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The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold

Nature Structural Biology volume 4, pages 317–326 (1997)Cite this article

Abstract

The first structure of an aldehyde dehydrogenase (ALDH) is described at 2.6 Å resolution. Each subunit of the dimeric enzyme contains an NAD-binding domain, a catalytic domain and a bridging domain. At the interface of these domains is a 15 Å long funnel-shaped passage with a 6 × 12 Å opening leading to a putative catalytic pocket. A new mode of NAD binding, which differs substantially from the classic β-α-β binding mode associated with the ‘Rossmann fold’, is observed which we term the β-α,β mode. Sequence comparisons of the class 3 ALDH with other ALDHs indicate a similar polypeptide fold, novel NAD-binding mode and catalytic site for this family. A mechanism for enzymatic specificity and activity is postulated.

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References

  1. Lindahl, R. Aldehyde dehydrogenases and their role in carcinogenesis. Crit. Rev. Biochem. Mol. Biol. 27, 283–335 (1992)..

    Article  CAS  Google Scholar 

  2. Lindahl, R. & Evces, S. Rat liver aldehyde dehydrogenase II: characterization of the four inducible enzymes. J. Biol. Chem 259, 11991–11996 (1984).

    CAS  PubMed  Google Scholar 

  3. Jacoby, W.B. & Ziegler, D.M. Enzymes of detoxication. J. Biol. Chem. 265, 20715–20718 (1990).

    Google Scholar 

  4. Crow, K.E. & Hardman, M.J. In Human Metabolism of Alcohol. (eds K.E. Crow and R.D. Batts) 3–16 (CRC Press, 1989).

    Google Scholar 

  5. De Laurenzi, V. et al. Sjögren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene. Nature Genetics 12, 52–57 (1996).

    Article  CAS  Google Scholar 

  6. Cui, X., Wise, R.P. & Schnable, P.S. The rf2 nuclear restorer gene of male-sterile T-cytoplasm maise. Science 272, 1334–1336 (1996).

    Article  CAS  Google Scholar 

  7. Tasayco, M.L. & Prestwich A specific affinity reagent to distinguish aldehyde dehydrogenases and oxidases. J. Biol. Chem. 265, 3094–3101 (1990).

    CAS  PubMed  Google Scholar 

  8. McCaffery, P. & Dräger, U.C. Hot spots of retinoic acid synthesis in spinal cord developement. Proc. Natl. Acad. Sci. USA. 91, 7194–7197 (1994).

    Article  CAS  Google Scholar 

  9. Racker, E. Actions and propertiesof pyridine-nucleotide linked enzymes. Phys. Rev. 35, 1–56 (1955).

    CAS  Google Scholar 

  10. Hempel, J., Vonbahr-Lindström, H. & Jörnvall, H. Aldehyde dehydrogenase from human liver: primary structure of the cytoplasmic enzyme. Eur. J. Biochem. 141, 21–35 (1984).

    Article  CAS  Google Scholar 

  11. Habenicht, A., Hellman, U. & Cerff, R. Non-phosphorylating GAPDH of higher plants is a member of the aldehyde dehydrogenase superfamily with no sequence homology tophosphorylating GAPDH. J. Mol. Biol. 237, 165–171 (1994).

    Article  CAS  Google Scholar 

  12. Brändén, C. & Tooze, J. Introduction to Protein Structure. (Garland, New York; 1991).

    Google Scholar 

  13. Rossmann, M.G., Moras, D. & Olsen, K.W. Chemical and biological evolution of a nucleotide binding protein. Nature 250, 194–199 (1974).

    Article  CAS  Google Scholar 

  14. Holm, L. & Sander, C. Protein structure comparison by alignment of distance matrices. J. Mol. Biol. 233, 123–138 (1993).

    Article  CAS  Google Scholar 

  15. Ghosh, D. et al. Three-dimensional structure of holo 3 alpha, 20 beta hydroxysteroid dehydrogenase: a member of the short chain dehydrogenase family. Proc. Natl. Acad. Sci USA 88, 10064–10068 (1991).

    Article  CAS  Google Scholar 

  16. Hempel, J., Nicholas, H. & Lindahl, R. Aldehyde dehydrogenases: widespread structural and functional diversity within a shared framework. Prot. Sci. 2, 1890–1900 (1993).

    Article  CAS  Google Scholar 

  17. von Bahr-Lindström, H. et al. Characterization of the coenzyme binding site of liver aldehyde dehydrogenase: differential reactivity of coenzyme analogs. Biochemistry 24, 5847–5851 (1985).

    Article  Google Scholar 

  18. Hempel, J. & Pietruszko, R. Selective chemical modification of human liver aldehyde dehydrogenases by iodoacetamide. J.Biol. Chem. 256, 10889–10896 (1981).

    CAS  PubMed  Google Scholar 

  19. Farrès, J. et al. Investigation of the active site cystine residue of rat liver mitochondrial aldehyde dehydrogenase by site-directed mutagenesis. Biochemistry 11, 2592–2598 (1995).

    Article  Google Scholar 

  20. Blatter, E.E. et al. Chemical modification of aldehyde dehydrogenase by a vinyl ketone analogue of an insect phermone. Biochem. J. 272, 351–358 (1990).

    Article  CAS  Google Scholar 

  21. Kitson, T.M., Hill, J.P. & Midwinter, G.G. Identification of a catalytically essential nucleophilic residue in sheep liver cytoplasmic aldehyde dehydrogenase. Biochem. J. 275, 207–210 (1991).

    Article  CAS  Google Scholar 

  22. Wierenga, R.K., Terpstra, P. & Hol, W.G.J. Prediction of the occurance of the ADP-binding βαβ-fold in proteins, using an amino acid fingerprint. J. Mol. Biol. 187, 101–107 (1986).

    Article  CAS  Google Scholar 

  23. Wilson, D.K., Bohren, K.M., Gabbay, K.H. & Quiocho, F.A. An unlikely sugar substrate site in the 1.65 Å structure of the human aldose reductase holoenzyme implicated in diabetic complications. Science 257, 81–84 (1992).

    Article  CAS  Google Scholar 

  24. Hoog, S.S., Pawlowski, J.E., Alzari, P.M. & Penning, T.M. Three dimensional structure of rat liver 3a-hydroxysteroid/dihydroidol dehydrogenase: a member of the aldo-keto reductase superfamily. Proc. Natal. Acad. Sci. USA 91, 2517–2521 (1994).

    Article  CAS  Google Scholar 

  25. Lesk, A.M. NAD-binding in dehydrogenases. Curr. Opin. Struct. Bio. 5, 775–783 (1995).

    Article  CAS  Google Scholar 

  26. Bellamacina, C.R. The nicotinamide dinucleotide binding motif: a comparison of nucleotide binding proteins. FASEB J. 10, 1257–1269 (1996).

    Article  CAS  Google Scholar 

  27. Hol, W.G., van Duijnen, P.T. & Berendsen, H.J.C. The alpha-helix dipole and the properties of protiens. Nature 273, 443–446 (1978).

    Article  CAS  Google Scholar 

  28. Wierenga, R.K., De Maeyer, M.C.H. & Hol, W.G.J. Interaction of pyrophosphate moieties with a-helixes in dinucleotide binding proteins. Biochemistry 24, 1346–1357 (1985).

    Article  CAS  Google Scholar 

  29. Ramakrishnan, C. & Ramachandran, G.N. Stereochemical criteria for polypeptide and protein chain conformation. Biophys. J. 5, 909–933 (1965).

    Article  CAS  Google Scholar 

  30. Eklund, H., Samama, J.-P. & Jones, T.A. Crystallographic investigations of nicotinamine adenine dinucleotide binding to horse liver alcohol dehydrogenase. Biochemistry 23, 5982–5996 (1984).

    Article  CAS  Google Scholar 

  31. Jones, K.H., Lindhahl, R., Baker, D.C. & Timkovich, R. Hydride transfer stereospecificity of rat liver aldehyde dehydrogenases. J. Bio. Chem. 262, 10911–10913 (1987).

    CAS  Google Scholar 

  32. Chan, M.K. et al. Structure of hyperthermophillic tungstopterin enzyme Aldehyde ferredoxin oxidoreductase. Science 267, 1463–1469 (1995).

    Article  CAS  Google Scholar 

  33. Romao, M.J. et al. Crystal Structure of the xanthine oxidase-related aldehyde oxido-reductase from D. gigas. Science 270, 1170–1176 (1995).

    Article  CAS  Google Scholar 

  34. Moore, S.A. & James, M.N.G. Structural refinement of the non-fluorescent flavoprotein from photobacterium leiognathi at 1.6 Å resolution. J. Mole. Biol. 249, 195–214 (1995).

    Article  CAS  Google Scholar 

  35. Fisher, A.J. et al. Three-dimensional structure of bacterial luciferase from vibrio harveyi at 2.4 Å resolution. Biochemistry 34, 6851–6586 (1995).

    Google Scholar 

  36. Rose, J.P. et al. Preliminary Crystallographic analysis of class 3 rat liver aldehyde dehydrogenase. Proteins 8, 305–308 (1991).

    Article  Google Scholar 

  37. Howard, A.J. et al. The use of an imaging proportional counter in macromolecular crystallography. J. Appl. Crystallogr. 20, 383–387 (1987).

    Article  CAS  Google Scholar 

  38. Wang, B.-C. Resolution of phase ambiguity in macromolecular crystallography. Methods Enzymol. 115, 90–112 (1985).

    Article  CAS  Google Scholar 

  39. Furey, W.F.J. & Swaminathan, S. Phases95: a program package for the processing and analysis of diffraction data from macromolecules. Methods Enzymol, in the press.

  40. Jones, T.A. et al. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr., A47, 110–119 (1991).

    Article  CAS  Google Scholar 

  41. Engh, R.A. & Huber, R. Accurate bond and angle parameters for X-ray protein structure refinement. Acta Crystallogr. A47, 392–400 (1991).

    Article  CAS  Google Scholar 

  42. Brünger, A.T., Karplus, M. & Petsko, G.A. Crystallographic refinement by simulated annealing: application to crambin. Acta Crystallogr. A45, 50–61 (1989).

    Article  Google Scholar 

  43. Brünger, A.T. Free R value: A novel statistical quantity for assessing the accuracy of crystal structures. Nature 355, 472–475 (1992).

    Article  Google Scholar 

  44. Laskowski, R.A. et al., PROCHECK: a program to check the Stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283–291 (1993).

    Article  CAS  Google Scholar 

  45. Bernstein, F.C. et al., The protein data bank: a computer-based archive-file for macromolecular structures. J. Mol. Biol. 112, 535–542 (1977).

    Article  CAS  Google Scholar 

  46. Luzzati, V. Traitement statistque des erreurs dans la determination des structures cristallines. Acta Crystallogr. 5, 802–810 (1952).

    Article  Google Scholar 

  47. Kabsch, W. & Sander, C. Dictionary of protein secondary structure: Pattern recognition of hydrogen bonded and geometrical features. Biopolymers 22, 2577–2637 (1983).

    Article  CAS  Google Scholar 

  48. Ferrin, T.E. et al. The MIDAS display system. J. Mol. Graphics 6, 13–27 (1988).

    Article  CAS  Google Scholar 

  49. Kleywegt, G.J. & Jones, T.A. Detection, delineation, measurement and display of cavities in macromolecular structures. Acta Crystallogr. D50, 178–185 (1994).

    CAS  Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, 30602, USA

    Zhi-Jie Liu, John Rose, Wen-Rui Chang & Bi-Cheng Wang

  2. Department of Crystallography, University of Pittsburgh, Pittsburgh, PA, 15260, USA

    Yuh-Ju Sun, Yong-Je Chung & Chwan-Deng Hsiao

  3. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, 15219, USA

    Ingrid Kuo & John Hempel

  4. Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, 15219, USA

    John Perozich

  5. Department of Biochemistry and Molecular Biology, University of South Dakota, Vermillion, SD, 57069, USA

    Ronald Lindahl

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Liu, ZJ., Sun, YJ., Rose, J. et al. The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold. Nat Struct Mol Biol 4, 317–326 (1997). https://doi.org/10.1038/nsb0497-317

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