Studying the parasite that causes African sleeping
sickness, scientists at Johns Hopkins have discovered a
previously unknown way of making fatty acids, a component
of fat and the outer layer of all cells. The find unveils
more about the biology of this hard-to-kill parasite and
could lead to a target for designing new drugs to fight the
illness that infects a half-million people and kills 50,000
a year worldwide.
Results of the study, in the Aug. 25 issue of Cell,
"show that this is a completely new biochemical pathway for
making fatty acids," said Soo Hee Lee, a postdoctoral
fellow in the
Department of Biological Chemistry at the Institute for
Basic Biomedical Sciences at Johns Hopkins. "It may be that
the enzymes in the pathway could be good targets for
designing drugs to treat sleeping sickness."
The single-celled trypanosome that causes African
sleeping sickness, transmitted between humans and animals
by bloodsucking tsetse flies, goes through several
different stages in its life cycle. One such form is
harbored by the insect, and the other multiplies in a
host's bloodstream. There, the parasite avoids detection by
the human immune system by replacing each of the 10 million
proteins on its outer layer, known as the cell membrane,
with different proteins that are not recognized by immune
cells. These proteins are attached to the cell membrane by
an anchor composed in part of a fatty acid only 14 units
long — dubbed myristate — whereas typically, in
other organisms, these types of anchors contain longer
fatty acids, generally 16 or 18 units long.
Paul Englund, a professor of biological chemistry in
the Institute of Basic Biomedical Sciences at Johns
Hopkins, said, "For many years we thought the parasite had
to get the myristate from its human host because we never
could see any evidence that it could make the fatty acid
itself. Several years ago we found that it does actually
make myristate as well as other fatty acids, and now we
found that it uses a biochemical pathway we never knew to
look for."
The researchers learned about this new fatty
acid-making pathway by hunting the trypanosome genome for
stretches of DNA known to be involved in fatty acid
synthesis in other organisms, such as animals and
plants.
They reasoned that knocking out the fatty acid-making
genes would prevent the parasite from making myristate and
other fatty acids.
But when one member of the research team, Jennifer
Stephens, knocked out a single gene in the trypanosome
known to make fatty acids in other organisms, there was no
change in the parasite's ability to make myristate.
Surprised, the researchers then examined the trypanosome
genome more carefully and discovered enzymes that in other
organisms are known to increase the size of a fatty acid
molecule — dubbed elongases, for making fatty acids
longer — but never have been shown to actually make a
new fatty acid molecule.
Lee knocked out these elongases to see if the parasite
might have difficulty making fatty acids. To the
researchers' surprise, the parasites lacking elongases were
unable to make the 14-unit myristate or other fatty
acids.
"A novel feature of the elongase pathway is that it
contains four different enzymes that take turns in
elongating fatty acids," Lee said. "This modular pathway
allows the parasite to control the size of the fatty acids
it makes."
"It turns out that trypanosomes use an entirely unique
mechanism of making fatty acids. No other organism ever
studied uses elongases to make them," said Englund,
suggesting that attacking biochemical pathways that make
fatty acids could be a way to treat sleeping sickness.
According to the scientists, the research community is
extremely interested in developing drugs that target
bacterial enzymes involved in fatty acid synthesis. One
example is isoniazid, which currently is used to treat
tuberculosis.
"Trypanosomes cause significant health problems in
remote areas of Africa with poor health care," Englund
said. "There is tremendous need for new drugs to cure these
diseases."
The researchers were funded by the National Institutes
of Health. Authors on this paper are Lee, Stephens,
Kimberly Paul and Englund, all of Johns Hopkins.