Skip to main content
SpringerLink
Log in

The effect of metal ions on the binding of ethanol to human alcohol dehydrogenase β2β2

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

Molecular docking simulations were performed in this study to investigate the importance of both structural and catalytic zinc ions in the human alcohol dehydrogenase β2β2 on substrate binding. The structural zinc ion is not only important in maintaining the structural integrity of the enzyme, but also plays an important role in determining substrate binding. The replacement of the catalytic zinc ion or both catalytic and structural zinc ions with Cu2+ results in better substrate binding affinity than with the wild-type enzyme. The width of the bottleneck formed by L116 and V294 in the substrate binding pocket plays an important role for substrate entrance. In addition, unfavorable contacts between the substrate and T48 and F93 prevent the substrate from moving too close to the metal ion. The optimal binding position occurs between 1.9 and 2.4 Å from the catalytic metal ion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barlow S, Rohl AL, O'Hare D. Molecular Mechanics Study of Oligomeric Models for Poly(ferrocenylsilanes) using the ESFF Forcefield. Chem Comm 257–260;1996.

  2. Barlow S, Rohl, AL, Shi S, Freeman CM, O'hare D. Molecular Mechanics Study of Oligomeric Models for Poly(Ferrocenylsilanes) using the Extensible Systematic Forcefield (ESFF). J Am Chem Soc 118:7578–7592;1996.

    Google Scholar 

  3. Bogin O, Peretz M, Burstein Y.Thermoanaerobacter brockii alcohol dehydrogenase: Characterization of the active site metal and its ligand amino acids. Protein Sci 6:450–458;1997.

    Google Scholar 

  4. Brown DC, Collins KD. Dihydroorotase fromEscherichia coli. Substitution of Co(II) for the active site Zn(II). J Biol Chem 266:1597–1604;1991.

    Google Scholar 

  5. Crosas B, Allali-Hassani A, Eva Martínez S, Martras S, Persson B, Jörnvall H, Parés X, Farrés H. Molecular basis for differential substrate specificity in class IV alcohol dehydrogenases. J Biol Chem 275:25180–25187;2000.

    Google Scholar 

  6. Duester G, Farrés J, Felder MR, Holmes R, Höög J-O, Parés X, Plapp BV, Yin S-J, Jörnvall H. Recommended nomenclature for the vertebrate alcohol dehydrogenase gene family. Biochem Pharm 58:389–395;1999.

    Google Scholar 

  7. Edenberg HJ, Bosron WF. Alcohol dehydrogenases. In: Guengerich FP. Comprehensive Toxicology, vol. 3. New York. Pergamon Press 119–131;1997.

    Google Scholar 

  8. Eklund H, Nordström B, Zeppezauer E, Söderlund G, Ohlsson I, Boiwe T, Söderberg B-O, Tapia O, Brändén C-I, Åkeson Å. Three-dimensional structure of horse liver alcohol dehydrogenase at 2.4 Å resolution. J Mol Biol 102:27–59;1976.

    Google Scholar 

  9. Eklund H, Plapp BV, Samama J-P, Brändén C-I. Binding of substrate in a ternary complex of horse liver alcohol dehydrogenase. J Biol Chem 257:14349–14358;1982.

    Google Scholar 

  10. Eklund H, Horjales E, Vallee BL, Jörnvall H. Computer-graphic interpretations of residue exchanges between the α, β, and γ subunits of human-liver alcohol dehydrogenase class I isoenzymes. Eur J Biochem 167:185–193;1987.

    Google Scholar 

  11. Foglio MH, Duester G. Molecular docking studies on interaction of diverse retinol structures with human alcohol dehydrogenases predict a broad role in retinoid ligand synthesis. Biochim Biophys Acta 1432:239–250;1999.

    Google Scholar 

  12. Holland DR, Hausrath AC, Juers D, Matthews BW. Structural analysis of zinc substitutions in the active site of thermolysin. Protein Sci 4:1955–1965;1995.

    Google Scholar 

  13. Holmquist B, Vallee BL. Metal-coordinating substrate analogs as inhibitors of metalloenzymes. Proc Natl Acad Sci USA 76:6216–6220;1979.

    Google Scholar 

  14. Hurley TD, Bosron WF, Stone CL, Amzel LM. Structures of three human beta alcohol dehydrogenase variants. Correlations with their functional differences. J Mol Biol 239:415–29;1994.

    Google Scholar 

  15. Jörnvall H, Höög J-O. Nomenclature of alcohol dehydrogenases. Alcohol Alcohol 30:153–161;1995.

    Google Scholar 

  16. Kabsch W, Sander C. Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22:2577–2637;1983.

    Google Scholar 

  17. Kägi JHR, Vallee BL. The role of zinc in alcohol dehydrogenase. J Biol Chem 235:3188–3192;1960

    Google Scholar 

  18. Marschall H-U, Opperman UCT, Svensson S, Nordling E, Persson B, Höög J-O, Jörnvall H. Human liver class I alcohol dehydrogenase γγ isozyme: The sole cytosolic 3β-hydroxysteroid dehydrogenase of iso-bile acids. Hepatology 31:990–996;2000.

    Google Scholar 

  19. Neale AD, Scopes RK, Kelly JM, Wettenhall RE. The two alcohol dehydrogenases ofZymomonas mobilis. Purification by differential dye ligand chromatography, molecular characterization and physiological roles. Eur J Biochem 154:119–124;1986.

    Google Scholar 

  20. Niederhut MS, Gibbsons BJ, Perez-Miller S, Hurley TD. Three-dimensional structures of the three human class I alcohol dehydrogenases. Protein Sci 10:697–706;2001.

    Google Scholar 

  21. Nowak W, Wojtczak A, Cody V. Computer modeling with the ESFF forcefield of human dihydrofolate reductase ternary complex with NADPH and piritrexim (PTX) inhibitor. 5th Electronic Computational Chem Conference paper 46;1998.

  22. Scopes RK. An iron-activated alcohol dehydrogenase. FEBS Lett 156:303–306;1983.

    Google Scholar 

  23. Svenssonm S, Some M, Lundsjö A, Helander A, Cronholm T, Höög J-O. Activities of human alcohol dehydrogenases in the metabolic pathways of ethanol and serotonin. Eur J Biochem 262:324–329;1999.

    Google Scholar 

  24. Svensson S, Höög J-O, Schneider G, Sandalova T. Crystal structures of mouse class II alcohol dehydrogenase reveal determinants of substrate specificity and efficiency. J Mol Biol 302:441–453;2000.

    Google Scholar 

  25. Vallee BL, Auld DS. Active-site zinc ligands and activated H2O of zinc enzymes. Proc Natl Acad Sci USA 87:220–224;1990.

    Google Scholar 

  26. Vallee BL, Auld DS. Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 29:5647–5659;1990.

    Google Scholar 

  27. Vallee BL, Auld DS. Cocatalytic zinc motifs in enzyme catalysis. Proc Natl Acad Sci USA 90:2715–2718;1993.

    Google Scholar 

  28. Vallee BL, Auld DS. New perspective on zinc biochemistry: Cocatalytic sites in multi-zinc enzymes. Biochemistry 32:6493–6500;1993.

    Google Scholar 

  29. Williamson VM, Paquin CE. Homology ofSaccharomyces cerevisiae ADH4 to an iron-activated alcohol dehydrogenase fromZymomonas mobilis. Mol Gen Genet 209:374–381;1987.

    Google Scholar 

  30. Yoshida A, Rzhetsky A, Hsu LC, Chang C. Human aldehyde dehydrogenase gene family. Eur J Biochem 251:549–557;1998.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Pharmacy, Taipei Medical University, Taipei, Taiwan, ROC

    Yih Ho

  2. Department of Chemical Engineering, National Taipei University of Technology, No. 1 Sec. 3 Chung-Hsiao E. Road, Taipei, Taiwan 106 (ROC)

    Hsuan-Liang Liu & Chia-Ming Hsu

Authors
  1. Hsuan-Liang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yih Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chia-Ming Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, HL., Ho, Y. & Hsu, CM. The effect of metal ions on the binding of ethanol to human alcohol dehydrogenase β2β2 . J Biomed Sci 10, 302–312 (2003). https://doi.org/10.1007/BF02256449

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02256449

Key Words

Search

Navigation