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BIOGRAPHY:
Dr. McFadden received his Ph.D. in cell biology in 1984 from the
University of Melbourne. He conducted postdoctoral research from 1984
to 1986 at the University of Münster in Germany. From 1986 to 1994
he returned to the University of Melbourne, first as Queen Elizabeth II
Fellow, and later as ARC Senior Research Fellow. From 1995 to 1996 he
was Guest Scientist at the Institute for Marine BioSciences, National
Research Council in Halifax, Canada. Among the awards he has received
are the 1998 Frederick White Prize from the Australian Academy of
Sciences, the 2001 David Syme Research Prize from the Australian Trust
of that name, and the 2003 Woodward Medal from the University of
Melbourne. He is currently Associate Professor in the School of Botany
at the University of Melbourne and holds a Australian Professorial
Fellowship from the Australian Research Council. His HHMI-funded
research is on the relict chloroplast of Plasmodium
falciparum.
RESEARCH ABSTRACT SUMMARY:
The Relict Chloroplast of Malaria Parasites: What Does it Do and Can We Kill it?
The apicoplast has emerged as a promising target for new
antimalarials. Apicoplasts are indispensable, but their exact function
remains uncertain. To understand more about the apicoplast, we
assembled a predicted organelle proteome. The apicoplast synthesizes 23
proteins but also imports numerous nuclear-encoded proteins. Targeting
of these proteins to the apicoplast requires a unique N-terminal
extension. After scrutinizing a large collection of these N-terminal
extensions from the Plasmodium falciparum genome, we were able
to extract a simple set of rules that could predict targeting of
proteins to the apicoplast from primary sequence. Strategic mutagenesis
of apicoplast-targeting peptides demonstrated that a net basic charge
and a chaperone-binding site are critical to accurate targeting. These
in vivo analyses allowed us to fine-tune our algorithms and increase
prediction accuracy. As an ultimate test of these algorithms, we
generated large numbers of random peptides in silico and screened them
with our bioinformatics tools. Synthetic peptides deemed likely to
mediate apicoplast targeting were coupled to a GFP reporter and
transfected into parasites. Using this approach, we have identified
completely artificial targeting peptides that are sufficient to target
a reporter gene to the apicoplast with high precision, which further
underscores the accuracy of our prediction software. Our current
estimates identify more that 500 apicoplast proteins, which represents
about 10 percent of the parasite genome, engaged in this compartment.
These apicoplast proteins constitute complete pathways for fatty acid
and isoprenoid biosynthesis plus a partial set of heme synthesis
enzymes. We believe that these anabolic pathways are essential to
parasite survival because end products are exported from the apicoplast
for use elsewhere in the parasite cell. Various lines of biochemical
and pharmacological evidence confirm the activity and indispensability
of these pathways, and numerous apicoplast enzymes for these pathways
as well as additional apicoplast housekeeping activities are excellent
drug targets.
Photo: Kent Kallberg, Kallberg Studios
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