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J. Biol. Chem., Vol. 278, Issue 9, 7206-7214, February 28, 2003
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,§,
, and
From the Wellcome Trust Laboratories for Molecular Parasitology,
Centre for Molecular Microbiology and Infection, Department of
Biological Sciences, Imperial College of Science, Technology and
Medicine, London SW7 2AZ, United Kingdom
Co-translational modification of eukaryotic
proteins by N-myristoylation aids subcellular targeting and
protein-protein interactions. The enzyme that catalyzes this process,
N-myristoyltransferase (NMT), has been characterized in the
kinetoplastid protozoan parasites, Leishmania and
Trypanosoma brucei. In Leishmania major, the
single copy NMT gene is constitutively expressed in all
parasite stages as a 48.5-kDa protein that localizes to both membrane
and cytoplasmic fractions. Leishmania NMT myristoylates the
target acylated Leishmania protein, HASPA, when both are
co-expressed in Escherichia coli. Gene targeting
experiments have shown that NMT activity is essential for viability in
Leishmania. In addition, overexpression of NMT causes gross
changes in parasite morphology, including the subcellular accumulation
of lipids, leading to cell death. This phenotype is more extreme than
that observed in Saccharomyces cerevisiae, in which
overexpression of NMT activity has no obvious effects on growth
kinetics or cell morphology. RNA interference assays in T. brucei have confirmed that NMT is also an essential protein in
both life cycle stages of this second kinetoplastid species, suggesting
that this enzyme may be an appropriate target for the development of
anti-parasitic agents.
These authors have contributed equally to this work.
§
Recipient of an Overseas Research Scholarship. Present address:
Division of Virology, National Institute for Medical Research, London
NW7 1AA, United Kingdom.
¶
Recipient of a research studentship from the UK Biological and
Biotechnological Scientific Research Council.
Present address: Dept. of Biological Sciences, Lancaster
University, Lancashire LA1 4YQ, United Kingdom.
**
To whom correspondence should be addressed. Tel.: 44-20-75945282;
Fax: 44-20-75945283; E-mail: d.smith@ic.ac.uk.
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