Functional activity of 3β-hydroxysteroid dehydrogenase/isomerase

Ji, Mason; Naville, Danielle; Evans, BW; Jl, Thomas

doi:10.3109/07435809809032644

Cited by 21 publications

(12 citation statements)

References 8 publications

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“…135 EIIQNGHEEEPLENTWPA-PY 154 PHSK 158 (22,23 (13) and spectral shifts (24) to be critical to the isomerase activity. Thus, the Y 269 -T-L-S-K 273 motif is part of a tryptic peptide that is associated with the isomerase site of the enzyme, and the Y 154 -P-H-S-K 158 motif resides outside of the isomerase domain.…”

Section: Discussionmentioning

confidence: 99%

Structure/Function Relationships Responsible for the Kinetic Differences between Human Type 1 and Type 2 3β-Hydroxysteroid Dehydrogenase and for the Catalysis of the Type 1 Activity

Thomas

Mason

Brandt

et al. 2002

Journal of Biological Chemistry

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Two distinct genes encode the 93% homologous type 1 (placenta, peripheral tissues) and type 2 (adrenals, gonads) 3␤-hydroxysteroid dehydrogenase/isomerase (3␤-HSD/isomerase) in humans. Mutagenesis studies using the type 1 enzyme have produced the Y154F and K158Q mutant enzymes in the Y ) in the type 1 enzyme. The mutant and wild-type enzymes have been expressed and purified. The K m value of dehydroepiandrosterone is 13-fold greater, and the maximal turnover rate (K cat ) is 2-fold greater for wild-type 2 3␤-HSD compared with the wild-type 1 3␤-HSD activity. The H156Y mutant of the type 1 enzyme has substrate kinetic constants for 3␤-HSD activity that are very similar to those of the wild-type 2 enzyme. Dixon analysis shows that epostane inhibits the 3␤-HSD activity of the wildtype 1 enzyme with 14 -17-fold greater affinity compared with the wild-type 2 and H156Y enzymes. The Y154F and K158Q mutants exhibit no 3␤-HSD activity, have substantial isomerase activity, and utilize substrate with K m values similar to those of wild-type 1 isomerase. The Y269S and K273Q mutants have low, pH-dependent 3␤-HSD activity, exhibit only 5% of the maximal isomerase activity, and utilize the isomerase substrate very poorly. From these studies, a structural basis for the profound differences in the substrate and inhibition kinetics of the wildtype 1 and 2 3␤-HSD, plus a catalytic role for the Tyr 154 and Lys 158 residues in the 3␤-HSD reaction have been identified. These advances in our understanding of the structure/function of human type 1 and 2 3␤-HSD/isomerase may lead to the design of selective inhibitors of the type 1 enzyme not only in placenta to control the onset of labor but also in hormone-sensitive breast, prostate, and choriocarcinoma tumors to slow their growth.

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Section: Discussionmentioning

confidence: 99%

Structure/Function Relationships Responsible for the Kinetic Differences between Human Type 1 and Type 2 3β-Hydroxysteroid Dehydrogenase and for the Catalysis of the Type 1 Activity

Thomas

Mason

Brandt

et al. 2002

Journal of Biological Chemistry

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“…In addition, enzymes of the HSD3B family also catalyze the formation and/or biotransformation of 5α-androstanes and 5α-pregnanes such as dihydrotestosterone and dihydroprogesterone [1][2][3]. Therefore, the two HSD3B isoenzymes control critical steroidogenic reactions in the adrenal cortex, gonads, placenta and a variety of peripheral tissues [44]. Mutations in the HSD3B2 gene result in classical HSD3B deficiency, a rare form of congenital adrenal hyperplasia that accounts for approximately 1% of all cases of that disease [45,46].…”

Section: Discussionmentioning

confidence: 99%

Human 3β-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics

Wang

Salavaggione

Pelleymounter

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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The 3β-hydroxysteroid dehydrogenase/Δ 5 -Δ 4 isomerase isoenzymes 1 and 2 (HSD3B1 and HSD3B2) are membrane-bound enzymes that play essential roles in the biosynthesis of steroid hormones. Therefore, variation in the HSD3B1 and HSD3B2 genes might play a role in the pathophysiology of steroid hormone-related disease. We set out to systematically identify common polymorphisms and haplotypes in human HSD3B1 and HSD3B2. We identified 17 single nucleotide polymorphisms (SNPs) in HSD3B1 and 9 in HSD3B2 -the majority of which were not present in public databases -by resequencing human HSD3B1 and HSD3B2 using 240 DNA samples from four different ethnic groups (60 samples per group). Functional genomic studies of the 5 nonsynonymous cSNPs in HSD3B1 and the one observed in HSD3B2 showed that two of these polymorphisms resulted in significant decreases in the quantity of enzyme protein expressed. However, none of the 3 nonsynonymous SNPs located in areas encoding putative membrane-binding domains altered subcellular localization of the enzyme as determined by immunofluorescence microscopy. Finally, common variant haplotypes in the 5′-flanking regions of these genes showed significant cell linedependent variation in their ability to drive transcription. In aggregate, these results provide a basis for study of the possible role in human disease of common genetic variation in HSD3B1 and HSD3B2.

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“…Enzymes of the 3β-HSD family also catalyze the formation and/or degradation of 5α-androstanes and 5α-pregnanes [2]. Thus, 3β-HSD controls critical steroid hormone-related reactions in the adrenal cortex, gonads, placenta, liver, and other peripheral target tissues [19,20]. …”

Section: 3β-hydroxysteroid Dehydrogenasementioning

confidence: 99%

Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase: A Review

Rasmussen

Ekstrand

Zamaratskaia

2013

IJMS

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This review focuses on the expression and regulation of 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase (3β-HSD), with emphasis on the porcine version. 3β-HSD is often associated with steroidogenesis, but its function in the metabolism of both steroids and xenobiotics is more obscure. Based on currently available literature covering humans, rodents and pigs, this review provides an overview of the present knowledge concerning the regulatory mechanisms for 3β-HSD at all omic levels. The HSD isoenzymes are essential in steroid hormone metabolism, both in the synthesis and degradation of steroids. They display tissue-specific expression and factors influencing their activity, which therefore indicates their tissue-specific responses. 3β-HSD is involved in the synthesis of a number of natural steroid hormones, including progesterone and testosterone, and the hepatic degradation of the pheromone androstenone. In general, a number of signaling and regulatory pathways have been demonstrated to influence 3β-HSD transcription and activity, e.g., JAK-STAT, LH/hCG, ERα, AR, SF-1 and PPARα. The expression and enzymic activity of 3β-HSD are also influenced by external factors, such as dietary composition. Much of the research conducted on porcine 3β-HSD is motivated by its importance for the occurrence of the boar taint phenomenon that results from high concentrations of steroids such as androstenone. This topic is also examined in this review.

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Functional activity of 3β-hydroxysteroid dehydrogenase/isomerase

Cited by 21 publications

References 8 publications

Structure/Function Relationships Responsible for the Kinetic Differences between Human Type 1 and Type 2 3β-Hydroxysteroid Dehydrogenase and for the Catalysis of the Type 1 Activity

Structure/Function Relationships Responsible for the Kinetic Differences between Human Type 1 and Type 2 3β-Hydroxysteroid Dehydrogenase and for the Catalysis of the Type 1 Activity

Human 3β-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics

Regulation of 3β-Hydroxysteroid Dehydrogenase/Δ5-Δ4 Isomerase: A Review

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