Research Network for Metals in Medicine

 

 

Dr Mitchell Guss

BSc(Hons), PhD(Syd)

Position: Principal Research Fellow

Affiliation: School of Molecular and Microbial Biosciences, University of Sydney

Postal Address:
School of Molecular and Microbial Biosciences Building G08
University of Sydney
NSW 2006
AUSTRALIA

Phone: +61 (2) 9351 4302
Fax: +61 (2) 9351 4726
Email: M.Guss@mmb.usyd.edu.au
Webpage: http://www.mmb.usyd.edu.au/research.php?person=gussm

Research Profile

The major focus of research in the laboratory for more than twenty years has been the way in which the versatile properties of metal ions are exploited by biological systems. The background to the work involved years of research using so-called model compounds to study biological systems at a time when experimental techniques were not available to study the “real” systems.

Specific research themes

Copper amine oxidases: this family of homologous enzymes are found in all three kingdoms of life. They carry out the same relatively simple chemical reaction – oxidising organic amines to aldehydes. This reaction is used however for a wide variety of biological functions. In bacteria and other simple organisms the principal function of these enzymes is to provide a source a nitrogen and carbon for metabolism. In plants the enzymes are thought to be recruited to sites of tissue damage where they participate in the wound healing process. In mammals copper amine oxidases perform a wide variety of functions depending on the tissue location. These functions include the catabolism of toxic amines, the crosslinking of connective tissue and the formation of artherosclerotic plaques. We are conducting structural studies with two broad aims. Firstly, to define the role of the copper atom in the formation of the organic quinone cofactor and in the enzyme mechanism. Secondly to provide a structural basis for the specificities of individual enzymes with a long term view to designing inhibitors which may act as drugs.

Enzymes with dincuclear metal sites: A large number of enzymes have been characterized which have a dinuclear metal cluster in their active sites. Despite having very active sites the enzymes performs a wide variety of functions and utilize different metal ions in their active forms. For example dihydroorotase, which performs an essential step in the synthesis of nucleic acids, has zinc in its active site. On the other hand despite having a very similar active site, prolidase – a proline-specific dipeptidase – is inactive in the presence of zinc but active in the presence of cobalt. We are interested in defining what makes enzymes specific for different metal ions and what differences the metals confer on the enzymes.

‘Blue’ copper proteins: The first de novo protein structure solved in Australia was that of the ‘blue’ or ‘type 1’ copper protein plastocyanin. This family of proteins is characterized by spectroscopic and redox properties not normally observed in low molecular weight copper complexes. Since we published the original structure we have since solved the structures of plastocyanin from a number of different plants, algae and cyanobacteria and of other blue copper proteins. One of these, cucumber basic protein, was solved by the then novel method of multiple wavelength anomalous dispersion.


Selected Publications

  1. Bond, C. S., Blankenship, R. E., Freeman, H. C., Guss, J. M., Maher, M. J., Selvaraj, F. M., Wilce, M. C., and Willingham, K. M. (2001) Crystal structure of auracyanin, a "blue" copper protein from the green thermophilic photosynthetic bacterium Chloroflexus aurantiacus. J. Mol. Biol. 306, 47-67.
  2. Maher, J. M., Ghosh, M., Grunden, A. M., Menon, A. L., Adams, M. W. W., Freeman, H. C., and Guss, J. M. (2004) Structure of the prolidase from Pyrococcus furiosus. Biochemistry accepted for publication.
  3. Maher, J. M., Cross, M., Wilce, M. C. J., Guss, J. M., and Wedd, A. G. (2003) Structures of metal-substituted derivatives of the rubredoxin from Clostridium pasteurianum. Acta Cryst. Accepted for publication.
  4. Duff, A. P., Cohen, A. E., Ellis, P. J., Kuchar, J. A., Langley, D. B., Shepard, E. M., Dooley, D. M., Freeman, H. C., and Guss, J. M. (2003) The crystal structure of Pichia pastoris lysyl oxidase. Biochemistry In press.
  5. Graham, S. C., Lee, M., Freeman, H. C., and Guss, J. M. (2003) An orthorhombic form of Escherichia coli aminopeptidase P at 2.4 A resolution. Acta Cryst. D59, 897-902.


Facilities

  • X-ray diffraction laboratory for macromolecular crystallography – Rigaku RU200 rotating anode generator
  • 2xMarresearch Desktop beamlines with 345 mm imaging plates. Each beamline is equipped with Osmic optics and Oxford cryosystems.
  • A protein production facility with incubators for bacteria and mammalian cells
  • Chromatography (FPLC and HPLC)
  • Mass spectroscopy
  • Ultracentrifuge
  • Biocore plasmon resonance
  • 600 MHz NMR
  • Multi-angle and dynamic light scattering


International Linkages

Harry Gray (Caltech, USA)
Dave Dooley (Montana State, USA)
Paul Ellis (SSRL, USA)
Michael Adams (University of Georgia, USA)
William Simmons (Loyola Medical School, USA)
Amy Grunden (North Carolina State University, USA)