Structural basis for the high all-trans -retinaldehyde reductase activity of the tumor marker AKR1B10
- 26 December 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (52), 20764-20769
- https://doi.org/10.1073/pnas.0705659105
Abstract
AKR1B10 is a human aldo-keto reductase (AKR) found to be elevated in several cancer types and in precancerous lesions. In vitro, AKR1B10 exhibits a much higher retinaldehyde reductase activity than any other human AKR, including AKR1B1 (aldose reductase). We here demonstrate that AKR1B10 also acts as a retinaldehyde reductase in vivo. This activity may be relevant in controlling the first step of retinoic acid synthesis. Up-regulation of AKR1B10, resulting in retinoic acid depletion, may lead to cellular proliferation. Both in vitro and in vivo activities of AKR1B10 were inhibited by tolrestat, an AKR1B1 inhibitor developed for diabetes treatment. The crystal structure of the ternary complex AKR1B10-NADP(+)-tolrestat was determined at 1.25-A resolution. Molecular dynamics models of AKR1B10 and AKR1B1 with retinaldehyde isomers and site-directed mutagenesis show that subtle differences at the entrance of the retinoid-binding site, especially at position 125, are determinant for the all-trans-retinaldehyde specificity of AKR1B10. Substitutions in the retinaldehyde cyclohexene ring also influence the specificity. These structural features should facilitate the design of specific inhibitors, with potential use in cancer and diabetes treatments.Keywords
This publication has 30 references indexed in Scilit:
- Expect the Unexpected or Caveat for Drug Designers: Multiple Structure Determinations Using Aldose Reductase Crystals Treated under Varying Soaking and Co-crystallisation ConditionsJournal of Molecular Biology, 2006
- Comparative functional analysis of human medium-chain dehydrogenases, short-chain dehydrogenases/reductases and aldo-keto reductases with retinoidsBiochemical Journal, 2006
- Synthesis of enantiopure C3- and C4-hydroxyretinals and their enzymatic reduction by ADH8 from Xenopus laevisOrganic & Biomolecular Chemistry, 2006
- New member of aldose reductase family proteins overexpressed in human hepatocellular carcinomaHepatology, 1998
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- VMD: Visual molecular dynamicsJournal of Molecular Graphics, 1996
- Human Aldose Reductase: Rate Constants for a Mechanism Including Interconversion of Ternary Complexes by Recombinant Wild-Type EnzymeBiochemistry, 1995
- 1.7 .ANG. Structure of FR-1, a Fibroblast Growth Factor-Induced Member of the Aldo-Keto Reductase Family, Complexed with Coenzyme and InhibitorBiochemistry, 1995
- AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of moleculesComputer Physics Communications, 1995
- The CCP4 suite: programs for protein crystallographyActa Crystallographica Section D-Biological Crystallography, 1994