REVIEW 17Β-Hydroxysteroid Dehydrogenase (HSD)/17-Ketosteroid Reductase (KSR) Family; Nomenclature and Main Characteristics of T
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1 REVIEW 17â-Hydroxysteroid dehydrogenase (HSD)/17-ketosteroid reductase (KSR) family; nomenclature and main characteristics of the 17HSD/KSR enzymes H Peltoketo, V Luu-The1, J Simard1 and Jerzy Adamski2 Biocenter Oulu and WHO Collaborating Center for Research on Reproductive Health, University of Oulu, FIN-90220 Oulu, Finland 1MRC Group in Molecular Endocrinology, CHUL Research Center and Laval University, Que´bec, Canada 2GSF National Research Center for Health and Environment, Institute for Mammalian Genetics, Genome Analysis Center, Neuherberg, Germany (Requests for offprints should be addressed to any author) ABSTRACT A number of enzymes possessing 17â- descriptions of the eight cloned 17HSD/KSRs are hydroxysteroid dehydrogenase/17-ketosteroid re- given and guidelines for the classification of novel ductase (17HSD/KSR) activities have been 17HSD/KSR enzymes are presented. described and cloned, but their nomenclature needs Journal of Molecular Endocrinology (1999) 23, 1–11 specification. To clarify the present situation, INTRODUCTION enzymatic activities, which has also complicated the definition of them. During the past decades, the Since the 1950s (Ryan & Engel 1953), 17â- names of the 17HSD/KSRs have become diverse hydroxysteroid dehydrogenase/17-ketosteroid re- and impractical, and therefore we attempt here to ductase (17HSD/KSR) activities have been clarify the nomenclature and specification of them. characterized, and 17HSD/KSR enzymes have been A brief description of individual and common purified from a large number of tissues of several features of the known 17HSD/KSR enzymes is species (see Jarabak 1969, Nicolas & Harris 1973, given, enough to identify each enzyme discussed. Bogovich & Payne 1980, Milewich et al. 1985, Inano & Tamaoki 1986, Murdock et al. 1986, Tait et al. 1989, Martel et al. 1992, Blomquist 1995, for WHAT ARE 17HSD/17KSRs example). Eight enzymes named HSD types 1–8, hereafter called 17HSD/KSR1–8, have so far been 17HSD/KSRs are NAD(H)- and/or NADP(H)- cloned (see Table 1). Kinetic data available suggest dependent enzymes that catalyze the oxidation and that more enzymes with 17HSD/KSR-activities reduction of 17â-hydroxy- and 17-ketosteroids will be cloned in the future. Before the cloning of respectively. Both estrogens and androgens have the the different types, 17HSD/KSRs had been suc- highest affinity for their receptors in the 17â- cessfully characterized based on their enzymatic hydroxy form and hence 17HSD/KSR enzymes properties and tissue and subcellular localization. regulate the biological activity of the sex hormones. However, the activities described generally reflected Certain 17HSD/KSRs are also involved in catabolic the sum of activities of several enzymes and not cascades of sex steroids. 17KSR activities are the characterization of an individual protein. On the essential for estradiol (1,3,5(10)-estratriene-3,17â- other hand, cloning of the 17HSD/KSR enzymes diol) and testosterone (4-androsten-17â-ol-3-one) has revealed that several of them possess further biosynthesis in the gonads, but they are also present Journal of Molecular Endocrinology (1999) 23, 1–11 Online version via http://www.endocrinology.org 0952–5041/99/023–001 1999 Society for Endocrinology Printed in Great Britain Downloaded from Bioscientifica.com at 10/03/2021 08:50:54AM via free access 2 Journal of Molecular Endocrinology 1. List of the cloned 17HSD/KSR enzymes Species References Accession Subcellular Tissue Other names Other cloned for cloning number localization distributiona used/in use references and others · Type/protein family 1/SDR Human Peltoketo et al. X13440 Cytosolic Ovary, placenta, Placental 17HSD, Fournet-Dulguerov et al. (1988), Luu The breast 17â,20á-HSD, estradiol (1987), Tremblay et al. et al. (1989) 17HSD, estradiol-17â- (1989), Dupont et al. (1991), dehydrogenase/oxidoreductase Ghersevich et al. (1994b,c), Rat Ghersevich et al. X78811, Sawetawan et al. (1994), Nomenclature of 17HSD/KSRs (1999) 17 -Hydroxysteroid (1994a), Akinola X97754 Membrane- â Sasano et al. (1996), Puranen Ovary oxidoreductase, estrogenic et al. (1996) associated? et al. (1997), Ghosh et al. 17KSR (1995), Azzi et al. (1996), 23, Mouse Nokelainen et al. X89627 (1996) Breton et al. (1996) 1–11 2/SDR Human Wu et al. (1993) L11708 Placenta, liver, gastrointestinal tract, kidney, Casey et al. (1994), Elo et al. uterus, breast, prostate (1996), Moghrabi et al. Microsomal (1997), Mustonen et al. Rat Akinola et al. X91234 (1996) Placenta, liver, (1997a, 1998a,b) gastrointestinal and Mouse Mustonen et al Y09517 urinary tracts (1997b) 3/SDR Human Geissler et al. U05659 (1994) Microsomal Testis Testicular 17KSR/17â- Luu-The et al. (1995) hydroxysteroid oxidoreductase Mouse Sha et al. (1997) U66827 4/SDR/MFE Porcine Leenders et al. X78201 Peroxisomal multifunctional (1994) enzyme II, MFP2, Downloaded fromBioscientifica.com at10/03/202108:50:54AM 2-enoyl-CoA hydratase 2 Human Adamski et al. X87176 D-specific hydroxyacyl (1995) dehydrogenase Mouse Normand et al. X89998 (1995) Novikov et al. (1994), Markus Rat Corton et al. X94978 Peroxisomal Widely distributed (1996), et al. (1995) Dieuaide-Noubhani et al. (1996), Qin et al. (1997) Chicken Kobayashi et al. U77911 (1997) Guinea Caira et al. (1998) Y13623 pig via freeaccess 1. Continued Species References Accession Subcellular Tissue Other names Other cloned for cloning number localization distributiona used/in use references Type/protein family 5/AKR Mouse Deyashiki et al. D45850 HAKRb, AKR1C3, type 2 (1995) Liver, kidney, 3áHSD, mouse estradiol Lin et al. (1992), Labrie et al. Cytosolic testis, prostate, 17â-dehydrogenase (1997), Dufort et al. (1999), adrenal, bone El-Alfy et al. (1999) Human Qin et al. (1993), S68288 Lin et al. (1997) 6/SDR Rat Biswas & Russell U89280 Membrane- Prostate, liver Nomenclature of 17HSD/KSRs (1997) bound 7/SDR Rat Duan et al. (1996) U44803 Ovary PRAP Membrane- Mouse Nokelainen et al. Y15733 bound/ Ovary, placenta, Duan et al. (1997) associated (1998) mammary gland Journal of Molecular Endocrinology 8/SDR Human Ando et al. (1996) D82061 Liver, pancreas, HKE6 kidney, skeletal Kikuti et al. (1997), Unknown muscle Fomitcheva et al. (1998) Mouse Aziz et al. (1993) U34072 Kidney, liver, Ke 6 Downloaded fromBioscientifica.com at10/03/202108:50:54AM ovary, testis, spleen aThe list is not all-inclusive, but the tissues in which each enzyme is most commonly expressed are mentioned. · (1999) and others 23, 1–11 via freeaccess 3 4 and others · Nomenclature of 17HSD/KSRs in certain extragonadal tissues and can convert recommend that new 17HSD/KSRs are numbered low-activity precursors to their more potent forms in the order in which they are cloned, regardless of in peripheral tissues. Instead, 17HSD activities the species the cDNA/gene is cloned from. The tend to decrease the potency of estrogens and corresponding enzymes from other species are then androgens and consequently may protect tissues labeled with the same number, although all types from excessive hormone action (Table 1). would not exist in some species. Such a procedure is 17HSD/KSRs differ from the majority of other suitable for the 17HSD/KSR family that possesses steroidogenic enzymes, because most of them are low sequence homology, and thus avoids confusing able to catalyze, at least to some extent, reverse situations in which enzymes in different species reactions under in vitro conditions. In the presence have been assigned the same type number but of a substantial excess of a suitable cofactor and/or actually are enzymatically distinct. For example, for in the absence of the preferred cofactor, 17HSD/ the members of the 3â-HSD family that share high KSRs can be compelled to catalyze both oxidative identity and diversity between species (Penning and reductive reactions. However, in cultured cells 1997), a similar procedure could not be applied. that better reflect in vivo conditions, the cloned There are two types of human 3â-HSD having 17HSD/KSRs are exclusively or mainly either 93·5% amino acid identity and similar substrate 17HSDs or 17KSRs (see Table 2). Therefore we specificity, and up to six rodent types of 3â-HSD. suggest that, in addition to kinetic characterization The rodent forms show variable patterns of with partially purified protein or cell extracts, substrate specificity, but their DNA sequences are enzymatic properties of each new 17HSD/KSR are not dissimilar enough to allow identification of tested without additional cofactors, using cultured inter-species counterparts by sequence homology. cells transfected with the novel cDNA. The 17HSD/KSR enzymes are expressed in distinct, physiological role of each enzyme in steroidogenesis though in some cases, overlapping patterns. can thus be estimated more reliably than by 17HSD/KSRs also differ in their substrate and comparing solely kinetic values for different cofactor specificities. Certain 17HSD/KSRs cata- substrates. To avoid more confusion, we also prefer lyze primarily estrogens or androgens, whereas to maintain the current and fixed numbering for the some of them accept both phenolic and neutral cloned type 1–8 enzymes, and do not consider it steroids as substrate. There are also species-specific practicable to divide 17HSD/KSRs further into differences in substrate specificities, such as in the 17HSD and 17KSR families. case of 17HSD/KSR1 (Nokelainen et al. 1996, Puranen et al. 1997).