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Structure of the tetrameric form of human L-Xylulose reductase: probing the inhibitor-binding site with molecular modeling and site-directed mutagenesis.

El-Kabbani O, Carbone V, Darmanin C, Ishikura S, Hara A
Proteins 60 424-32 (2005)
Cited: 14 times
EuropePMC logo PMID: 15906319

Abstract

L-Xylulose reductase (XR) is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. In this study we report the structure of the biological tetramer of human XR in complex with NADP(+) and a competitive inhibitor solved at 2.3 A resolution. A single subunit of human XR is formed by a centrally positioned, seven-stranded, parallel beta-sheet surrounded on either side by two arrays of three alpha-helices. Two helices located away from the main body of the protein form the variable substrate-binding cleft, while the dinucleotide coenzyme-binding motif is formed by a classical Rossmann fold. The tetrameric structure of XR, which is held together via salt bridges formed by the guanidino group of Arg203 from one monomer and the carboxylate group of the C-terminal residue Cys244 from the neighboring monomer, explains the ability of human XR to prevent the cold inactivation seen in the rodent forms of the enzyme. The orientations of Arg203 and Cys244 are maintained by a network of hydrogen bonds and main-chain interactions of Gln137, Glu238, Phe241, and Trp242. These interactions are similar to those defining the quaternary structure of the closely related carbonyl reductase from mouse lung. Molecular modeling and site-directed mutagenesis identified the active site residues His146 and Trp191 as forming essential contacts with inhibitors of XR. These results could provide a structural basis in the design of potent and specific inhibitors for human XR.

Articles - 1wnt mentioned but not cited (2)

  1. Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells. Yang S, Jan YH, Mishin V, Heck DE, Laskin DL, Laskin JD. Chem Res Toxicol 30 1406-1418 (2017)
  2. Biochemical characterization of an L-Xylulose reductase from Neurospora crassa. Nair N, Zhao H. Appl Environ Microbiol 73 2001-2004 (2007)


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  1. Design and applications of biodegradable polyester tissue scaffolds based on endogenous monomers found in human metabolism. Barrett DG, Yousaf MN. Molecules 14 4022-4050 (2009)
  2. Human DCXR - another 'moonlighting protein' involved in sugar metabolism, carbonyl detoxification, cell adhesion and male fertility? Ebert B, Kisiela M, Maser E. Biol Rev Camb Philos Soc 90 254-278 (2015)
  3. Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity. Anders MW. Toxicology 388 21-29 (2017)

Articles citing this publication (9)

  1. The human short-chain dehydrogenase/reductase (SDR) superfamily: a bioinformatics summary. Bray JE, Marsden BD, Oppermann U. Chem Biol Interact 178 99-109 (2009)
  2. L-Xylulose reductase is involved in 9,10-phenanthrenequinone-induced apoptosis in human T lymphoma cells. Matsunaga T, Kamiya T, Sumi D, Kumagai Y, Kalyanaraman B, Hara A. Free Radic Biol Med 44 1191-1202 (2008)
  3. Molecular and functional evolution of human DHRS2 and DHRS4 duplicated genes. Gabrielli F, Tofanelli S. Gene 511 461-469 (2012)
  4. Transgenic mice over-expressing dicarbonyl/L-xylulose reductase gene crossed with KK-Ay diabetic model mice: an animal model for the metabolism of renal carbonyl compounds. Sudo T, Ishii A, Asami J, Uematsu Y, Saitoh M, Nakamura A, Tada N, Ohnuki T, Komurasaki T, Nakagawa J. Exp Anim 54 385-394 (2005)
  5. Up-regulation of multiple proteins and biological processes during maxillary expansion in rats. Ma J, Wu Y, Zhang W, Smales RJ, Huang Y, Pan Y, Wang L. BMC Musculoskelet Disord 9 37 (2008)
  6. Suppression of AGE precursor formation following unilateral ureteral obstruction in mouse kidneys by transgenic expression of alpha-dicarbonyl/L-xylulose reductase. Asami J, Odani H, Ishii A, Oide K, Sudo T, Nakamura A, Miyata N, Otsuka N, Maeda K, Nakagawa J. Biosci Biotechnol Biochem 70 2899-2905 (2006)
  7. Structural insights into cold inactivation of tryptophanase and cold adaptation of subtilisin S41. Almog O, Kogan A, Leeuw Md, Gdalevsky GY, Cohen-Luria R, Parola AH. Biopolymers 89 354-359 (2008)
  8. Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria. Pierce SB, Spurrell CH, Mandell JB, Lee MK, Zeligson S, Bereman MS, Stray SM, Fokstuen S, MacCoss MJ, Levy-Lahad E, King MC, Motulsky AG. Proc Natl Acad Sci U S A 108 18313-18317 (2011)
  9. (-)-Epigallocatechin-3-gallate, a potential inhibitor to human dicarbonyl/L-xylulose reductase. Hu XH, Ding LY, Huang WX, Yang XM, Xie F, Xu M, Yu L. J Biochem 154 167-175 (2013)


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