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Divisions of Endocrinology and Metabolism (R.J.A.) and Nutrition and Metabolic Diseases (A.K.A.), Department of Internal Medicine, The Donald W. Reynolds Cardiovascular Clinical Research Center (R.J.A.), and the Center for Human Nutrition (A.K.A.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-8857
Address all correspondence and requests for reprints to: Richard J. Auchus, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8857. E-mail: richard.auchus{at}UTSouthwestern.edu.
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Abstract |
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 Top Abstract Cellular Redox State and...Cellular Redox State and...Structural and Functional...Structural and Cellular...Future StudiesReferences |
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Cellular Redox State and Redox Sensing |
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Nicotinamide cofactors and redox state
The relative ratio of oxidized and reduced cofactors varies with the amount and type of metabolic fuels and with oxygen supply. Reducing equivalents are generated by the oxidation of hydrocarbon substrates, and, collectively, the abundance of reducing equivalents determines the redox state of the cell. In the fed state with abundant fuel and oxygen, cells have high reductive capacity, reflected by a high ratio of the reduced and oxidized forms of nicotinamide adenine dinucleotide phosphate (NADPH >> NADP+) (1). However, specialized cellular enzymatic activities, including the synthesis or degradation of biomolecules, also require nicotinamide cofactors. Consequently, the capacity of cells to perform these specialized functions is inherently linked to intermediary metabolism, redox state, and the supply of proper cofactors. However, little is known about the capacity of eukaryotic cells to monitor redox state for supporting specialized functions.
Cellular mechanisms for sensing and responding to redox state
Although formerly an area of intense study when the pathways of intermediary metabolism was first elucidated, interest in mechanisms controlling the redox state of cells and sensing mechanisms has surfaced again over the last few years. Lower eukaryotes have evolved proteins like Rex in Streptomyces coelicolor A3(2) (2) or OxyR (3) and RegB (4), which react to changing redox state of the cells. Most commonly, these proteins contain disulfide bonds, which can be oxidized (-S-S-) or reduced (-SH HS-) conveniently and proportionately to redox state. Additional protein prosthetic groups that undergo redox chemistry and, hence, serve as sensors include iron-sulfur clusters, iron-protoporphyrins (hemes), and flavins (flavin adenine dinucleotide and flavin mononitrate) (5). Redox-sensing prosthetic groups can alter the function of the protein itself, or the redox-sensing protein can alter the function of other proteins. In most cases, electrons from NADPH, the common electron currency of the cytoplasm, reduce the prosthetic groups, and the extent to which reduction occurs depends on the abundance of NADPH. The process may be reversible or irreversible, and the mechanism may involve a two-electron hydride transfer or two discreet one-electron steps.
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Cellular Redox State and the Nicotinamide Cofactor Gradients |
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). The two key enzymes involved in this process, glucose-6-phosphate (G6P) dehydrogenase (G6PDH) and 6-phosphogluconate (6PG) dehydrogenase (6PGDH), sequentially oxidize G6P and use those electrons to reduce NADP+ to NADPH. Because glucose is a major fuel for many tissues, these two enzymes are the major source of NADPH in most cells for biosynthetic purposes. Because most tissue culture is performed in high-glucose medium, the PPP is also the principal mechanism for regenerating NADPH in cultured cell lines used for various experiments. In addition, G6PDH plus G6P is commonly employed as an NADPH regeneration system for in vitro experiments. G6PDH is the first committed step in the PPP, and dysregulation of the enzyme will have an effect on the abundance of NADPH in cells. Glucocorticoids increase G6PDH activity in the rat hepatocytes, and insulin exerts a cooperative effect on the enzyme in the presence of glucocorticoids. Similar regulation by glucocorticoids and insulin are also observed in the adipose tissue, but the comprehensive hormonal, nutritional, and transcriptional regulation of this isoform is not well understood. The 6PGDH enzyme of the PPP also generates NADPH but demonstrates product inhibition by high concentrations of NADPH, and additional regulatory mechanisms for this enzyme are not known.
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-ketoglutarate (Fig. 1
). All of the reactions of the TCA occur in the mitochondria, and the mitochondrial isoform of isocitrate dehydrogenase reduces NAD+ to NADH. However, a cytoplasmic form of isocitrate dehydrogenase uses NADP+ as the electron acceptor and therefore provides another mechanism for generating cytoplasmic NADPH (7). Other minor pathways also regenerate NADPH, but flux through these pathways is not a significant source of NADPH.
Although these major routes of NADPH regeneration service the cytoplasm, nicotinamide pools appear to be compartmentalized within cells and may not equilibrate across organelles. In the endoplasmic reticulum, which is primarily an oxidizing environment that favors protein processing and disulfide bond formation, hexose-6-phosphate dehydrogenase (H6PDH; or salivary and microsomal glucose-1-dehydrogenase) provides a local supply of NADPH (8). H6PDH, the microsomal counterpart of the cytoplasmic G6PDH, has much broader substrate specificity than G6PDH and oxidizes other substrates such as glucose-6-sulfate and galactose-6-phosphate to generate reduced cofactor. H6PDH is ubiquitously expressed, except in erythrocytes, and this enzyme is not part of any known biosynthetic pathways. Proteins or enzymes that are localized to the lumen of the endoplasmic reticulum and that require NADPH for its activity are likely to be dependent on the action of H6PDH (Fig. 1). The regulation of H6PDH activity by hormones and nutrient supply has not been studied in detail, and the mechanisms for supplying the intralumenal compartment with nicotinamide cofactors remain unknown.
Maintaining an inverse NADH/NAD+ gradient
In contrast, cells maintain a concentration gradient that favors the oxidized form of NADH, with NAD+ concentrations exceeding NADH by nearly 3 orders of magnitude (9). Analogous to the role of NADPH as the common electron currency in cells, NAD+ is the prototypical electron acceptor for several dehydrogenase reactions involved in glycolysis and fatty acid oxidation. Just as NADPH is constantly regenerated when glucose is abundant, electrons from NADH are constantly removed for use in the mitochondrial electron transport chain that drives oxidative phosphorylation and ATP generation during aerobic metabolism. This insatiable drain of electrons from NADH maintains a high NAD+ to NADH ratio and assures that cofactor is available for oxidation of fuel substrates.
Despite elaborate systems for maintaining cellular cofactor gradients, disruption of fuel and oxygen supply will lower these gradients. Massive changes may not be compatible with cell survival, but small changes are tolerated given the magnitude of these gradients. However, alterations in cofactor gradients may have consequences on other cellular functions that require large gradients for optimal function.
Nontraditional redox-sensing transcription factors and steroid hormones
The abundance of reduced and oxidized pairs of intermediary metabolism products, such as NADPH/NADP+ and malate/oxaloacetate, reflect the redox state of the cell. Although these molecules are present at high concentrations in cells, it is now recognized that the amounts and activities of other, less abundant molecules and proteins are also influenced by redox state. For example, the activities of transcription factor Sir2 (10) and the transcriptional corepressor carboxyl-terminal binding protein (11) are regulated via their binding NADH/NAD+; hence, these proteins sense the cellular composition of these cofactors. PAS domain proteins are basic helix-loop-helix transcription factors that are regulated by ligands, light, and other factors (12). The NPAS2-BMAL1 heterodimer, which maintains the circadian rhythm, senses the cellular redox state by binding NADPH/NADP+, which in turn regulates its transcriptional activity (13).
Additional metabolic pathways that require oxidized or reduced cofactor(s) require intermediary metabolism to maintain cellular cofactor concentration gradients necessary for these reactions. Consequently, these pathways are vulnerable to disruption if cellular redox state and, hence, cofactor gradients are not maintained. Steroid hormones are examples of a low-abundance (
1 nM) compounds that undergo redox reactions. Cytochrome P450 reactions, including the steroid hydroxylation and side-chain cleavage reactions, all require NADPH and molecular oxygen (14), and these reactions irreversibly oxidize the steroid nucleus (15). P450 reactions are rather limited, encompassing the biosynthetic transformations in the adrenal, gonad, and placenta plus the catabolic reactions in the liver and some other tissues. More globally, peripheral steroid metabolism is dominated by the hydroxysteroid dehydrogenases (HSDs). HSD reactions convert hydroxysteroids to ketosteroids and vice versa using nicotinamide cofactors (15). The key positions of metabolism are C-11 for glucocorticoids and mineralocorticoids, C-20 for progestins, C-17 for androgens and estrogens, and C-3 for all 5-reduced steroids. The two members of a ketosteroid-hydroxysteroid pair often differ dramatically in affinities for their cognate receptors; consequently, HSD reactions are critical to determining steroid bioactivity.
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Structural and Functional Characteristics of HSDs |
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-ß fold with core of parallel ß-strands fanning across the center and -helices draped on the outside (16). The SDR enzymes contain a Rossman fold and GXXXGXG motif (where G is glycine and X is any other amino acid) characteristic of oxidation/reduction enzymes that bind nicotinamide cofactors, plus the YXXXK (where Y is tyrosine and K is lysine) sequence that participates in catalysis. This structural fold, which was first described for glyceralde 3-phosphate dehydrogenase, is the fold observed in x-ray structures of bacterial 3,20ß-HSD (17), human 17ß-HSD1 (18), and guinea pig 11ß-HSD1 (19). Sequence analysis indicates that 17ß-HSDs1–3, 11ß-HSDs1 and 2, and the oxidative 3-HSDs of the retinol dehydrogenase variety all belong to the SDR superfamily. The SDR-type HSDs are active only as dimers or tetramers, and most are tightly membrane-bound (Fig. 2, left).
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-HSD (AKR1C9) (21), AKR1C2 (22), and AKR1C3 (23) also demonstrate this fold. A TIM barrel also exhibits a continuous ß--ß pattern, but the eight ß-strands lie in a tilted circular array like the staves of a barrel, with -helices stitching the strands together on the outside of the barrel. Analogous tyrosine and lysine residues that participate in catalysis are adjacent in space but distant in linear sequence, and cofactor drapes across the edge of the barrel without a Rossman fold (Fig. 2, right). Functionally, the HSDs can be divided into true dehydrogenases, which oxidize hydroxysteroids to ketosteroids, and reductases, which reduce ketosteroids to hydroxysteroids. This distinction is based on the observed flux of substrates obtained when the cDNA for the enzyme in question is expressed in a cell line with low background steroid metabolism, such as HEK-293 cells. For example, the reductive 17ß-HSD1 converts estrone almost completely to estradiol (24), whereas oxidative 17ß-HSD2 converts over 95% of estradiol to estrone (25). However, all HSDs employ a common hydride transfer mechanism using nicotinamide cofactors, and all steps of these reactions are reversible. Consequently, some HSDs, when purified and studied in vitro, have been shown to catalyze either steroid oxidation or reduction depending on assay conditions. So what factors control HSD directionality in intact cells and explain the discrepancy of results from in vivo and in vitro experiments?
Regulation of HSD activity by cofactor preference and redox state
Under conditions where enzyme concentrations and pH remain stable, HSD reactions obey second order kinetics. For a reductive HSD:
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Unlike the P450 reactions that are mechanistically irreversible, all steps of the hydride transfer reactions are freely reversible. Therefore, the reactions are also governed by the kinetic expression for the oxidation reaction:
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Theoretically, these reactions should come to an equilibrium state when enough substrate has been depleted that the rate of the reverse reaction rises and Ratered = Rateox. These equilibrium states are observed when purified enzyme is studied in vitro, and the equilibrium steroid distribution can be shifted by altering cofactor concentrations and pH (26). Do similar reversible equilibria also occur in intact cells?
The simplistic equations above neglect the fact that the nicotinamide cofactors are used by other cellular processes and are constantly regenerated via intermediary metabolism as described above (Fig. 1). Consequently, cofactor concentrations remain relatively constant during short-term experiments in transfected cells, allowing steroid conversion to proceed nearly to completion. Yet, no matter how long incubations are continued or how much enzyme is expressed, some steroid substrate persists, and metabolism proceeds asymptotically to a final state in which metabolism appears to cease because no net mass flux occurs. Nonetheless, double-isotope experiments demonstrate that, at least in the case of 17ß-HSDs types 1–3, steroids are rapidly interconverted at these apparent equilibrium states and that the rates of the forward and reverse reactions are essentially equal (27). Cell culture experiments are not a closed system as are enzyme assays in a test tube that achieve a true equilibrium, but to a first approximation, these HSD reactions achieve a pseudoequilibrium state in intact cells. However, in all cases, the final steroid proportions prominently favor either oxidation or reduction depending on the enzyme.
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Structural and Cellular Determinants of Directional Preference |
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In HSD-catalyzed reactions, the hydride transfer or chemical step occurs in the ternary enzyme-steroid-cofactor complex. If both 17ß-HSD1 and 17ß-HSD2 interconvert estrone and estradiol from similar ternary complexes, then how does 17ß-HSD1 achieve net steroid reduction, whereas 17ß-HSD2 efficiently oxidizes estradiol? The answer cannot be in the handling of steroid but rather in the use of cofactor. Indeed, cytoplasmic free nicotinamide cofactor concentrations (1 mM) exceed steroid hormone concentrations (1 nM) by many orders of magnitude, even for the low-abundance members of the cofactor pairs NADH and NADP+. Consequently, rate expressions are dominated not by steroid but by the cofactor term. As explained above, intermediary metabolism normally establishes large cofactor concentration gradients, with [NADPH] >> [NADP+] and [NAD+] >> [NADH]. Therefore, if cofactor binding by each HSD isoform is restricted to one pair of cofactors, then mass action will drive steroid flux for either ketosteroid reduction (by NADPH) or hydroxysteroid oxidation (by NAD+). Although this paradigm may be oversimplified, it does rationalize the observed chemistry. Steroid oxidation by 17ß-HSD2 proceeds because the NADH so generated is reoxidized via the electron transport chain and coupled to reduction of oxygen, providing the ultimate thermodynamic drive (Fig. 2).
Both 17ß-HSD1 and 17ß-HSD2 are SDR enzymes, for which considerable functional and structural information is available. The SDR enzymes bind cofactor within a Rossman fold, and residues within this fold interact with cofactor in the vicinity of the 2' position, where a phosphate group distinguishes NADP(H) from NAD(H). In the early 1990s, crystal structures and sequence alignments suggested that enzymes such as glutathione reductase, which use NADPH, contain a positively charged arginine that forms a salt bridge with the 2'-phosphate of NADPH, stabilizing the binding of NADP(H). In contrast, oxidative enzymes like dihydrolipoamide dehydrogenase and alcohol dehydrogenase contain a negatively charged residue at the corresponding position, which would repel the 2'-phosphate of NADP(H) but might hydrogen bond to the 2'-hydroxyl group of NAD(H). Site-directed mutagenesis experiments demonstrated that swapping the charged residues of these enzymes reversed the relative affinities of purified enzymes for these cofactor pairs (28, 29).
Analogously, mutation of leucine 36 to aspartate reverses the cofactor preference of 17ßHSD1 from NADPH/NADP+ to NAD+/NADH by introducing a negative charge adjacent to the 2'-phosphate (30) (Fig. 3). This mutation also reverses the directional preference of 17ßHSD1 in intact cells, strongly favoring estradiol oxidation yet still catalyzing rapid and bidirectional metabolism that achieves a pseudoequilibrium state (27). Mutation of arginine 80, the corresponding residue in 17ß-HSD3, to glutamine causes male pseudohermaphroditism primarily by disrupting NADPH binding, not steroid binding (31, 32). Conversely, mutation aspartate 36 to alanine + lysine 37 to arginine reverses cofactor preference of the oxidative human 3ß-HSD1 from NAD(H) to NADP(H) (33). However, it is not known whether these simple rules for cofactor binding, which translate to directional preference in intact cells, are unique to these few HSDs or general. The oxidative 3-HSD from prostate (34), which belongs to the retinol dehydrogenase family (35), appears to be a hydroxysteroid epimerase (36), ultimately reducing the 3-ketosteroid (i.e. 5-androstane-3,17-dione) to a 3ß-hydroxysteroid (i.e. epi-androsterone) after prolonged incubations, somehow managing to reverse its directional preference. Finally, the cofactor binding determinants for the AKR isoforms, which lack a Rossman fold, have received limited study (37, 38) (Fig. 3).
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The directional preference of 11ß-HSD1 in transfected cells favors the reduction of cortisone to cortisol, presumably using NADPH as do all other reductive HSDs. Paradoxically, recombinant 11ß-HSD1, overexpressed in cultured cells infected with vaccinia virus (40) or in Escherichia coli (41), reduces cortisone poorly in vitro with NADPH. In contrast, recombinant 11ß-HSD1 readily oxidizes cortisol to cortisone in vitro using either NADP+ or NAD+, a result that seemingly violates all of the principles established above. Addition of an NADPH-regenerating system (G6PDH plus G6P) to the in vitro assay, however, enables recombinant 11ß-HSD1 to reduce cortisone almost completely to cortisol. Therefore, it appears that the reductive activity of 11ß-HSD1 in vivo requires a particularly high NADPH/NADP+ gradient for maximal activity. This condition is fulfilled in some cells for which 11ß-HSD1 activity appears important such as adipocytes, where its cortisone reductase activity may contribute to fat accumulation (42). During lipogenesis, NADPH abundance increased considerably to provide reducing equivalents necessary to elongate fatty acid chains with two-carbon acetate units (43). This rise in the NADPH to NADP+ ratio would activate the reductase activity of 11ß-HSD1 (6).
To complicate matters further, 11ß-HSD1 resides in the endoplasmic reticulum lumen (42), which normally maintains a highly oxidative redox state (44). Within the intralumenal compartment, the processing of nascent proteins occurs, including the formation of intramolecular disulfide bonds and their rearrangement by protein disulfide isomerase. How, then, can an enzyme that functions as a reductase only when available NADP+ is scrupulously reoxidized to NADPH function in a strongly oxidizing environment? The answer appears to be that this requisite supply of NADPH derives from the intralumenal enzyme H6PDH (Fig. 1). This role of H6PDH has been substantiated by studies of subjects with apparent cortisone reductase deficiency in whom cortisone reduction to cortisol is impaired. These subjects have intronic polymorphisms in the HSD11B1 gene that reduce expression and, more importantly, mutations in the H6PDH gene that impair intralumenal NADPH regeneration (45). Although these results are consistent with a model whereby H6PDH supplies NADPH to 11-ßHSD1, the stoichiometry of the two proteins appears to show less H6PDH than expected (46), and other intralumenal HSDs, such as 17ß-HSD2, retain an oxidative preference in this environment (25). Therefore, additional and yet unknown properties of H6PDH and 11-ßHSD1 appear to cooperate and allow this unique intralumenal reductive preference. Alternatively, excess NADPH from the cytoplasmic pool might also transport, actively or passively, into the endoplasmic reticulum lumen to provide needed reducing equivalents under some conditions.
Significance of bidirectional metabolism and directional preference
Our analysis of the kinetic and metabolic determinants of HSD function illustrates the fundamental principle that HSD-catalyzed reactions are not driven by steroid but by cofactor concentration gradients. Although each HSD has a limited repertoire of keto- and hydroxysteroid substrate pairs that it will metabolize, it is cofactor abundance and relative affinities of the enzymes for cofactors that determine the directional preference of HSDs and, thus, their physiologic roles. Because the chemical mechanisms of these reactions are inherently reversible, the HSDs can only shuttle steroid pairs to a certain pseudoequilibrium distribution that is limited by cofactor gradients.
Two important correlates of this analysis emerge. First, when HSDs are presented with the wrong steroid, which is normally the product of the preferred half-reaction, rapid bidirectional metabolism will force some steroid flux in the reverse direction. In model systems, this backwards metabolism by 17ß-HSD2 is sufficient to activate reporter gene expression with physiologic concentrations of estrone via its conversion to estradiol (27). Second, because the magnitude of the directional preference is intimately linked to cofactor abundance, conditions of altered intermediary metabolism that significantly deplete intracellular cofactor gradients should shift the pseudoequilibrium of HSDs in cells and tissues. These shifts in intermediary metabolism can occur when the supply, composition, or combustion of fuel is changed, such as in fasting, hypoxia, and reduced blood flow. It is difficult to predict how the results obtained in model systems extrapolate the tissues of an animal; nonetheless, the regulation of steroid hormone potency via intermediary metabolism, mediated by the impact of cofactor abundance on HSD activities, requires further study.
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Future Studies |
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Additional methods to track cofactor flux involve stable isotope and nuclear magnetic resonance (NMR) techniques. By incorporating stable isotopes into cofactors, flux may be quantitated by mass spectrometry, which is an extremely accurate and sensitive yet destructive technique. NMR methods are theoretically nondestructive, but only in cells and tissues that can be studied in an NMR magnet. Both methods might be adapted to tracking specific subcellular pools by selectively introducing stable isotopes to one compartment or by exploiting differences in relaxation times for cofactors in different compartments. Significant technical hurdles must be overcome for any of these approaches can be exploited experimentally.
Finally, the regulatory mechanisms for sensing, synthesizing, and consuming nicotinamide cofactors in higher eukaryotes have not been adequately defined. For example, NAD+ is converted to NADP+ by NAD kinase, affording a mechanism for transfer of cofactor mass from the NADH/NAD+ pool to the NADPH/NADP+ pool. However, it is not known how this flux is regulated and whether different mechanisms exist for pools in different compartments such as the cytoplasm, endoplasmic reticulum lumen, and nucleus, which all have characteristic proteins that respond to cofactor gradients (Fig. 1). Rapid depletion of NADPH by NADPH oxidase during the oxidative burst phase of neutrophil activation has been studied for years; however, it is now clear that other cells posses the NADPH oxidase protein complex. This system can rapidly alter cofactor gradients either in response to stimuli or as a primary process, which will necessarily alter both the potency of steroid hormones in cells containing HSDs and the activity of redox-sensitive transcription factors.
Although it has long been recognized that steroid hormones regulate cellular metabolism, it is only recently that we are beginning to recognize that cellular metabolism can regulate the response to steroid hormones. Our understanding of how cellular redox state translates to altered responses to circulating hormones remains in its infancy. Significant advances in this area await the application of better methods to monitor several cellular processes simultaneously.
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Acknowledgments |
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Footnotes |
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First Published Online March 17, 2005
Abbreviations: AKR, Aldo-keto reductase; GFP, green fluorescent protein; G6P, glucose-6-phosphate; G6PDH, glucose-6-phosphate dehydrogenase; H6PDH, hexose-6-phosphate dehydrogenase; HSD, hydroxysteroid dehydrogenase; NMR, nuclear magnetic resonance; 6PG, 6-phosphogluconate; 6PGDH, 6-phosphogluconate dehydrogenase; PPP, pentose phosphate pathway; SDR, short-chain dehydrogenase reductase; TCA, tricarboxylic acid cycle; TIM, triosephosphate isomerase.
Received January 14, 2005.
Accepted for publication February 2, 2005.
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References |
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, 20ß-hydroxysteroid dehydrogenase and possible roles of the residues conserved in short-chain dehydrogenases. Structure 2:629–640[Medline]
-hydroxysteroid/dihydrodiol dehydrogenase: a member of the aldo-keto reductase superfamily. Proc Natl Acad Sci USA 91:2517–2521-hydroxysteroid dehydrogenase/bile acid binding protein complexed with NADP+ and ursodeoxycholate. Biochemistry 40:10161–10168[CrossRef][Medline]
-hydroxysteroid dehydrogenase activity. J Biol Chem 268:12964–12969-hydroxysteroid dehydrogenase by an acetylenic secoestradiol. Biochemistry 25:7295–7300[CrossRef][Medline]
-hydroxysteroid dehydrogenases from rat and human prostate. J Biol Chem 272:15959–15966-hydroxysteroid metabolism. Mol Cell Endocrinol 171:103–109[CrossRef][Medline]
ß)-hydroxysteroid epimerase. J Biol Chem 275:29452–29457-hydroxysteroid dehydrogenase, a representative aldo-keto reductase. Biochemistry 38:7856–7864[CrossRef][Medline]
-DHT and 3-diol by rat 3-HSD via transient kinetics shows that the chemical step is rate-determining: effect of mutating cofactor and substrate-binding pocket residues on catalysis. Biochemistry 43:12028–12037[CrossRef][Medline]
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