Mammalian 3α-hydroxysteroid dehydrogenases

Penning, T.M.; Pawlowski, John E.; Schlegel, Brian P.; Jez, Joseph M.; Lin, Hseuh Kung; Hoog, Susan S.; Bennett, M. J.; Lewis, Mitchell

doi:10.1016/s0039-128x(96)00093-1

Cited by 62 publications

(46 citation statements)

References 56 publications

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“…In this superfamily of proteins, Tyr-55 is absolutely conserved in all active members. The reductive reaction involves 4-pro-R hydride ion transfer from NAD(P)H to the substrate carbonyl and protonation of the oxygen by an enzyme residue acting as a general acid (46). The reverse process occurs in the oxidative reaction.…”

Section: Resultsmentioning

confidence: 99%

Dynamics of protein nitration in cells and mitochondria

Aulak

Koeck

Crabb

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

174

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Aulak, Kulwant S., Thomas Koeck, John W. Crabb, and Dennis J. Stuehr. Dynamics of protein nitration in cells and mitochondria. Am J Physiol Heart Circ Physiol 286: H30-H38, 2004; 10.1152/ ajpheart.00743.2003.-Nitric oxide is a precursor of reactive nitrating species such as peroxynitrite and nitrogen dioxide that modify proteins to generate 3-nitrotyrosine. Many diseases are associated with increased levels of protein-bound nitrotyrosine, and this is used as a marker for oxidative damage. However, the regulation of protein nitration and its role in cell function are unclear. We demonstrate that biological protein nitration can be a specific and dynamic process. Proteins were nitrated in distinct temporal patterns in cells undergoing inflammatory activation, and protein denitration and renitration occurred rapidly in respiring mitochondria. The targets of protein nitration varied over time, which may reflect their sensitivity to nitration, expression pattern, or turnover. The dynamic nature of the nitration process was revealed by denitration and renitration of proteins occurring within minutes in mitochondria that were subject to hypoxiaanoxia and reoxygenation. Our results have implications that are particularly important for ischemia-reperfusion injury.

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Section: Resultsmentioning

confidence: 99%

Dynamics of protein nitration in cells and mitochondria

Aulak

Koeck

Crabb

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

174

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“…Physiologically, this enzyme acts as an oxidoreductase (reductase-dehydrogenase) catalysing the reduction of the 3-ketogroup on steroids into a 3α-hydroxygroup and vice versa. This enzyme is also able to metabolise many non-oestrogenic compounds thereby acting mainly as a dehydrogenase [30,31,33]. 3β-hydroxysteroid dehydrogenase occurs in humans in two distinct forms, 3β-HSD-1 and 3β-HSD-2.…”

Section: Discussionmentioning

confidence: 99%

Bioactivation of zearalenone by porcine hepatic biotransformation

2005

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-Zearalenone (ZEA) is a resorcylic acid lactone derivative produced by various Fusarium species that are widely found in food and feeds. The structure of zearalenone is flexible enough to allow a conformation able to bind to mammalian oestrogen receptors, where it acts as an agonist. Using oestrogen-dependent Human Breast Cancer (MCF-7) cells, the oestrogenic activity of zearalenone and its derivatives were compared using 17 β-oestradiol as a positive control. The results obtained demonstrate that the oestrogenic potency of ZEA derivatives could be ranked in the following order: α-zearalenol > α-zearalanol > zearalenone > β-zearalenol. Since pigs have been reported to be among the most sensitive animal species, biotransformation studies with pig liver subcellular fractions were conducted. These studies indicated that α-zearalenol is the main hepatic metabolite of zearalenone in pigs, and it is assumed that 3α-and 3β-hydroxysteroid dehydrogeneases are involved in the hepatic biotransformation, since the formation of α-zearalenol and β-zearalenol could be inhibited by prototypic substrates for either enzyme. The bioactivation of ZEA into the more active α-zearalenol seems to provide a possible explanation for the observed high sensitivity of pigs towards feedingstuffs contaminated with the mycotoxin. zearalenone / MCF-7 cells / oestrogenic effects / biotransformation / pigs

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“…The AKRs catalyze the metabolism of a diverse array of substrates, and individual family members have been implicated in human diseases such as diabetes and asthma (28). Our sequence analysis has placed mAKRa into the AKR1C subfamily (30), which includes proteins such as 3␣-HSD, chlordecone reductase, 20␣-HSD, and prostaglandin F synthase (28,43). Proteins within this subfamily catalyze the interconversion of weak and potent forms of steroid hormones and prostaglandins among their many functions and have been proposed to act as "molecular switches" by regulating the amount of hormone available to bind to a nuclear hormone receptor (43).…”

Section: Fig 5 Expression Pattern Of Makra In Mouse Tissues Panel Amentioning

confidence: 99%

“…Our sequence analysis has placed mAKRa into the AKR1C subfamily (30), which includes proteins such as 3␣-HSD, chlordecone reductase, 20␣-HSD, and prostaglandin F synthase (28,43). Proteins within this subfamily catalyze the interconversion of weak and potent forms of steroid hormones and prostaglandins among their many functions and have been proposed to act as "molecular switches" by regulating the amount of hormone available to bind to a nuclear hormone receptor (43). Potential physiological substrates for mAKRa include steroids, prostaglandins, and retinoids, and identification of the specific substrate(s) for mAKRa will be critical for determining whether it does indeed serve as "molecular switch" in the regulation of myelopoiesis.…”

Section: Fig 5 Expression Pattern Of Makra In Mouse Tissues Panel Amentioning

confidence: 99%

Identification of an Interleukin-3-regulated Aldoketo Reductase Gene in Myeloid Cells Which May Function in Autocrine Regulation of Myelopoiesis

Du¹,

Tsai²,

Keller³

et al. 2000

Journal of Biological Chemistry

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The EML hematopoietic progenitor cell line is a model system for studying molecular events regulating myeloid commitment and terminal differentiation. We used representational difference analysis to identify genes that are expressed differentially during myeloid differentiation of EML cells. One gene (named mAKRa) encoded a novel member of the aldoketo reductase (AKR) superfamily of cytosolic NAD(P)(H)-dependent oxidoreductases. mAKRa mRNA was detected in murine hematopoietic tissues including bone marrow, spleen, and thymus. In myeloid cell lines, mAKRa was expressed at highest levels in cells representative of promyelocytes. mAKRa mRNA levels increased rapidly in response to interleukin-3 over the first 24 h of EML cell differentiation when the cells undergo lineage commitment and extensive proliferation. mAKRa mRNA levels decreased later in the differentiation process particularly when the EML cells were cultured with granulocyte/macrophage colony-stimulating factor and retinoic acid to induce terminal granulocytic maturation. mAKRa mRNA levels decreased during retinoic acidinduced terminal granulocytic differentiation of the MPRO promyelocyte cell line. AKRs act as molecular switches by catalyzing the interconversion or inactivation of bioactive molecules including steroids and prostaglandins. We propose that mAKRa may catalyze the production or catabolism of autocrine factors that promote the proliferation and/or lineage commitment of early myeloid progenitors.

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Mammalian 3α-hydroxysteroid dehydrogenases

Cited by 62 publications

References 56 publications

Dynamics of protein nitration in cells and mitochondria

Dynamics of protein nitration in cells and mitochondria

Bioactivation of zearalenone by porcine hepatic biotransformation

Identification of an Interleukin-3-regulated Aldoketo Reductase Gene in Myeloid Cells Which May Function in Autocrine Regulation of Myelopoiesis

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