17B-hydroxysteroid dehydrogenases as acyl thioester metabolizing enzymes
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.
References (148)
- et al.
Peroxisomal disorders
Handb. Clin. Neurol.
(2013) - et al.
Inactivation of the peroxisomal multifunctional protein-2 in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids
J. Biol. Chem.
(2000) - et al.
Evolution of 17beta-HSD type 4, a multifunctional protein of beta-oxidation
Mol. Cell. Endocrinol.
(2001) - et al.
Mitochondrial acyl Carrier protein is involved in lipoic acid synthesis in Saccharomyces cerevisiae
FEBS Lett.
(1997) - et al.
A structural appraisal of sterol Carrier protein 2
Biochim. Biophys. Acta
(2017) - et al.
Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing
Mitochondrion
(2015) - et al.
A novel case of ACOX2 deficiency leads to recognition of a third human peroxisomal acyl-CoA oxidase
Biochim. Biophys. Acta
(2018) - et al.
Delta3,5-delta2,4-dienoyl-CoA isomerase from rat liver. Molecular characterization
J. Biol. Chem.
(1998) - et al.
Characterization of Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal tissues
J. Biol. Chem.
(1998) - et al.
Cloning and expression of cDNA for a newly identified isozyme of bovine liver 3-hydroxyacyl-CoA dehydrogenase and its import into mitochondria
Biochim. Biophys. Acta
(1997)
Fatty acid and lipoic acid biosynthesis in higher plant mitochondria
J. Biol. Chem.
Binary structure of the two-domain (3R)-hydroxyacyl-CoA dehydrogenase from rat peroxisomal multifunctional enzyme type 2 at 2.38 A resolution
Structure
Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 A resolution
J. Mol. Biol.
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.
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.
Peroxisomes contain delta 3,5,delta 2,4-dienoyl-CoA isomerase and thus possess all enzymes required for the beta-oxidation of unsaturated fatty acids by a novel reductase-dependent pathway
Biochem. Biophys. Res. Commun.
Abundant type 10 17 beta-hydroxysteroid dehydrogenase in the hippocampus of mouse Alzheimer's disease model
Brain Res. Mol. Brain Res.
MECR mutations cause childhood-onset dystonia and optic atrophy, a mitochondrial fatty acid synthesis disorder
Am. J. Hum. Genet.
Mitochondrial fatty acid synthesis--an adopted set of enzymes making a pathway of major importance for the cellular metabolism
Prog. Lipid Res.
Mitochondrial fatty acid synthesis type II: more than just fatty acids
J. Biol. Chem.
Peroxisomal multifunctional beta-oxidation protein of Saccharomyces cerevisiae. Molecular analysis of the fox2 gene and gene product
J. Biol. Chem.
Crystal structure of the (R)-specific enoyl-CoA hydratase from Aeromonas caviae involved in polyhydroxyalkanoate biosynthesis
J. Biol. Chem.
RNase P without RNA: identification and functional reconstitution of the human mitochondrial tRNA processing enzyme
Cell
17beta-Hydroxysteroid dehydrogenase type 13 is a liver-specific lipid droplet-associated protein
Biochem. Biophys. Res. Commun.
Identification and characterization of the ER/lipid droplet-targeting sequence in 17beta-hydroxysteroid dehydrogenase type 11
Arch. Biochem. Biophys.
A two-domain structure of one subunit explains unique features of eukaryotic hydratase 2
J. Biol. Chem.
The sequence of porcine 80 kDa 17 beta-estradiol dehydrogenase reveals similarities to the short chain alcohol dehydrogenase family, to actin binding motifs and to sterol Carrier protein 2
Mol. Cell. Endocrinol.
Structure of a dehydratase-isomerase from the bacterial pathway for biosynthesis of unsaturated fatty acids: two catalytic activities in one active site
Structure
Response of SCP-2L domain of human MFE-2 to ligand removal: binding site closure and burial of peroxisomal targeting signal
J. Mol. Biol.
Characterization of a monoclonal antibody for human aldo-keto reductase AKR1C3 (type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase); immunohistochemical detection in breast and prostate
Steroids
Structure and function of human 17beta-hydroxysteroid dehydrogenases
Mol. Cell. Endocrinol.
Short-chain 3-hydroxy-2-methylacyl-CoA dehydrogenase from rat liver: purification and characterization of a novel enzyme of isoleucine metabolism
Arch. Biochem. Biophys.
Analysis and characteristics of multiple types of human 17beta-hydroxysteroid dehydrogenase
J. Steroid Biochem. Mol. Biol.
The subcellular localization of 17 beta-hydroxysteroid dehydrogenase type 4 and its interaction with actin
J. Steroid Biochem. Mol. Biol.
Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing
J. Neurol. Sci.
Quaternary structure of human, Drosophila melanogaster and Caenorhabditis elegans MFE-2 in solution from synchrotron small-angle X-ray scattering
FEBS Lett.
Biosynthesis and intracellular transport of enzymes of peroxisomal beta-oxidation
J. Biol. Chem.
Integrated view on 17beta-hydroxysteroid dehydrogenases
Mol. Cell. Endocrinol.
Multifunctionality of human 17beta-hydroxysteroid dehydrogenases
Mol. Cell. Endocrinol.
Molecular basis of D-bifunctional protein deficiency
Mol. Cell. Endocrinol.
Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade
J. Biol. Chem.
Transcriptional regulation of 17beta-hydroxysteroid dehydrogenase type 12 by SREBP-1
Mol. Cell. Endocrinol.
L-3-hydroxyacyl coenzyme A dehydrogenase from pig heart muscle. I. Purification and properties
J. Biol. Chem.
Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein
Biochim. Biophys. Acta
2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene
Am. J. Hum. Genet.
Peroxisomal bifunctional protein from rat liver is a trifunctional enzyme possessing 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and delta 3, delta 2-enoyl-CoA isomerase activities
J. Biol. Chem.
A protein-truncating HSD17B13 variant and protection from chronic liver disease
N. Engl. J. Med.
Hydroxysteroid (17beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice
Faseb. J.
Purification and properties of oestradiol 17 beta-dehydrogenase extracted from cytoplasmic vesicles of porcine endometrial cells
Biochem. J.
Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV
Biochem. J.
Cited by (27)
Changes to PUFA-PPAR pathway during mesaconitine induced myocardial coagulative necrosis
2023, Food and Chemical Toxicology17β-hydroxysteroid dehydrogenases in the progression of nonalcoholic fatty liver disease
2023, Pharmacology and TherapeuticsRelationships between prostaglandin concentrations, a single nucleotide polymorphism in HSD17B12, and reproductive performance in dairy cows
2022, Journal of Dairy ScienceCitation Excerpt :This SNP results in a change of the amino acid at position 243, toward the C-terminus of the protein, from arginine to glycine, that is predicted to alter the function of the protein (SIFT score 0.01; Ng and Henikoff, 2003). Hydroxysteroid (17B) dehydrogenases are multifunctional proteins, involved in roles such as conversion of steroids between low- and high-activity forms, peroxisomal b-oxidation of fatty acids, elongation of long-chain fatty acids, and mitochondrial oxidation of 3R-hydroxyacyl-groups (Saloniemi et al., 2012; Hiltunen et al., 2019). It is possible that this SNP affects fertility in cattle through altering prostaglandin biosynthesis, as deficiency of Hsd17b12 in mouse embryonic stem cells has been associated with a reduced production of arachidonic acid (Rantakari et al., 2010), which plays a key role in prostaglandin biosynthesis.
Bulk and single-cell RNA-seq reveal the sexually dimorphic expression pattern of dmrtb1 in zig-zag eel (Mastacembelus armatus)
2021, AquacultureCitation Excerpt :After data mining, the candidate genes cyp11b, cyp51, foxl2a, and hsd17b1 are required for steroid hormone biosynthesis. The 17beta-hydroxysteroid dehydrogenase 1 (hsd17b1) is an important enzyme that can oxidize or reduce the C17 in the C18- and C19 hydroxy/keto group of androgens and estrogens, and is able to regulate the biological activity of steroid hormones (Hiltunen et al., 2019). Forkhead box L2 (Foxl2) is involved in the differentiation of granulosa cells of gonad, and promotes the expression of aromatase (cyp19a), which is the key rate-limiting enzyme in the synthesis of estrogen(Wang et al., 2007).
Multiple catalytic activities of human 17β-hydroxysteroid dehydrogenase type 7 respond differently to inhibitors
2020, BiochimieCitation Excerpt :In fact, several enzymes that are capable of reducing the keto group at the C-17 position of the steroid nucleus also display some reductase activity on the C-3 position [9]. Furthermore, many HSD17Bs display catalytical activities other than ketoreductase activity (e.g.: processing thioesters of carboxylic acids) on non-steroid substrates [42,43]. HSD17B7, however, possesses a unique feature: it plays the role as ketoreductase in the path that builds the molecule, cholesterol, from which all the steroid hormones are generated through a network of reactions that involves HSD17B7 itself and other ketoreductase enzymes.
Involvement of Type 10 17β-Hydroxysteroid Dehydrogenase in the Pathogenesis of Infantile Neurodegeneration and Alzheimer’s Disease
2023, International Journal of Molecular Sciences