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Dr Merridee A Wouters

Victor Chang Cardiac Research Institute
384 Victoria St, Darlinghurst, Sydney 2010
Email: m.wouters@victorchang.unsw.edu.au
Tel: +61-2-9295-8508
Fax: +61-2-9295-8501

I am interested in applying bioinformatics techniques to study the evolution of proteases with particular regard to the application of evolutionary processes to the design of proteases, and enzymes in general, that attack novel substrates.
My past work includes a study of the zinc hydrolases that shows that, contrary to the view that important active site residues are absolutely conserved in active enzymes, the active site can change over very long timescales. At least three catalytic zinc-binding sites have existed in the structural scaffold over the period of history defined by available structures. Comparison of enzyme-inhibitor complexes show that major remodeling of the substrate-binding site has occurred in association with each change in zinc ligation in the binding site. These changes involve re-registration and re-orientation of the substrate. We are currently investigating changes in other enzymes groups, such as cysteine proteases, to determine whether if these large changes are unique to metalloenzymes.
Previous work in the area of ancestral reconstruction, or paleomolecular biochemistry, attempted to create serine proteases with custom specificities. To do this an ancestor to several daughter enzymes with diverse unique specificities was created using phylogenetic inference, gene synthesis, and protein expression. The ancestor had two unusual properties. Firstly, it had a broad primary specificity encompassing the entire repertoire of novel primary specificities found in its descendents. Secondly, unlike extant daughter enzymes which have narrow primary specificities, the ancestor exhibited tolerance to mutational changes in primary specificity-conferring residues-that is, structural plasticity.
Dr Siiri Iismaa
Dr Robert Graham
Wouters MA, Liu K, Riek P, Husain A. A despecialization step underlying evolution of a family of serine proteases. Mol Cell. 2003 Aug; 12(2): 343-54.

Wouters MA, Husain A. Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily.
J Mol Biol. 2001 Dec 14; 314(5): 1191-207.

Iismaa SE, Holman S, Wouters MA, Lorand L, Graham RM, Husain A. Evolutionary specialization of a tryptophan indole group for transition-statestabilization by eukaryotic transglutaminases. Proc Natl Acad Sci U S A. 2003 Oct 28; 100(22): 12636-41. Epub 2003 Oct 17.

Liu X, Fernandez M, Wouters MA, Heyberger S, Husain A.
Arg(1098) is critical for the chloride dependence of human angiotensinI-converting enzyme C-domain catalytic activity.
J Biol Chem. 2001 Sep 7; 276(36): 33518-25. Epub 2001 Jun 29. PMID: 11432860 [PubMed - indexed for MEDLINE]

Fernandez M, Liu X, Wouters MA, Heyberger S, Husain A.
Angiotensin I-converting enzyme transition state stabilization by HIS1089:evidence for a catalytic mechanism distinct from other gluzincinmetalloproteinases.J Biol Chem. 2001 Feb 16; 276(7): 4998-5004. Epub 2000 Nov 06.

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