17B-hydroxysteroid dehydrogenases as acyl thioester metabolizing enzymes

https://doi.org/10.1016/j.mce.2018.11.012Get rights and content

Highlights

  • Several HSD17Bs display functional diversity and are multitasking.

  • At least HSD17B4, 8, 10 and 12 accept acyl-thioester (CoA or ACP) substrates.

  • Involved metabolic processes include both breakdown and synthetic pathways.

  • Crystal structures of HSD17B4, 8 and 10 give into insights their functions.

Abstract

17β-Hydroxysteroid dehydrogenases (HSD17B) catalyze the oxidation/reduction of 17β-hydroxy/keto group in position C17 in C18- and C19 steroids. Most HSD17Bs are also catalytically active with substrates other than steroids. A subset of these enzymes is able to process thioesters of carboxylic acids. This group of enzymes includes HSD17B4, HSD17B8, HSD17B10 and HSD17B12, which execute reactions in intermediary metabolism, participating in peroxisomal β-oxidation of fatty acids, mitochondrial oxidation of 3R-hydroxyacyl-groups, breakdown of isoleucine and fatty acid chain elongation in endoplasmic reticulum. Divergent substrate acceptance capabilities exemplify acquirement of catalytic site adaptiveness during evolution. As an additional common feature these HSD17Bs are multifunctional enzymes that arose either via gene fusions (HSD17B4) or are incorporated as subunits into multifunctional protein complexes (HSD17B8 and HSD17B10). Crystal structures of HSD17B4, HSD17B8 and HSD17B10 give insight into their structure-function relationships. Thus far, deficiencies of HSD17B4 and HSD17B10 have been assigned to inborn errors in humans, underlining their significance as enzymes of metabolism.

Introduction

17β-Hydroxysteroid dehydrogenases (HSD17Bs) in mammals are represented by at least as 14 separate enzymes that all display catalytic activities towards 17β-hydroxy and – keto steroid substrates, at least if tested in vitro. Amino acid sequence similarities between HSD17Bs are in the range of 25–30%. Except HSD17B5 (AKR1C3) that is an aldo-ketoreductase (AKR) (Matsuura et al., 1998; Lin et al., 2004), these proteins have been assigned as members of the short chain alcohol reductase/dehydrogenase (SDR) protein superfamily (Moeller and Adamski, 2006). Although the perceived function of HSD17B enzymes is to maintain estrogen and androgen balance, their functional roles under physiological conditions have not always been easy to visualize, because their expression is not limited to steroidogenic tissues and protein abundance is highly variable. Characterization of HSD17B enzymes has shown that most of them, in parallel with their action on sex steroids, display catalytic activities with non-sex steroid substrates including retinols, cholesterol, secondary alcohols and ketones, xenobiotics and thioesters of various long-chain carboxylic acids including fatty acids and their metabolites (Table 1). Mounting evidence that their main physiological functions are other than sex steroid interconversion is in line with subcellular localizations inconsistent with sex steroid metabolism and in some case with existence of their orthologues in unicellular eukaryotes in which cell physiology is not regulated by sex steroid hormones. The dehydrogenase units (DH) of HSD17Bs belong to the short chain alcohol dehydrogenase/reductase (SDR) superfamily of oxidoreductases and possess a canonical Rossmann fold that provides structural scaffold for binding site for NAD+-dependent dehydrogenase as well as for NADPH-dependent reductase (Moeller and Adamski, 2009; Thomas and Potter, 2013; Kavanagh et al., 2008; Peltoketo et al., 1999). A nomenclature for human SDR enzymes has been established (Kallberg et al., 2010; Persson et al., 2009) (see Table 1), but in this article we follow names used for 17β-hydroxysteroid dehydrogenase as stipulated by the HUGO Gene Nomenclature Committee (https://www.genenames.org/).

This review deals with HSD17Bs catalyzing reactions with an acyl-group attached to phosphopantetheine of CoA or holo acyl carrier protein (ACP) and which have been identified as participants in intermediary metabolism. The target atoms of the reactions catalyzed by these HSD17Bs are keto or hydroxyl-groups on the third carbon in the acyl chain of substrate molecules. The overall reactions proceed towards both degradative (chain shortening) and synthetic directions (chain elongation) and the catalyzing enzymes are typically found in mitochondria, peroxisomes or endoplasmic reticulum (ER) (Lukacik et al., 2006). We will discuss in detail the evidence implying that HSD17B4, HSD17B8, HSD17B10 and HSD17B12 acting also as acyl thioester metabolizing enzymes, in addition to their function as 17β-hydroxysteroid dehdyrogenases.

Section snippets

HSD17B4 as a peroxisomal multifunctional multidomain β-oxidation enzyme

HSD17B4 was isolated from porcine endometrium as an enzyme catalyzing the oxidation of estradiol to estrone in vitro (Adamski et al., 1992), and it was found to localize to peroxisomes (Markus et al., 1995). Curiously, this protein was cloned independently by five research groups studying various aspects of mammalian steroid and lipid metabolism and using different cloning strategies (Leenders et al., 1994; Adamski et al., 1995; Corton et al., 1996; Dieuaide-Noubhani et al., 1997; Qin et al.,

HSD17B8 as a subunit of the ketoacyl reductase 1 (KAR1) of mitochondrial fatty acid synthesis

HSD17B8 was first identified as Ke6 linked to polycystic disease in mouse, where its expression is downregulated in affected animals (Aziz et al., 1993). The enzyme was later classified as HSD17B based on its sequence similarity to other HSD17Bs and its activity with sex steroids, preferentially towards oxidation of estradiol, testosterone, and dihydrotestosterone (Fomitcheva et al., 1998). Thus far, there are not much data elucidating the endocrine function of HSD17B8, other than studies on

HSD17B10 as a multitasking dehydrogenase

The HSD17B10 protein, encoded by the HSD17B10 gene located on the X chromosome in humans, is known under a plethora different names and has been reported to play roles in a variety of different, seemingly unrelated mitochondrial pathways and processes (Holzmann et al., 2008; Vilardo et al., 2012; Yang et al 2005b, 2009; Oerum et al., 2017). The homotetrameric protein was initially assigned to the ER (Yan et al., 1997), but later studies have identified HSD17B10 as a mitochondrial protein. The

HSD17B12

The fatty acid elongation system in the ER is in charge of endogenous synthesis of very long chain fatty acid including endogenous synthesis of arachidonic acid from shorter ω-6 unsaturated fatty acids, using long chain fatty acyl-CoA esters as primers and malonyl-CoA functioning as a two-carbon fragment donor. The second reaction of the pathway is catalyzed by ketoacyl reductase (KAR) reducing 3-ketoacyl-CoA to 3-hydroxyacyl-CoA in an NADPH-dependent manner. The enzyme identified to catalyze

Future directions

An interesting aspect of acyl-CoA esters-metabolizing HSD17Bs is that they appear to have been recruited to participate simultaneously in intermediary and sex steroid metabolism. The understanding of their roles in intermediary metabolism has been facilitated by identification of inborn errors resulting from HSD17B deficiencies, genetic association studies and by studies of the phenotypes of genetically modified mouse models. Because lipid metabolizing HSD17Bs operate at the interface of

Acknowledgements

Our original work was supported by grants from the Academy of Finland, Finland and Sigrid Jusélius Foundation, Finland.

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