Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.1.1.3 (HSD)
 3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3 Alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) from Pseudomonas testosteroni was shown to reduce the xenobiotic carbonyl compound metyrapone (MPON). Reversely, MPON reductase purified from mouse liver microsomes and previously characterized as aldehyde reductase, was competitively inhibited by 3 alpha-HSD steroid substrates. For MPON reduction both enzymes can use either NADH or NADPH as co-substrate. Immunoblot analysis after native and SDS gel electrophoresis of 3 alpha-HSD gave a specific crossreaction with the antibodies against the microsomal mouse liver MPON reductase pointing to structural homologies between these enzymes. In conclusion, there seem to exist structural as well as functional relationships between a mammalian liver aldehyde reductase and prokaryotic 3 alpha-HSD. Moreover, based on the molecular weights and the co-substrate specificities microsomal mouse liver MPON reductase and Pseudomonas 3 alpha-HSD seem to be members of the short-chain alcohol dehydrogenase family.
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PMID:Functional and immunological relationships between metyrapone reductase from mouse liver microsomes and 3 alpha-hydroxysteroid dehydrogenase from Pseudomonas testosteroni. 155 29

Reactions of oestrogens and androgens at position C-17 are catalysed by 17 beta-hydroxysteroid dehydrogenases (17 beta-HSDs). Cloning of the cDNA of a novel human 17 beta-HSD IV and expression of its mRNA are described. A probe derived from the recently discovered porcine 17 beta-oestradiol dehydrogenase (17 beta-EDH) was used to isolate a 2.6 kb human cDNA encoding a continuous protein of 736 amino acids of high (84%) similarity to the porcine 17 beta-EDH. The calculated molecular mass of the human enzyme is 79,595 Da. Other sequence similarities shared by the two enzymes are: an N-terminal sequence which is similar to that of members of the short-chain alcohol dehydrogenase family; amino acids 343-607 which are similar to the C-terminal domains of a trifunctional Candida tropicalis enzyme and the FOX2 gene product of Saccharomyces cerevisiae; amino acids 596-736 which are similar to human sterol carrier protein 2. The previously cloned human 17 beta-HSD I, II and III are less than 25% identical with 17 beta-HSD IV. mRNA for HSD IV is a single species of 3.0 kb, present in many tissues with highest concentrations in liver, heart, prostate and testes. When over-expressed in mammalian cells, the human 17 beta-HSD IV enzyme displays a specific unidirectional oxidative 17 beta-HSD activity.
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PMID:Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV. 748 79

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) converts glucocorticoids to receptor inactive metabolites. Two isoforms of the enzyme exist. 11 beta HSD1 is a low affinity NADP dependent enzyme, while 11 beta HSD2 is a high affinity NAD dependent species thought to be responsible for endowing specificity on the mineralocorticoid receptor and for protecting the fetus from high circulating levels of maternal glucocorticoids. We have recently cloned the human renal 11 beta HSD2 enzyme. In this report we show that 11 beta HSD2 potently inactivates the synthetic glucocorticoid dexamethasone, producing a single product thought to be the 11-dehydrodexamethasone metabolite. Sequence analysis shows that the new isoform is a member of the short-chain alcohol dehydrogenase superfamily (SCAD), most closely related to 17 beta HSD2 and distantly related to 11 beta HSD1.
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PMID:Cloning of the 11 beta HSD type II enzyme from human kidney. 758 4

The 3.0-A-resolution x-ray structure of rat liver 3 alpha-hydroxysteroid dehydrogenase/dihydrodiol dehydrogenase (3 alpha-HSD, EC 1.1.1.50) was determined by molecular replacement using human placental aldose reductase as the search model. The protein folds into an alpha/beta or triose-phosphate isomerase barrel and lacks a canonical Rossmann fold for binding pyridine nucleotide. The structure contains a concentration of hydrophobic amino acids that lie in a cavity near the top of the barrel and that are presumed to be involved in binding hydrophobic substrates (steroids, prostaglandins, and polycyclic aromatic hydrocarbons) and inhibitors (nonsteroidal antiinflammatory drugs). At the distal end of this cavity lie three residues in close proximity that have been implicated in catalysis by site-directed mutagenesis--Tyr-55, Asp-50, and Lys-84. Tyr-55 is postulated to act as the general acid. 3 alpha-HSD shares significant sequence identity with other HSDs that belong to the aldo-keto reductase superfamily and these may show similar architecture. Other members of this family include prostaglandin F synthase and rho-crystallin. By contrast, 3 alpha-HSD shares no sequence identity with HSDs that are members of the short-chain alcohol dehydrogenase family but does contain the Tyr-Xaa-Xaa-Xaa-Lys consensus sequence implicated in catalysis in this family. In the 3 alpha-HSD structure these residues are on the periphery of the barrel and are unlikely to participate in catalysis.
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PMID:Three-dimensional structure of rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase: a member of the aldo-keto reductase superfamily. 814 47

The overexpression and purification of recombinant rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase (3 alpha-HSD; EC 1.1.1.50) in Escherichia coli are described. The properties of the homogeneous recombinant 3 alpha-HSD (r3 alpha-HSD) confirm that a single polypeptide can function as a HSD, as a dihydrodiol dehydrogenase, and as an aromatic aldehyde, ketone, and quinone reductase. Cys-170, Cys-242, and Cys-217, implicated by bromoacetoxysteroid affinity-labeling agents as points of contact for the C-3, C-11, and C-17 positions of steroid ligands, were mutated to alanines. Unexpectedly, the homogeneous C170A and C242A mutants were kinetically similar to wild-type r3 alpha-HSD. By contrast, the C217A mutant gave Km values that were 4-fold higher for androstanedione and 2-fold higher for NADH. Inspection of the recently solved crystal structure of rat liver 3 alpha-HSD (Hoog, S. S., Pawlowski, J. E., Alzari, P. M., Penning, T. M., and Lewis, M. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 2517-2521) places Cys-170 and Cys-242 on the periphery of an alpha/beta-barrel so that they cannot be involved in catalysis of steroid recognition. This demonstrates that bromoacetoxysteroid affinity-labeling agents may provide misleading information regarding the topography of steroid hormone binding sites. When NADPH was modeled into the crystal structure of 3 alpha-HSD, Tyr-55 was implicated as the general acid, since it is in close proximity to the C-4 position of the nicotinamide ring and could polarize the substrate carbonyl. In support of this model, the purified Y55F mutant was found to be catalytically inactive, but still formed an E-NADPH complex (measured by fluorescence titration) and an E-NADH-testosterone complex (measured by equilibrium dialysis). The ability of the Y55F mutant to form binary and ternary complexes, but not aid in hydride transfer, is consistent with Tyr-55 acting as the general acid. 3 alpha-HSD is a member of the aldo-keto reductase superfamily, and Tyr-55 is invariant in members of this family where it may perform a similar function. Tyr-205 is present in a pentapeptide sequence that is conserved in HSDs that belong to the short-chain alcohol dehydrogenase family and has been implicated as the general acid within these enzymes. The Y205F mutant was found to be kinetically similar to wild-type r3 alpha-HSD.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Overexpression and mutagenesis of the cDNA for rat liver 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase. Role of cysteines and tyrosines in catalysis. 817 84

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) play a crucial role in the control of active sex steroid intracellular levels. Seven types of 17beta-HSD have been described. In this study, we report the cloning and characterization of the mouse type 5 17beta-HSD belonging to the aldo-keto reductase superfamily, in contrast with types 1, 2, 3, 4, 6, and 7 17beta-HSD which belong to the short-chain alcohol dehydrogenase family. The gene spans 16 kb and contains 9 exons separated by 8 introns. Primer extension analysis identified a major transcription start site beginning 50 nucleotides upstream from the ATG initiation codon. Northern blot analysis showed a high mRNA expression level in the liver and a weaker signal in the kidney. To determine more precisely the substrate specificity of the enzyme, we established a stable cell line expressing mouse type 5 17beta-HSD in transformed human embryonic kidney (293) cells. The transfected cell line preferentially catalyzes the transformation of 4-androstenedione (4-dione) and androstanedione (A-dione) into testosterone (T) and dihydrotestosterone (DHT), respectively. This data is somewhat in contradiction with a previous study that described the enzyme as estradiol 17beta-dehydrogenase. Our results indicate that the rate of transformation of estradiol (E(2)) to estrone (E(1)) represents only 1% of the rate of transformation of 4-dione to T. Mouse type 5 17beta-HSD shares 76% amino acid sequence identity with human type 5 17beta-HSD; 71%, 76%, 76% with rat 3alpha-HSD and human types 1 and 3 3alpha-HSDs, respectively; and 71%, 69% and 77% with mouse, rat and human 20alpha-HSD, respectively.
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PMID:Structure and activity of the murine type 5 17beta-hydroxysteroid dehydrogenase gene(1). 1050 Feb 39