Review
Integrated view on 17beta-hydroxysteroid dehydrogenases

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Abstract

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are important enzymes in steroid metabolism. Long known members of the protein family seemed to be well characterised concerning their role in the regulation of the biological potency of steroid hormones, but today more and more evidence points to pivotal contributions of these enzymes in a variety of other metabolic pathways. Therefore, studies on 17beta-HSDs develop towards metabolomic survey. Latest research results give new insights into the complex metabolic interconnectivity of the 17beta-HSDs. In this paper metabolic activities of 17beta-HSDs will be compared, their interplay with endogenous substrates summarised, and interlacing pathways depicted. Strategies on deciphering the physiological role of 17beta-HSDs and the genetic predisposition for associated diseases will be presented.

Introduction

17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyse the interconversion between the active and inactive forms of specific steroidal hormones on the final steps of their biosynthesis. They are named according to their ability to catalyse oxidation or reduction of the 17-hydroxy or 17-keto functions of specific physiologically relevant steroids. This catalysis is co-factor (NAD(P)/NAD(P)H) dependent. Up to now, 14 types of 17beta-HSDs are reported in vertebrates of which 12 are also present in humans, while 17beta-HSD6 and 9 are only reported for rodents. With the exception of 17beta-HSD5, which is a member of the aldoketo-reductase (AKR) family, all 17beta-HSDs belong to the short chain dehydrogenase/reductase (SDR) superfamily. In vertebrates the enzymes show generally low sequence homology (15–20%) but some elements characteristic for SDR members are very similar, e.g. the Rossman fold involved in cofactor binding and several conserved motifs including the active center motif “YXXXK” (Oppermann et al., 2003). Despite this structural conservation, substrate specificities among the family members are diverse and for some 17beta-HSDs substrates such as fatty acids or bile acids are preferred over sex steroids.

Section snippets

Novel functional aspects of selected 17beta-HSDs

The multifunctionality of 17beta-HSDs was already addressed in an earlier review (Moeller and Adamski, 2006). This report now will focus on latest findings on 17beta-HSD function, mostly for the enzymes with broad substrate specificity, and will mention some aspects concerning the role of 17beta-HSDs in disease.

Crystal structures of 17beta-HSDs

The first report about a 17beta-HSD crystal structure was given in 1993. Zhu and co-workers presented the crystal structure of human 17beta-HSD1 in complex with the cofactor NADP+ (Zhu et al., 1993). The refined structure of the enzyme was afterwards published in 1995 (Ghosh et al., 1995). Since then 14 more 17beta-HSD1 structures were submitted to the protein data bank (PDB), some in complex with cofactor, some with substrate or inhibitor and some in combination with substrate/inhibitor and

Animal models for 17beta-HSDs

The first mouse models for 17beta-HSDs were published in 2000, namely a knockout for 17beta-HSD4 (Baes et al., 2000) and a transgenic mouse over-expressing human 17beta-HSD10 (Du Yan et al., 2000). Since then, two more transgenic mice for human 17beta-HSD type 1 and 2 (Saloniemi et al., 2007, Zhongyi et al., 2007) were generated as well as two knockout mice for 17beta-HSD2 (Rantakari et al., 2008) and 17beta-HSD7 (Shehu et al., 2008). An overview can be found in Table 5.

The phenotype of

Polymorphisms in HSD17B genes in connection to diseases

The physiological significance of steroid hormones in diseases like for example cancer or endometriosis is well known (Kitawaki et al., 2002, Sasano et al., 2008). Therefore, in the last years, more and more efforts were made to predict susceptibility to diseases on the basis of gene variations in HSD17B genes. Up to now, we are aware of at least 35 studies dealing with the analysis of HSD17B polymorphisms in connection with cancer, polycystic ovary syndrome (PCOS), endometriosis as well as

Outlook

Although all the enzymes described here were named as 17beta-HSDs, and therewith suggested to be most important in sex steroid metabolism, we now know that many of the enzymes play more important roles in other metabolic pathways as for example in fatty acid metabolism. Therefore, 17beta-HSDs contribute to our knowledge on the metabolome, specifically the lipidome.

We are awaiting the discovery of more so-called 17beta-HSDs. Indeed, inhibitor studies against estrogenic enzymes suggest the

References (166)

  • J. Fomitcheva et al.

    Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues

    J. Biol. Chem.

    (1998)
  • G. Froyen et al.

    Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation

    Am. J. Hum. Genet.

    (2008)
  • Y. Fujimoto et al.

    Identification of major proteins in the lipid droplet-enriched fraction isolated from the human hepatocyte cell line HuH7

    Biochim. Biophys. Acta

    (2004)
  • D. Ghosh et al.

    Structure of human estrogenic 17 beta-hydroxysteroid dehydrogenase at 2.20 A resolution

    Structure

    (1995)
  • A.M. Haapalainen et al.

    Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 A resolution

    J. Mol. Biol.

    (2001)
  • Q. Han et al.

    Dehydroepiandrosterone and dihydrotestosterone recognition by human estrogenic 17beta-hydroxysteroid dehydrogenase. C-18/c-19 steroid discrimination and enzyme-induced strain

    J. Biol. Chem.

    (2000)
  • X.Y. He et al.

    Human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase is a single-domain multifunctional enzyme. Characterization of a novel 17beta-hydroxysteroid dehydrogenase

    J. Biol. Chem.

    (1999)
  • X.Y. He et al.

    Function of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in androgen metabolism

    Biochim. Biophys. Acta

    (2000)
  • X.Y. He et al.

    A human brain L-3-hydroxyacyl-coenzyme A dehydrogenase is identical to an amyloid beta-peptide-binding protein involved in Alzheimer's disease

    J. Biol. Chem.

    (1998)
  • X.Y. He et al.

    Type 10 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid modulators of gamma-aminobutyric acid type A receptors

    Mol. Cell. Endocrinol.

    (2005)
  • X.Y. He et al.

    Oxidative 3alpha-hydroxysteroid dehydrogenase activity of human type 10 17beta-hydroxysteroid dehydrogenase

    J. Steroid Biochem. Mol. Biol.

    (2003)
  • Y. Horiguchi et al.

    17beta-Hydroxysteroid dehydrogenase type 13 is a liver-specific lipid droplet-associated protein

    Biochem. Biophys. Res. Commun.

    (2008)
  • X.F. Huang et al.

    Molecular characterization of a first human 3(alpha-->beta)-hydroxysteroid epimerase

    J. Biol. Chem.

    (2000)
  • X.F. Huang et al.

    Gene structure, chromosomal localization and analysis of 3-ketosteroid reductase activity of the human 3(alpha-->beta)-hydroxysteroid epimerase

    Biochim. Biophys. Acta

    (2001)
  • S. Huyghe et al.

    Peroxisomal multifunctional protein-2: the enzyme, the patients and the knockout mouse model

    Biochim. Biophys. Acta

    (2006)
  • S. Huyghe et al.

    Peroxisomal multifunctional protein-2 deficiency causes motor deficits and glial lesions in the adult central nervous system

    Am. J. Pathol.

    (2006)
  • M.R. Jones et al.

    Polymorphism in HSD17B6 is associated with key features of polycystic ovary syndrome

    Fertil. Steril.

    (2006)
  • C.R. Kissinger et al.

    Crystal structure of human ABAD/HSD10 with a bound inhibitor: implications for design of Alzheimer's disease therapeutics

    J. Mol. Biol.

    (2004)
  • J. Kitawaki et al.

    Endometriosis: the pathophysiology as an estrogen-dependent disease

    J. Steroid Biochem. Mol. Biol.

    (2002)
  • H.M. Kravitz et al.

    Cognitive functioning and sex steroid hormone gene polymorphisms in women at midlife

    Am. J. Med.

    (2006)
  • A. Krazeisen et al.

    Determination of cDNA, gene structure and chromosomal localization of the novel human 17beta-hydroxysteroid dehydrogenase type 7

    FEBS Lett.

    (1999)
  • C. Lenski et al.

    The reduced expression of the HADH2 protein causes X-linked mental retardation, choreoathetosis, and abnormal behavior

    Am. J. Hum. Genet.

    (2007)
  • P. Lukacik et al.

    Structure and function of human 17beta-hydroxysteroid dehydrogenases

    Mol. Cell. Endocrinol.

    (2006)
  • C. Mazza et al.

    Unusual charge stabilization of NADP+ in 17beta-hydroxysteroid dehydrogenase

    J. Biol. Chem.

    (1998)
  • R. Mindnich et al.

    Identification and characterization of 17 beta-hydroxysteroid dehydrogenases in the zebrafish, Danio rerio

    Mol. Cell. Endocrinol.

    (2004)
  • G. Moeller et al.

    Multifunctionality of human 17beta-hydroxysteroid dehydrogenases

    Mol. Cell. Endocrinol.

    (2006)
  • Y.A. Moon et al.

    Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade

    J. Biol. Chem.

    (2003)
  • J. Adamski et al.

    Purification and properties of oestradiol 17 beta-dehydrogenase extracted from cytoplasmic vesicles of porcine endometrial cells

    Biochem. J.

    (1992)
  • J. Adamski et al.

    Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV

    Biochem. J.

    (1995)
  • N. Aziz et al.

    Downregulation of Ke 6, a novel gene encoded within the major histocompatibility complex, in murine polycystic kidney disease

    Mol. Cell Biol.

    (1993)
  • J. Beesley et al.

    Association between single-nucleotide polymorphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: results from two Australian studies and an additional validation set

    Cancer Epidemiol. Biomarkers Prev.

    (2007)
  • O.V. Belyaeva et al.

    Role of microsomal retinol/sterol dehydrogenase-like short-chain dehydrogenases/reductases in the oxidation and epimerization of 3alpha-hydroxysteroids in human tissues

    Endocrinology

    (2007)
  • P.G. Blanchard et al.

    Differential androgen and estrogen substrates specificity in the mouse and primates type 12 17beta-hydroxysteroid dehydrogenase

    J. Endocrinol.

    (2007)
  • M.L. Casey et al.

    17 beta-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium

    J. Clin. Invest.

    (1994)
  • Z. Chai et al.

    17 beta-hydroxysteroid dehydrogenase type XI localizes to human steroidogenic cells

    Endocrinology

    (2003)
  • L.W. Chu et al.

    Androgens and the molecular epidemiology of prostate cancer

    Curr. Opin. Endocrinol. Diabetes Obes.

    (2008)
  • A.M. Corbould et al.

    The effect of obesity on the ratio of type 3 17beta-hydroxysteroid dehydrogenase mRNA to cytochrome P450 aromatase mRNA in subcutaneous abdominal and intra-abdominal adipose tissue of women

    Int. J. Obes. Relat. Metab. Disord.

    (2002)
  • C.J. Crandall et al.

    Vasomotor symptom prevalence is associated with polymorphisms in sex steroid-metabolizing enzymes and receptors

    Am. J. Med.

    (2006)
  • J.M. Cunningham et al.

    Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer

    Cancer Epidemiol. Biomarkers Prev.

    (2007)
  • Q. Dai et al.

    Interaction of soy and 17beta-HSD1 gene polymorphisms in the risk of endometrial cancer

    Pharmacogenet. Genomics

    (2007)
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