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Trevor M. Penning – One of the best experts on this subject based on the ideXlab platform.

  • potent and highly selective aldo keto reductase 1c3 akr1c3 inhibitors act as chemotherapeutic potentiators in acute myeloid leukemia and t cell acute lymphoblastic leukemia
    Journal of Medicinal Chemistry, 2019
    Co-Authors: Kshitij Verma, Trevor M. Penning, Tianzhu Zang, Paul C Trippier

    Abstract:

    Aldo–keto reductase 1C3 (AKR1C3) catalyzes the synthesis of 9α,11β-prostaglandin (PG) F2α and PGF2α prostanoids that sustain the growth of myeloid precursors in the bone marrow. The enzyme is overexpressed in acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). Moreover, AKR1C3 confers chemotherapeutic resistance to the anthracyclines: first-line agents for the treatment of leukemias. The highly homologous isoforms AKR1C1 and AKR1C2 inactivate 5α-dihydrotestosterone, and their inhibition would be undesirable. We report herein the identification of AKR1C3 inhibitors that demonstrate exquisite isoform selectivity for AKR1C3 over the other closely related isoforms to the order of >2800-fold. Biological evaluation of our isoform-selective inhibitors revealed a high degree of synergistic drug action in combination with the clinical leukemia therapeutics daunorubicin and cytarabine in in vitro cellular models of AML and primary patient-derived T-ALL cells. Our developed compounds exhibi…

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  • Role of Human Aldo-Keto Reductases in the Metabolic Activation of the Carcinogenic Air Pollutant 3-Nitrobenzanthrone.
    Chemical research in toxicology, 2018
    Co-Authors: Jessica R. Murray, Ian A. Blair, Volker M. Arlt, Clementina Mesaros, Albrecht Seidel, Trevor M. Penning

    Abstract:

    3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen detected in diesel exhaust particulate and ambient air pollution. It requires metabolic activation via nitroreduction to promote DNA adduct formation and tumorigenesis. NAD(P)H:quinone oxidoreductase 1 (NQO1) has been previously implicated as the major nitroreductase responsible for 3-NBA activation, but it has recently been reported that human aldo-keto reductase 1C3 (AKR1C3) displays nitroreductase activity toward the chemotherapeutic agent PR-104A. We sought to determine whether AKR1C isoforms could display nitroreductase activity toward other nitrated compounds and bioactivate 3-NBA. Using discontinuous enzymatic assays monitored by UV-HPLC, we determined that AKR1C1-1C3 catalyze three successive two-electron nitroreductions toward 3-NBA to form the reduced product 3-aminobenzanthrone (3-ABA). Evidence of the nitroso- and hydroxylamino- intermediates were obtained by UPLC-HRMS. Km, kcat, and kcat/ Km values were determined for recombinant AKR1C and NQO1 and compared. We found that AKR1C1, AKR1C3, and NQO1 have very similar apparent catalytic efficiencies (8 vs 7 min-1 mM-1) despite the higher kcat of NQO1 (0.058 vs 0.012 min-1). AKR1C1-1C3 possess a Km much lower than that of NQO1, which suggests that they may be more important than NQO1 at the low concentrations of 3-NBA to which humans are exposed. Given that inhalation represents the primary source of 3-NBA exposure, we chose to evaluate the relative importance of AKR1C1-1C3 and NQO1 in human lung epithelial cell lines. Our data suggest that the combined activities of AKR1C1-1C3 and NQO1 contribute equally to the reduction of 3-NBA in A549 and HBEC3-KT cell lines and together represent approximately 50% of the intracellular nitroreductase activity toward 3-NBA. These findings have significant implications for the metabolism of nitrated polycyclic aromatic hydrocarbons and suggest that the hitherto unrecognized nitroreductase activity of AKR1C enzymes should be further investigated.

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  • Abstract 4580A: Metabolic activation of 3-nitrobenzanthrone by human aldo-keto reductases (AKR1C1-AKR1C4)
    Cancer Chemistry, 2015
    Co-Authors: Jessica R. Murray, Tianzhu Zang, Meng Huang, Volker M. Arlt, Heinz H. Schmeiser, Trevor M. Penning

    Abstract:

    In 2012, the International Agency for Research on Cancer (IARC) classified diesel exhaust as a Group 1 carcinogen due to sufficient evidence that exposure is associated with increased risk for lung cancer in humans. However, only a subset of individuals exposed to diesel exhaust develops cancer, indicating the need to identify the genes involved in metabolic activation of these compounds and their genetic variants. Nitro-polycyclic aromatic hydrocarbons (NO2-PAH) are a major component of diesel exhaust and require metabolic activation to exert their carcinogenic activity. A representative NO2-PAH, 3-nitrobenzanthrone (3-NBA), is metabolically activated to 3-aminobenzanthrone (3-ABA) via a 6-electron nitroreduction catalyzed by NQO1 and POR. The reaction leads to the formation of 3-aminobenzanthrone (3-ABA) derived DNA adducts which promote G to T transversions. Building upon previous data that shows human aldo-keto reductase 1C3 (AKR1C3) contains nitroreductase activity towards chemotherapeutic agents (Guise, C.P., Abbattista, M.R., et al., Cancer Res, 70(4), 2010), we chose to examine the nitroreductase activity of AKR1C1-AKR1C4 towards NO2-PAH. We have demonstrated here for the first time that AKR1C enzymes catalyze the nitroreduction of 3-NBA to 3-ABA. We monitored reactions with reverse phase HPLC coupled to in-line photo-diode-array detection (PDA) and fluorescence detection (FLD) to quantify 3-NBA and 3-ABA levels. Fluorescence and UV spectroscopy were used to validate the identity of the compounds. This method was adapted for discontinuous enzymatic assays to measure steady state kinetic parameters for the nitoreductase activity of AKR1C1-AKR1C4 and NQO1. Results indicate that the NQO1 catalyzed reduction of 3-NBA has a higher specific activity, but the combined specific activities of AKR1C catalyzed reduction may play a more significant role in the overall production of 3-ABA. These results suggest that the relative expression of NQO1 and AKR1C enzymes will determine their respective contribution to 3-NBA reduction, especially since all the aforementioned enzymes are inducible by the Nrf2-Keap1 system. This work is supported by P30E513508 and RO1 CA39504 to TMP. Citation Format: Jessica R. Murray, Meng Huang, Tianzhu Zang, Volker M. Arlt, Heinz H. Schmeiser, Trevor M. Penning. Metabolic activation of 3-nitrobenzanthrone by human aldo-keto reductases (AKR1C1-AKR1C4). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4580A. doi:10.1158/1538-7445.AM2015-4580A

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M E Burczynski – One of the best experts on this subject based on the ideXlab platform.

  • the reactive oxygen species and michael acceptor inducible human aldo keto reductase AKR1C1 reduces the α β unsaturated aldehyde 4 hydroxy 2 nonenal to 1 4 dihydroxy 2 nonene
    Journal of Biological Chemistry, 2001
    Co-Authors: M E Burczynski, N Palackal, Gopishetty R. Sridhar, T M Penning

    Abstract:

    Abstract The human aldo-keto reductase AKR1C1 (20α(3α)-hydroxysteroid dehydrogenase) is induced by electrophilic Michael acceptors and reactive oxygen species (ROS) via a presumptive antioxidant response element (Burczynski, M. E., Lin, H. K., and Penning, T. M. (1999) Cancer Res. 59, 607–614). Physiologically, AKR1C1 regulates progesterone action by converting the hormone into its inactive metabolite 20α-hydroxyprogesterone, and toxicologically this enzyme activates polycyclic aromatic hydrocarbon trans-dihydrodiols to redox-cycling o-quinones. However, the significance of its potent induction by Michael acceptors and oxidative stress is unknown. 4-Hydroxy-2-nonenal (HNE) and other α,β-unsaturated aldehydes produced during lipid peroxidation were reduced by AKR1C1 with high catalytic efficiency. Kinetic studies revealed that AKR1C1 reduced HNE (K m = 34 μm,k cat = 8.8 min− 1) with a k cat/K m similar to that for 20α-hydroxysteroids. Six other homogeneous recombinant AKRs were examined for their ability to reduce HNE. Of these, AKR1C1 possessed one of the highest specific activities and was the only isoform induced by oxidative stress and by agents that deplete glutathione (ethacrynic acid). Several hydroxysteroid dehydrogenases of the AKR1C subfamily catalyzed the reduction of HNE with higher activity than aldehyde reductase (AKR1A1). NMR spectroscopy identified the product of the NADPH-dependent reduction of HNE as 1,4-dihydroxy-2-nonene. The K m of recombinant AKR1C1 for nicotinamide cofactors (K m NADPH ∼6 μm,K m(app) NADH >6 mm) suggested that it is primed for reductive metabolism of HNE. Isoform-specific reverse transcription-polymerase chain reaction showed that exposure of HepG2 cells to HNE resulted in elevated levels of AKR1C1 mRNA. Thus, HNE induces its own metabolism via AKR1C1, and this enzyme may play a hitherto unrecognized role in a response mounted to counter oxidative stress. AKRs represent alternative GSH-independent/NADPH-dependent routes for the reductive elimination of HNE. Of these, AKR1C1 provides an inducible cytosolic barrier to HNE following ROS exposure.

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  • structure function aspects and inhibitor design of type 5 17β hydroxysteroid dehydrogenase akr1c3
    Molecular and Cellular Endocrinology, 2001
    Co-Authors: Trevor M. Penning, Kavitha Ratnam, M E Burczynski, Margaret Moore, N Palackal

    Abstract:

    Abstract 17β-Hydroxysteroid dehydrogenase (17β-HSD) type 5 has been cloned from human prostate and is identical to type 2 3α-HSD and is a member of the aldo-keto reductase (AKR) superfamily; it is formally AKR1C3. In vitro the homogeneous recombinant enzyme expressed in Escherichia coli functions as a 3-keto-, 17-keto- and 20-ketosteroid reductase and as a 3α-, 17β- and 20α-hydroxysteroid oxidase. The enzyme will reduce 5α-DHT, Δ4-androstene-3,17-dione, estrone and progesterone to produce 3α-androstanediol, testosterone, 17β-estradiol and 20α-hydroxprogesterone, respectively. It will also oxidize 3α-androstanediol, testosterone, 17β-estradiol and 20α-hydroxyprogesterone to produce 5α-androstane-3,17-dione, Δ4-androstene-3,17-dione, and progesterone, respectively. Many of these properties are shared by the related AKR1C1, AKR1C2 and AKR1C4 isoforms. RT-PCR shows that AKR1C3 is dominantly expressed in the human prostate and mammary gland. Examination of kcat/Km for these reactions indicates that as a reductase it prefers 5α-dihydrotestosterone and 5α-androstane-3,17-dione as substrates to Δ4-androstene-3,17-dione, suggesting that in the prostate it favors the formation of inactive androgens. Its concerted reductase activity may, however, lead to a pro-estrogenic state in the breast since it will convert estrone to 17β-estradiol; convert Δ4-androstene-3,17-dione to testosterone (which can be aromatized to 17β-estradiol); and it will reduce progesterone to its inactive metabolite 20α-hydroxyprogesterone. Drawing on detailed structure-function analysis of the related rat 3α-HSD (AKR1C9), which shares 69% sequence identity with AKR1C3, it is predicted that AKR1C3 catalyzes an ordered bi bi mechanism, that the rate determining step is kchem, and that an oxyanion prevails in the transition state. Based on these relationships steroidal-based inhibitors that compete with the steroid product would be desirable since they would act as uncompetitive inhibitors. With regards to transition state analogs steroid carboxylates and pyrazoles may be preferred while 3α, 17β or 20α-spiro-oxiranes may act as mechanism-based inactivators.

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  • Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3).
    Molecular and cellular endocrinology, 2001
    Co-Authors: Trevor M. Penning, Kavitha Ratnam, M E Burczynski, H. Ma, M. Moore, N Palackal

    Abstract:

    17beta-Hydroxysteroid dehydrogenase (17beta-HSD) type 5 has been cloned from human prostate and is identical to type 2 3alpha-HSD and is a member of the aldo-keto reductase (AKR) superfamily; it is formally AKR1C3. In vitro the homogeneous recombinant enzyme expressed in Escherichia coli functions as a 3-keto-, 17-keto- and 20-ketosteroid reductase and as a 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidase. The enzyme will reduce 5alpha-DHT, Delta(4)-androstene-3,17-dione, estrone and progesterone to produce 3alpha-androstanediol, testosterone, 17beta-estradiol and 20alpha-hydroxprogesterone, respectively. It will also oxidize 3alpha-androstanediol, testosterone, 17beta-estradiol and 20alpha-hydroxyprogesterone to produce 5alpha-androstane-3,17-dione, Delta(4)-androstene-3,17-dione, and progesterone, respectively. Many of these properties are shared by the related AKR1C1, AKR1C2 and AKR1C4 isoforms. RT-PCR shows that AKR1C3 is dominantly expressed in the human prostate and mammary gland. Examination of k(cat)/K(m) for these reactions indicates that as a reductase it prefers 5alpha-dihydrotestosterone and 5alpha-androstane-3,17-dione as substrates to Delta(4)-androstene-3,17-dione, suggesting that in the prostate it favors the formation of inactive androgens. Its concerted reductase activity may, however, lead to a pro-estrogenic state in the breast since it will convert estrone to 17beta-estradiol; convert Delta(4)-androstene-3,17-dione to testosterone (which can be aromatized to 17beta-estradiol); and it will reduce progesterone to its inactive metabolite 20alpha-hydroxyprogesterone. Drawing on detailed structure-function analysis of the related rat 3alpha-HSD (AKR1C9), which shares 69% sequence identity with AKR1C3, it is predicted that AKR1C3 catalyzes an ordered bi bi mechanism, that the rate determining step is k(chem), and that an oxyanion prevails in the transition state. Based on these relationships steroidal-based inhibitors that compete with the steroid product would be desirable since they would act as uncompetitive inhibitors. With regards to transition state analogs steroid carboxylates and pyrazoles may be preferred while 3alpha, 17beta or 20alpha-spiro-oxiranes may act as mechanism-based inactivators.

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N Palackal – One of the best experts on this subject based on the ideXlab platform.

  • the reactive oxygen species and michael acceptor inducible human aldo keto reductase AKR1C1 reduces the α β unsaturated aldehyde 4 hydroxy 2 nonenal to 1 4 dihydroxy 2 nonene
    Journal of Biological Chemistry, 2001
    Co-Authors: M E Burczynski, N Palackal, Gopishetty R. Sridhar, T M Penning

    Abstract:

    Abstract The human aldo-keto reductase AKR1C1 (20α(3α)-hydroxysteroid dehydrogenase) is induced by electrophilic Michael acceptors and reactive oxygen species (ROS) via a presumptive antioxidant response element (Burczynski, M. E., Lin, H. K., and Penning, T. M. (1999) Cancer Res. 59, 607–614). Physiologically, AKR1C1 regulates progesterone action by converting the hormone into its inactive metabolite 20α-hydroxyprogesterone, and toxicologically this enzyme activates polycyclic aromatic hydrocarbon trans-dihydrodiols to redox-cycling o-quinones. However, the significance of its potent induction by Michael acceptors and oxidative stress is unknown. 4-Hydroxy-2-nonenal (HNE) and other α,β-unsaturated aldehydes produced during lipid peroxidation were reduced by AKR1C1 with high catalytic efficiency. Kinetic studies revealed that AKR1C1 reduced HNE (K m = 34 μm,k cat = 8.8 min− 1) with a k cat/K m similar to that for 20α-hydroxysteroids. Six other homogeneous recombinant AKRs were examined for their ability to reduce HNE. Of these, AKR1C1 possessed one of the highest specific activities and was the only isoform induced by oxidative stress and by agents that deplete glutathione (ethacrynic acid). Several hydroxysteroid dehydrogenases of the AKR1C subfamily catalyzed the reduction of HNE with higher activity than aldehyde reductase (AKR1A1). NMR spectroscopy identified the product of the NADPH-dependent reduction of HNE as 1,4-dihydroxy-2-nonene. The K m of recombinant AKR1C1 for nicotinamide cofactors (K m NADPH ∼6 μm,K m(app) NADH >6 mm) suggested that it is primed for reductive metabolism of HNE. Isoform-specific reverse transcription-polymerase chain reaction showed that exposure of HepG2 cells to HNE resulted in elevated levels of AKR1C1 mRNA. Thus, HNE induces its own metabolism via AKR1C1, and this enzyme may play a hitherto unrecognized role in a response mounted to counter oxidative stress. AKRs represent alternative GSH-independent/NADPH-dependent routes for the reductive elimination of HNE. Of these, AKR1C1 provides an inducible cytosolic barrier to HNE following ROS exposure.

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  • structure function aspects and inhibitor design of type 5 17β hydroxysteroid dehydrogenase akr1c3
    Molecular and Cellular Endocrinology, 2001
    Co-Authors: Trevor M. Penning, Kavitha Ratnam, M E Burczynski, Margaret Moore, N Palackal

    Abstract:

    Abstract 17β-Hydroxysteroid dehydrogenase (17β-HSD) type 5 has been cloned from human prostate and is identical to type 2 3α-HSD and is a member of the aldo-keto reductase (AKR) superfamily; it is formally AKR1C3. In vitro the homogeneous recombinant enzyme expressed in Escherichia coli functions as a 3-keto-, 17-keto- and 20-ketosteroid reductase and as a 3α-, 17β- and 20α-hydroxysteroid oxidase. The enzyme will reduce 5α-DHT, Δ4-androstene-3,17-dione, estrone and progesterone to produce 3α-androstanediol, testosterone, 17β-estradiol and 20α-hydroxprogesterone, respectively. It will also oxidize 3α-androstanediol, testosterone, 17β-estradiol and 20α-hydroxyprogesterone to produce 5α-androstane-3,17-dione, Δ4-androstene-3,17-dione, and progesterone, respectively. Many of these properties are shared by the related AKR1C1, AKR1C2 and AKR1C4 isoforms. RT-PCR shows that AKR1C3 is dominantly expressed in the human prostate and mammary gland. Examination of kcat/Km for these reactions indicates that as a reductase it prefers 5α-dihydrotestosterone and 5α-androstane-3,17-dione as substrates to Δ4-androstene-3,17-dione, suggesting that in the prostate it favors the formation of inactive androgens. Its concerted reductase activity may, however, lead to a pro-estrogenic state in the breast since it will convert estrone to 17β-estradiol; convert Δ4-androstene-3,17-dione to testosterone (which can be aromatized to 17β-estradiol); and it will reduce progesterone to its inactive metabolite 20α-hydroxyprogesterone. Drawing on detailed structure-function analysis of the related rat 3α-HSD (AKR1C9), which shares 69% sequence identity with AKR1C3, it is predicted that AKR1C3 catalyzes an ordered bi bi mechanism, that the rate determining step is kchem, and that an oxyanion prevails in the transition state. Based on these relationships steroidal-based inhibitors that compete with the steroid product would be desirable since they would act as uncompetitive inhibitors. With regards to transition state analogs steroid carboxylates and pyrazoles may be preferred while 3α, 17β or 20α-spiro-oxiranes may act as mechanism-based inactivators.

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  • Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3).
    Molecular and cellular endocrinology, 2001
    Co-Authors: Trevor M. Penning, Kavitha Ratnam, M E Burczynski, H. Ma, M. Moore, N Palackal

    Abstract:

    17beta-Hydroxysteroid dehydrogenase (17beta-HSD) type 5 has been cloned from human prostate and is identical to type 2 3alpha-HSD and is a member of the aldo-keto reductase (AKR) superfamily; it is formally AKR1C3. In vitro the homogeneous recombinant enzyme expressed in Escherichia coli functions as a 3-keto-, 17-keto- and 20-ketosteroid reductase and as a 3alpha-, 17beta- and 20alpha-hydroxysteroid oxidase. The enzyme will reduce 5alpha-DHT, Delta(4)-androstene-3,17-dione, estrone and progesterone to produce 3alpha-androstanediol, testosterone, 17beta-estradiol and 20alpha-hydroxprogesterone, respectively. It will also oxidize 3alpha-androstanediol, testosterone, 17beta-estradiol and 20alpha-hydroxyprogesterone to produce 5alpha-androstane-3,17-dione, Delta(4)-androstene-3,17-dione, and progesterone, respectively. Many of these properties are shared by the related AKR1C1, AKR1C2 and AKR1C4 isoforms. RT-PCR shows that AKR1C3 is dominantly expressed in the human prostate and mammary gland. Examination of k(cat)/K(m) for these reactions indicates that as a reductase it prefers 5alpha-dihydrotestosterone and 5alpha-androstane-3,17-dione as substrates to Delta(4)-androstene-3,17-dione, suggesting that in the prostate it favors the formation of inactive androgens. Its concerted reductase activity may, however, lead to a pro-estrogenic state in the breast since it will convert estrone to 17beta-estradiol; convert Delta(4)-androstene-3,17-dione to testosterone (which can be aromatized to 17beta-estradiol); and it will reduce progesterone to its inactive metabolite 20alpha-hydroxyprogesterone. Drawing on detailed structure-function analysis of the related rat 3alpha-HSD (AKR1C9), which shares 69% sequence identity with AKR1C3, it is predicted that AKR1C3 catalyzes an ordered bi bi mechanism, that the rate determining step is k(chem), and that an oxyanion prevails in the transition state. Based on these relationships steroidal-based inhibitors that compete with the steroid product would be desirable since they would act as uncompetitive inhibitors. With regards to transition state analogs steroid carboxylates and pyrazoles may be preferred while 3alpha, 17beta or 20alpha-spiro-oxiranes may act as mechanism-based inactivators.

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