Associate Professor A. Ian Smith Baker Heart Research Institute PO Box 6492, St Kilda Road Central, Melbourne, Vic 8008 Email: ian.smith@baker.edu.au Tel: +61-3-8532 1185 Fax: +61-3-8532 1100 Homepage: http://www.baker.edu.au Research Our research focuses on the membrane associated and soluble zinc metallopeptidases, that are crucially involved in the activation and degradation of bioactive peptides in a range of tissues. Our particular interests have been the role of these enzymes in the cardiovascular system and in the brain, but our investigations are currently expanding into their roles in other tissues. We have a specific interest in the metallopeptidases that are expressed on the surface of the vascular endothelium which lines the blood vessels. Among their many functions, these enzymes can inactivate vasodilator peptides as well as generate potent vasoconstrictor peptides. These peptidases are also capable of converting inactive peptides such as angiotensin I into active vasoconstrictors and dilators eg, angiotensin II and angiotensin 1-7. Thus, by manipulating the expression and activities of these enzymes we may be able to develop therapeutics to control cardiovascular function Our recent research has focused on the physiology, pathophysiology and structure activity relationships of endothelin converting enzyme (ECE), the soluble peptidases EC 3.4.24.15 & EC 3.4.24.16, angiotensin converting enzyme (ACE) and its the recently identified homologue, ACE2. For all these peptidases we have developed specific antibodies for high resolution (confocal microscopy) localization, immunoblot and pull down experiments, high throughput activity assays (largely based on quenched fluorescent substrates), mammalian cell expression systems for generating large amounts of both membrane and soluble forms of these peptidasesand specific inhibitors. These tools, together with access to unique animal models, allow us to explore the physiological and pathological functions of these peptidases in depth. Collaborations Professor Tony Turner (University of Leeds, UK) Professor Mark Glucksman (Chicago Medical School, Chicago, USA) Professor Jim Roberts (University of San Antonio, San Antonio, USA) Dr Elizabeth Scalbert (Servier, Paris France) Dr Emer Ferro (University of Sao Paulo, Sao Paulo, Brazil) Professor Vincent Dive (CNRS, Paris France) Professor Peter Klinken (WAIMR Perth Australia) Professor Colin Johnson (Baker Heart Research Institute, Melbourne, Australia) Assoc Professor Phil Bird (Monash University, Melbourne Australia) Dr David Small (Monash University, Melbourne Australia) Professor Fred Mendelshon, Howard Florey Institute, Melbourne Australia) Professor Colin Masters (University of Melbourne, Melbourne, Australia) Assoc. Professor Peter Dodd (University of Queensland, Brisbane, Australia) Assoc. Professor Mibel Aguilar (Monash University, Melbourne Australia) Dr Paul Simmons (Peter Macallum Institute, Melbourne, Australia) Assoc Professor Patrick Perlmutter (Monash University, Melbourne Australia) Professor Mark Cooper (Baker Heart Research Institute, Melbourne Australia) Assoc Professor Louise Burrell (Austin Hospital, Melbourne Australia) Professor Peter Angus (Austin Hospital, Melbourne Australia) Publications Lew R, Boulos E, Stewart K, Perlmutter P, Harte M, Bond S, Reeve S, Norman U, Lew M , Aguilar M-I and Smith A I. Substrate Analogues Incorporating b_Amino Acids: Potential Application for Peptidase Inhibition. FASEB Journal 10.1096/fj.00-0805fje, May 29, 2001 Sun J, Whisstock JC, Harriott P, Walker B, Novak A, Thompson PE, Smith AI, Bird PI. Importance of the P4prime residue in human granzyme B inhibitors and substrates revealed by scanning mutagenesis of the proteinase inhibitor 9 reactive center loop. J Biol Chem. 2001 May 4;276(18):15177-84 Steer, D.S., R.A. Lew, P. Perlmutter, A.I. Smith and M.-I. Aguilar. Inhibitors of metalloendopeptidase EC 3.4.24.15 stabilised against proteolysis by the incorporation of b_amino acids. Biochemistry 2002 Sep 3;41(35):10819-26 C.N. Shrimpton, A.I. Smith and R.A. Lew Soluble Metalloendopeptidases and Neuroendocrine Signalling Endocrine Reviews. 2002 Oct;23(5):647-64 Small DH & Smith AI. Proteases and Proteolytic Processing in the Nervous System: Key Targets for Drug Development J Neurosci Res, 2003 Nov 1;74(3): Questions/suggestions? Please contact the Network Administrator. Copyright © by International Protease Network All Right Reserved.