Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Jun 15;16(12):3386–3395. doi: 10.1093/emboj/16.12.3386

Crystal structure of human glyoxalase I--evidence for gene duplication and 3D domain swapping.

A D Cameron 1, B Olin 1, M Ridderström 1, B Mannervik 1, T A Jones 1
PMCID: PMC1169964  PMID: 9218781

Abstract

The zinc metalloenzyme glyoxalase I catalyses the glutathione-dependent inactivation of toxic methylglyoxal. The structure of the dimeric human enzyme in complex with S-benzyl-glutathione has been determined by multiple isomorphous replacement (MIR) and refined at 2.2 A resolution. Each monomer consists of two domains. Despite only low sequence homology between them, these domains are structurally equivalent and appear to have arisen by a gene duplication. On the other hand, there is no structural homology to the 'glutathione binding domain' found in other glutathione-linked proteins. 3D domain swapping of the N- and C-terminal domains has resulted in the active site being situated in the dimer interface, with the inhibitor and essential zinc ion interacting with side chains from both subunits. Two structurally equivalent residues from each domain contribute to a square pyramidal coordination of the zinc ion, rarely seen in zinc enzymes. Comparison of glyoxalase I with other known structures shows the enzyme to belong to a new structural family which includes the Fe2+-dependent dihydroxybiphenyl dioxygenase and the bleomycin resistance protein. This structural family appears to allow members to form with or without domain swapping.

Full Text

The Full Text of this article is available as a PDF (804.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aronsson A. C., Sellin S., Tibbelin G., Mannervik B. Probing the active site of glyoxalase I from human erythrocytes by use of the strong reversible inhibitor S-p-bromobenzylglutathione and metal substitutions. Biochem J. 1981 Jul 1;197(1):67–75. doi: 10.1042/bj1970067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barton G. J. ALSCRIPT: a tool to format multiple sequence alignments. Protein Eng. 1993 Jan;6(1):37–40. doi: 10.1093/protein/6.1.37. [DOI] [PubMed] [Google Scholar]
  3. Bennett M. J., Schlunegger M. P., Eisenberg D. 3D domain swapping: a mechanism for oligomer assembly. Protein Sci. 1995 Dec;4(12):2455–2468. doi: 10.1002/pro.5560041202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brünger A. T., Krukowski A., Erickson J. W. Slow-cooling protocols for crystallographic refinement by simulated annealing. Acta Crystallogr A. 1990 Jul 1;46(Pt 7):585–593. doi: 10.1107/s0108767390002355. [DOI] [PubMed] [Google Scholar]
  5. Christianson D. W. Structural biology of zinc. Adv Protein Chem. 1991;42:281–355. doi: 10.1016/s0065-3233(08)60538-0. [DOI] [PubMed] [Google Scholar]
  6. Corpet F. Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 1988 Nov 25;16(22):10881–10890. doi: 10.1093/nar/16.22.10881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dumas P., Bergdoll M., Cagnon C., Masson J. M. Crystal structure and site-directed mutagenesis of a bleomycin resistance protein and their significance for drug sequestering. EMBO J. 1994 Jun 1;13(11):2483–2492. doi: 10.1002/j.1460-2075.1994.tb06535.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Espartero J., Sánchez-Aguayo I., Pardo J. M. Molecular characterization of glyoxalase-I from a higher plant; upregulation by stress. Plant Mol Biol. 1995 Dec;29(6):1223–1233. doi: 10.1007/BF00020464. [DOI] [PubMed] [Google Scholar]
  9. Fleischmann R. D., Adams M. D., White O., Clayton R. A., Kirkness E. F., Kerlavage A. R., Bult C. J., Tomb J. F., Dougherty B. A., Merrick J. M. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science. 1995 Jul 28;269(5223):496–512. doi: 10.1126/science.7542800. [DOI] [PubMed] [Google Scholar]
  10. Garcia-Iniguez L., Powers L., Chance B., Sellin S., Mannervik B., Mildvan A. S. X-ray absorption studies of the Zn2+ site of glyoxalase I. Biochemistry. 1984 Feb 14;23(4):685–689. doi: 10.1021/bi00299a016. [DOI] [PubMed] [Google Scholar]
  11. Gillespie E. Effects of S-lactoylglutathione and inhibitors of glyoxalase I on histamine release from human leukocytes. Nature. 1979 Jan 11;277(5692):135–137. doi: 10.1038/277135a0. [DOI] [PubMed] [Google Scholar]
  12. Han S., Eltis L. D., Timmis K. N., Muchmore S. W., Bolin J. T. Crystal structure of the biphenyl-cleaving extradiol dioxygenase from a PCB-degrading pseudomonad. Science. 1995 Nov 10;270(5238):976–980. doi: 10.1126/science.270.5238.976. [DOI] [PubMed] [Google Scholar]
  13. Holm L., Ouzounis C., Sander C., Tuparev G., Vriend G. A database of protein structure families with common folding motifs. Protein Sci. 1992 Dec;1(12):1691–1698. doi: 10.1002/pro.5560011217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Holm L., Sander C. Protein structure comparison by alignment of distance matrices. J Mol Biol. 1993 Sep 5;233(1):123–138. doi: 10.1006/jmbi.1993.1489. [DOI] [PubMed] [Google Scholar]
  15. Holm L., Sander C. The FSSP database of structurally aligned protein fold families. Nucleic Acids Res. 1994 Sep;22(17):3600–3609. [PMC free article] [PubMed] [Google Scholar]
  16. Inoue Y., Kimura A. Identification of the structural gene for glyoxalase I from Saccharomyces cerevisiae. J Biol Chem. 1996 Oct 18;271(42):25958–25965. [PubMed] [Google Scholar]
  17. Jones T. A., Zou J. Y., Cowan S. W., Kjeldgaard M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A. 1991 Mar 1;47(Pt 2):110–119. doi: 10.1107/s0108767390010224. [DOI] [PubMed] [Google Scholar]
  18. Kim N. S., Umezawa Y., Ohmura S., Kato S. Human glyoxalase I. cDNA cloning, expression, and sequence similarity to glyoxalase I from Pseudomonas putida. J Biol Chem. 1993 May 25;268(15):11217–11221. [PubMed] [Google Scholar]
  19. Kleywegt G. J., Jones T. A. Phi/psi-chology: Ramachandran revisited. Structure. 1996 Dec 15;4(12):1395–1400. doi: 10.1016/s0969-2126(96)00147-5. [DOI] [PubMed] [Google Scholar]
  20. Lan Y., Lu T., Lovett P. S., Creighton D. J. Evidence for a (triosephosphate isomerase-like) "catalytic loop" near the active site of glyoxalase I. J Biol Chem. 1995 Jun 2;270(22):12957–12960. doi: 10.1074/jbc.270.22.12957. [DOI] [PubMed] [Google Scholar]
  21. Marmstål E., Aronsson A. C., Mannervik B. Comparison of glyoxalase I purified from yeast (Saccharomyces cerevisiae) with the enzyme from mammalian sources. Biochem J. 1979 Oct 1;183(1):23–30. doi: 10.1042/bj1830023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. McCarter L. L. MotY, a component of the sodium-type flagellar motor. J Bacteriol. 1994 Jul;176(14):4219–4225. doi: 10.1128/jb.176.14.4219-4225.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ranganathan S., Walsh E. S., Godwin A. K., Tew K. D. Cloning and characterization of human colon glyoxalase-I. J Biol Chem. 1993 Mar 15;268(8):5661–5667. [PubMed] [Google Scholar]
  24. Reinemer P., Dirr H. W., Ladenstein R., Schäffer J., Gallay O., Huber R. The three-dimensional structure of class pi glutathione S-transferase in complex with glutathione sulfonate at 2.3 A resolution. EMBO J. 1991 Aug;10(8):1997–2005. doi: 10.1002/j.1460-2075.1991.tb07729.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Richard J. P. Kinetic parameters for the elimination reaction catalyzed by triosephosphate isomerase and an estimation of the reaction's physiological significance. Biochemistry. 1991 May 7;30(18):4581–4585. doi: 10.1021/bi00232a031. [DOI] [PubMed] [Google Scholar]
  26. Ridderström M., Mannervik B. Optimized heterologous expression of the human zinc enzyme glyoxalase I. Biochem J. 1996 Mar 1;314(Pt 2):463–467. doi: 10.1042/bj3140463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ridderström M., Mannervik B. The primary structure of monomeric yeast glyoxalase I indicates a gene duplication resulting in two similar segments homologous with the subunit of dimeric human glyoxalase I. Biochem J. 1996 Jun 15;316(Pt 3):1005–1006. doi: 10.1042/bj3161005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schad E. M., Zaitseva I., Zaitsev V. N., Dohlsten M., Kalland T., Schlievert P. M., Ohlendorf D. H., Svensson L. A. Crystal structure of the superantigen staphylococcal enterotoxin type A. EMBO J. 1995 Jul 17;14(14):3292–3301. doi: 10.1002/j.1460-2075.1995.tb07336.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sellin S., Eriksson L. E., Aronsson A. C., Mannervik B. Octahedral metal coordination in the active site of glyoxalase I as evidenced by the properties of Co(II)-glyoxalase I. J Biol Chem. 1983 Feb 25;258(4):2091–2093. [PubMed] [Google Scholar]
  30. Sellin S., Eriksson L. E., Mannervik B. Fluorescence and nuclear relaxation enhancement studies of the binding of glutathione derivatives to manganese-reconstituted glyoxalase I from human erythrocytes. A model for the catalytic mechanism of the enzyme involving a hydrated metal ion. Biochemistry. 1982 Sep 28;21(20):4850–4857. doi: 10.1021/bi00263a004. [DOI] [PubMed] [Google Scholar]
  31. Sellin S., Mannervik B. Metal dissociation constants for glyoxalase I reconstituted with Zn2+, Co2+, Mn2+, and Mg2+. J Biol Chem. 1984 Sep 25;259(18):11426–11429. [PubMed] [Google Scholar]
  32. Sellin S., Rosevear P. R., Mannervik B., Mildvan A. S. Nuclear relaxation studies of the role of the essential metal in glyoxalase I. J Biol Chem. 1982 Sep 10;257(17):10023–10029. [PubMed] [Google Scholar]
  33. Senda T., Sugiyama K., Narita H., Yamamoto T., Kimbara K., Fukuda M., Sato M., Yano K., Mitsui Y. Three-dimensional structures of free form and two substrate complexes of an extradiol ring-cleavage type dioxygenase, the BphC enzyme from Pseudomonas sp. strain KKS102. J Mol Biol. 1996 Feb 9;255(5):735–752. doi: 10.1006/jmbi.1996.0060. [DOI] [PubMed] [Google Scholar]
  34. Sträter N., Klabunde T., Tucker P., Witzel H., Krebs B. Crystal structure of a purple acid phosphatase containing a dinuclear Fe(III)-Zn(II) active site. Science. 1995 Jun 9;268(5216):1489–1492. doi: 10.1126/science.7770774. [DOI] [PubMed] [Google Scholar]
  35. Thornalley P. J. The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J. 1990 Jul 1;269(1):1–11. doi: 10.1042/bj2690001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Vander Jagt D. L., Han L. P. Deuterium isotope effects and chemically modified coenzymes as mechanism probes of yeast glyoxalase-I. Biochemistry. 1973 Dec 4;12(25):5161–5167. doi: 10.1021/bi00749a022. [DOI] [PubMed] [Google Scholar]
  37. Vince R., Wadd W. B. Glyoxalase inhibitors as potential anticancer agents. Biochem Biophys Res Commun. 1969 Jun 6;35(5):593–598. doi: 10.1016/0006-291x(69)90445-8. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES