Nicholas Hoogenraad

2004 LEMBERG MEDAL: NICHOLAS HOOGENRAAD

Nick HoogenraadNick Hoogenraad gained a B.Agric.Sci in 1965 at the University of Melbourne and a PhD in Biochemistry under the supervision of Frank Hird, at the same university in 1969. In his PhD studies, he investigated the contribution of rumen microbes to the glucose requirements of sheep. After an 18-month post doctoral fellowship in the Department of Pediatrics at Stanford University with Norman Kretchmer, he was appointed to the position of Assistant Professor in Human Biology at Stanford (1971-1974). During this time, he developed an interest in compartmentation in vertebrate cells, initially through the discovery of a multi-enzyme complex at the head of the pyrimidine biosynthetic pathway which proved to be a mechanism for the compartmentation of carbamyl-phosphate. During this time, his work on the reaction mechanism of mammalian aspartate transcarbamylase, led to the development of a long-standing collaboration with George Stark on the use of transition-state-analogs in studying enzyme reaction mechanisms, and on a return visit of one year to the Biochemistry department at Stanford, on the development of the Western Transfer procedure.

In 1974, he returned to Australia to join the recently established Department of Biochemistry at La Trobe University. There, he developed an interest in the mitochondrial urea cycle enzymes and established a collaboration with the late David Danks at the Murdoch Institute. This collaboration led to the development of sensitive techniques for identifying genetic defects responsible for hyperammonemia and to the discovery of many variants in defective urea cycle enzymes. The work on these enzymes culminated in the cloning of the first cDNA encoding a mammalian mitochondrial protein, ornithine transcarbamylase in 1982. A collaboration during this period with Paul Alewood on a peptide derivative of the transition state analog inhibitor of this enzyme, d-PALO, also showed that the unique distribution of the mitochondrial urea cycle enzymes in liver and gut is a mechanism to separate ammonia detoxification by liver from arginine biosynthesis by gut and peripheral tissues.

The cloning of the mitochondrial enzymes led to an interest in the mechanism of targeting proteins to mitochondria and the eventual isolation, cloning and characterisation of components of the protein import machinery of mitochondria from mammalian cells. In 1990, Nick established a highly productive association with Peter Høj in the Department of Biochemistry on the role of molecular chaperones in mitochondrial biogenesis. This led to the cloning of many of the chaperones of the mitochondrial matrix and characterisation of the role of these chaperones in protein folding in the mitochondrion. In the mid 1990s, Nick also established a close collaboration with Masataka Mori from Kumamoto University on the functional characterisation of the protein import machinery of mitochondria. More recently, his work, in collaboration with Michael Ryan in the Department of Biochemistry has focused on broader questions of mitochondrial biogenesis and function and culminated in the discovery of a new stress response pathway, the mitochondrial stress response, where unfolding of mitochondrial proteins leads to the induction of genes encoding mitochondrial chaperones and proteases. Investigations into the interaction of molecular chaperones with the Tom70 receptor also revealed a docking mechanism for the delivery of pre-proteins to mitochondria.

Nick was appointed Professor of Biochemistry in 1992 and has been Head of the Department of Biochemistry at LaTrobe since that time. He has supervised 35 PhD students. In 1994 he was awarded the AMRAD/Pharmacia Medal of the ASBMB and was the 1997 Leach lecturer at the Lorne Protein Structure and Function Conference. He was President of ASBMB 1997-1998, and serves on a number of Editorial and Scientific Boards.