow 4 Summary the direct analysis of CSs in plant tissues.7,8 These techniques 5 Abbreviations include HPLC or gas chromatographic (GC) methodologies, 6 References and rely either on the direct measurement of the CS following derivatisation or measurement of their respective degradation 1 Introduction products. One popular method that circumvents the problem of low sensitivity experienced with HPLC techniques is the use of Although formally classified in the family Liliaceae, represented GC. In the studies of Kubec et al.9,10 GC methodologies were by 280 separate genera and 4000 species, recent taxonomic developed to determine the distribution of CSs within the genus revisions have seen members of the genus Allium placed in Allium. Initially, the CSs are derivatised due to their apparent the family Alliaceae. Distributed throughout most regions of thermal instability, using ethyl chloroformate prior to GC the temperate world including Europe, Asia, North America analysis (Fig. 1). Data from these studies provided a quantitative and Africa, Allium species have a long history in common method to measure the nonvolatile CSs in 15 separate Allium folklore and as sources of therapeutic principles. In addition species (Table 2). Moreover, using this technique Kubec and to preventing the nocturnal bloodthirsty pursuits of vampires, colleagues identified S-ethylcysteine sulfoxide (ethiin; ECSO), one of the most famous members of the Alliaceae, garlic Allium not previously reported to occur in Allium species, as a minor sativum L. has been used throughout the centuries to treat animal component of most extracts.11 Similarly, S-n-butylcysteine sul- bites, leprosy, the plague, heart disease and cancer. Indeed, the foxide (BCSO) was identified and isolated from the tissues of A. realisation in 1858 by Louis Pasteur that garlic had potent siculum using this same method, and confirmed the earlier report antibacterial properties later led to its use in the First and by Horhammer¨ et al. on the occurrence of BCSO in garlic (A. Second World Wars to prevent gangrene. Of approximately 700 sativum).12,13 To date, four major and two minor CS have been species, it is the edible members including onion (A. cepa L.), identified and isolated from Allium vegetables. garlic (A. sativum L.), chives (A. schoenoprasum L.), leek (A. After the discovery of stable CSs, attention was next directed porrum L.) and Welsh onion (A. fistulosum L.)thatarehighly towards the elucidation of the biosynthetic pathway. Much of 1 prized. Ordinarily, the vegetative parts are odour-free, and it our knowledge of this area comes from radiolabel feeding studies is only during tissue damage that volatile flavour principles are and direct chemical analysis. What is apparent from these studies generated. Interestingly, these volatile chemicals are produced is that CSs have a common origin in plant sulfur metabolism. through enzymatic hydrolysis of non-volatile sulfur storage 2− In plants, sulfate (SO4 ) is used as the primary source of compounds, termed S-alk(en)yl-L-cysteine sulfoxides (CSs). To sulfur for the biosynthesis of the amino acid cysteine and date, four major and two minor CSs are have been identified 14 2− also the antioxidant glutathione. Initially, SO4 is transported in the genus Allium, and it is from these that approximately 50 across the root plasma membrane, whereupon it accumulates additional sulfur compounds can be generated. It is therefore 2− within plant cells. In order for SO4 to be utilised for cysteine not surprising that the composition and quantity of each CS biosynthesis it must first be converted to the intermediate determines the odour, flavour variation and biological activities compound 5-adenylylsulfate (APS). This reaction is catalysed observed for Allium vegetables. Given such chemical diversity, by the enzyme ATP sulfurylase in the plastids. APS can then be members of the genus Allium have received considerable atten- used by the enzyme APS reductase to form sulfite, prior to its tion from both chemists and biologists alike as new sources of conversion to sulfide by the enzyme sulfide reductase.