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Crystal structure of human L-xylulose reductase holoenzyme: probing the role of Asn107 with site-directed mutagenesis.

El-Kabbani O, Ishikura S, Darmanin C, Carbone V, Chung RP, Usami N, Hara A
Proteins 55 724-32 (2004)
Cited: 21 times
EuropePMC logo PMID: 15103634

Abstract

L-Xylulose reductase (XR), an enzyme in the uronate cycle of glucose metabolism, belongs to the short-chain dehydrogenase/reductase (SDR) superfamily. Among the SDR enzymes, XR shows the highest sequence identity (67%) with mouse lung carbonyl reductase (MLCR), but the two enzymes show different substrate specificities. The crystal structure of human XR in complex with reduced nicotinamide adenine dinucleotide phosphate (NADPH) was determined at 1.96 A resolution by using the molecular replacement method and the structure of MLCR as the search model. Features unique to human XR include electrostatic interactions between the N-terminal residues of subunits related by the P-axis, termed according to SDR convention, and an interaction between the hydroxy group of Ser185 and the pyrophosphate of NADPH. Furthermore, identification of the residues lining the active site of XR (Cys138, Val143, His146, Trp191, and Met200) together with a model structure of XR in complex with L-xylulose, revealed structural differences with other members of the SDR family, which may account for the distinct substrate specificity of XR. The residues comprising a recently proposed catalytic tetrad in the SDR enzymes are conserved in human XR (Asn107, Ser136, Tyr149, and Lys153). To examine the role of Asn107 in the catalytic mechanism of human XR, mutant forms (N107D and N107L) were prepared. The two mutations increased K(m) for the substrate (>26-fold) and K(d) for NADPH (95-fold), but only the N107L mutation significantly decreased k(cat) value. These results suggest that Asn107 plays a critical role in coenzyme binding rather than in the catalytic mechanism.

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  1. 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)
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  1. Molecular docking for substrate identification: the short-chain dehydrogenases/reductases. Favia AD, Nobeli I, Glaser F, Thornton JM. J Mol Biol 375 855-874 (2008)
  2. Molecular basis for peroxisomal localization of tetrameric carbonyl reductase. Tanaka N, Aoki K, Ishikura S, Nagano M, Imamura Y, Hara A, Nakamura KT. Structure 16 388-397 (2008)
  3. Automated extraction and semantic analysis of mutation impacts from the biomedical literature. Naderi N, Witte R. BMC Genomics 13 Suppl 4 S10 (2012)
  4. 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 60 424-432 (2005)
  5. Tsc10p and FVT1: topologically distinct short-chain reductases required for long-chain base synthesis in yeast and mammals. Gupta SD, Gable K, Han G, Borovitskaya A, Selby L, Dunn TM, Harmon JM. J Lipid Res 50 1630-1640 (2009)
  6. Expression of dicarbonyl/L-xylulose reductase (DCXR) in human skin and melanocytic lesions: morphological studies supporting cell adhesion function of DCXR. Cho-Vega JH, Vega F, Schwartz MR, Prieto VG. J Cutan Pathol 34 535-542 (2007)
  7. Molecular determinants for the stereospecific reduction of 3-ketosteroids and reactivity towards all-trans-retinal of a short-chain dehydrogenase/reductase (DHRS4). Endo S, Maeda S, Matsunaga T, Dhagat U, El-Kabbani O, Tanaka N, Nakamura KT, Tajima K, Hara A. Arch Biochem Biophys 481 183-190 (2009)
  8. Biochemical and structural characterization of a short-chain dehydrogenase/reductase of Thermus thermophilus HB8: a hyperthermostable aldose-1-dehydrogenase with broad substrate specificity. Asada Y, Endo S, Inoue Y, Mamiya H, Hara A, Kunishima N, Matsunaga T. Chem Biol Interact 178 117-126 (2009)
  9. DHS-21, a dicarbonyl/L-xylulose reductase (DCXR) ortholog, regulates longevity and reproduction in Caenorhabditis elegans. Son le T, Ko KM, Cho JH, Singaravelu G, Chatterjee I, Choi TW, Song HO, Yu JR, Park BJ, Lee SK, Ahnn J. FEBS Lett 585 1310-1316 (2011)
  10. 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)
  11. 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)
  12. An intact eight-membered water chain in drosophilid alcohol dehydrogenases is essential for optimal enzyme activity. Wuxiuer Y, Morgunova E, Cols N, Popov A, Karshikoff A, Sylte I, Gonzàlez-Duarte R, Ladenstein R, Winberg JO. FEBS J 279 2940-2956 (2012)
  13. Structure-based discovery of human L-xylulose reductase inhibitors from database screening and molecular docking. Carbone V, Ishikura S, Hara A, El-Kabbani O. Bioorg Med Chem 13 301-312 (2005)
  14. Low expression of DCXR protein indicates a poor prognosis for hepatocellular carcinoma patients. Hang X, Wu Z, Chu K, Yu G, Peng H, Xin H, Miao X, Wang J, Xu W. Tumour Biol 37 15079-15085 (2016)
  15. (-)-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)


Related citations provided by authors (1)

  1. Crystallization and preliminary crystallographic analysis of human L-xylulose reductase.. El-Kabbani O, Chung RP, Ishikura S, Usami N, Nakagawa J, Hara A Acta Crystallogr D Biol Crystallogr 58 1379-80 (2002)

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