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      Asborin Inhibits Aldo/Keto Reductase 1A1

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          Most cited references23

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          The Role of Chemistry in the Development of Boron Neutron Capture Therapy of Cancer

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            Aldo-keto reductases and bioactivation/detoxication.

            Aldo-keto reductases (AKRs) are soluble NAD(P)(H) oxidoreductases that primarily reduce aldehydes and ketones to primary and secondary alcohols, respectively. The ten known human AKR enzymes can turnover a vast range of substrates, including drugs, carcinogens, and reactive aldehydes. They play central roles in the metabolism of these agents, and this can lead to either their bioactivation or detoxication. AKRs are Phase I drug metabolizing enzymes for a variety of carbonyl-containing drugs and are implicated in cancer chemotherapeutic drug resistance. They are involved in tobacco-carcinogenesis because they activate polycyclic aromatic trans-dihydrodiols to yield reactive and redox active o-quinones, but they also catalyze the detoxication of nicotine derived nitrosamino ketones. They also detoxify reactive aldehydes formed from exogenous toxicants, e.g., aflatoxin, endogenous toxicants, and those formed from the breakdown of lipid peroxides. AKRs are stress-regulated genes and play a central role in the cellular response to osmotic, electrophilic, and oxidative stress.
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              An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications.

              Aldose reductase, which catalyzes the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of a wide variety of aromatic and aliphatic carbonyl compounds, is implicated in the development of diabetic and galactosemic complications involving the lens, retina, nerves, and kidney. A 1.65 angstrom refined structure of a recombinant human placenta aldose reductase reveals that the enzyme contains a parallel beta 8/alpha 8-barrel motif and establishes a new motif for NADP-binding oxidoreductases. The substrate-binding site is located in a large, deep elliptical pocket at the COOH-terminal end of the beta barrel with a bound NADPH in an extended conformation. The highly hydrophobic nature of the active site pocket greatly favors aromatic and apolar substrates over highly polar monosaccharides. The structure should allow for the rational design of specific inhibitors that might provide molecular understanding of the catalytic mechanism, as well as possible therapeutic agents.
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                Author and article information

                Journal
                ChemMedChem
                ChemMedChem
                Wiley
                18607179
                January 03 2011
                January 03 2011
                October 21 2010
                : 6
                : 1
                : 89-93
                Article
                10.1002/cmdc.201000368
                1223844b-4727-4b75-a794-a26f6145ff80
                © 2010

                http://doi.wiley.com/10.1002/tdm_license_1.1

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