Professor Andrew Brown
Research Lab, Room 256, Biological Sciences; Phone 9385-2005
- 2013 - current: Head of School
- 2013 - current: Professor, School of BABS
- 2008 - 2012: Associate Professor, School of BABS
- 2002 - 2008: Senior Lecturer, School of BABS, UNSW
- 2000 - 2002: Visiting Scientist, UT Southwestern, Dallas
- 1994 - 2000: Research Scientist/Project Leader, Heart Research Institute, Sydney
Since my undergraduate studies, my research has focused on various aspects of biochemistry involving fats (or lipids). Over the past 14 years, my focus has concentrated on one particular lipid which has become a by-word for heart disease risk, cholesterol. In fact, the cells in our body need cholesterol. However, too much cholesterol in our cells can cause disease, including heart disease. Therefore we have evolved an elaborate system for keeping the cholesterol content of our cells under tight-control.
I had the privilege to work in the laboratory of Nobel laureates, Drs Joe Goldstein and Mike Brown in Dallas, who over the past three decades have revealed layer after layer of complexity of how cells regulate their cholesterol levels. Since arriving at UNSW, I have found two important new players involved in how our cells achieve cholesterol balance. First, I discovered that our cells can make a cholesterol-like molecule that helps to control cholesterol metabolism. Second, I discovered that a critical signalling pathway, often associated with cancer, plays an important role in cholesterol metabolism.
Active Research Projects
Ongoing Research Project
Employing posttranslational modifications (PTMs) to probe membrane topology of proteins: Structural information about membrane-associated proteins is lacking, due to limited methods for mapping membrane topology. The Brown lab is the first to propose using the expanding database of posttranslational modifications as a valuable resource for mapping the topology of membrane-associated proteins. Phosphorylation and ubiquitination sites must be accessible to cytosolic kinases and ubiquitin ligases respectively, and therefore we have used these data to refine the membrane topology model of an important enzyme in cholesterol synthesis, DHCR24.
Buoyed by its involvement in basic biological processes (including oxidative stress, lipid raft formation, and brain function) as well as various diseases (such as cardiovascular disease, hepatitis C infection, and certain cancers), DHCR24 is gaining a reputation for being a heavyweight in human health and disease. The Brown lab has reported on a novel aspect of regulating DHCR24, by signalling.
HMG-CoA reductase (HMGCR) and squalene monooxygenase (SM) are the rate-limiting enzymes of cholesterol biosynthesis. When cellular cholesterol levels rise, HMGCR and SM are rapidly degraded by Endoplasmic Reticulum Associated Degradation (ERAD) to prevent further synthesis of cholesterol. However, the identity of the E3-ubiquitin ligase responsible for promoting degradation of SM had remained elusive. The Brown lab, with Noam Zelcer's group from The Netherlands, identified membrane-associated RING finger 6 (MARCH6) as the E3 ligase controlling the sterol-induced degradation of SM. Additionally, MARCH6 controls the basal abundance of HMGCR, positioning this ligase as an important regulator of flux through the mevalonate pathway.
|Reference: Luu W, Zerenturk EJ, Kristiana I, Bucknall MP, Sharpe LJ & Brown AJ, 2013, 'Signalling regulates activity of DHCR24, the final enzyme in cholesterol synthesis', Journal of Lipid Research.
|Reference: Zelcer N, Sharpe LJ, Loregger A, Kristiana I, Cook EC, Phan L, Stevenson J & Brown AJ, 2013, 'The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase (SM), and affects HMG-CoA reductase (HMGCR) and the cholesterol synthesis pathway', Molecular and Cellular Biology.