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VIDEO: Three snapshots of the 3-D structure of
Mycobacterium tuberculosis' enzyme PriA are combined in this
video to show the changes the enzyme is capable of
undergoing.
Click here for more information.
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In a paper published today in PNAS, scientists from the European
Molecular Biology Laboratory (EMBL) in Hamburg, Germany, reveal new
insights into the workings of enzymes from a group of bacteria
including Mycobacterium tuberculosis, the bacterium that
causes tuberculosis. The new findings present possible new
opportunities for developing organism-specific drugs, which target
the pathogen but leave other microorganisms, which are beneficial
to us, untouched.
Tuberculosis remains one of the largest threats to human health
worldwide, and one of the most frequent causes of death in HIV
patients. With the increasing emergence of strains of
Mycobacterium tuberculosis that are hyper-resistant to
drugs, it becomes ever more urgent that novel treatments be
developed, and the search for novel strategies for drug development
is an important step in this process.
In the current study, Matthias Wilmanns and his group at EMBL
identified a multi-tasking enzyme from Mycobacterium
tuberculosis that catalyses reactions on two different
molecules, or substrates. In most organisms, cells need two
specific enzymes, known as HisA and TrpF, in order to produce two
essential amino acids – histidine and tryptophan. However, in
Mycobacterium tuberculosis, the encoding gene for TrpF is
missing, and the two reactions are instead catalysed by a single
enzyme, which is able to recognize and bind to two different
substrates. This enzyme is known as PriA.
Using the Mycobacterium tuberculosis version of the PriA
enzyme as a model, the researchers were able to unravel the
hitherto unknown mechanism of bi-substrate specific binding
observed in this group of bacteria.
"When we solved the three-dimensional structure of PriA, we
found that it has the unique ability to form two different
substrate-specific active sites," Wilmanns says: "it can form a
reaction-specific active site, or undergo what we call
'substrate-induced metamorphosis' to form a different active
site."
To further verify these observations, Wilmanns and colleagues
screened 20,000 small molecule compounds, and identified a handful
which inhibited both PriA-catalysed reactions but had no effect on
TrpF activity.
"We believe that this ability for bi-substrate catalysis in
Mycobacterium tuberculosis could be a new opportunity for
future drug development," Wilmanns concludes: "This
organism-specific reaction process could be exploited, since only
the pathogen but none of the other bacteria living in or on humans,
many of which are important for our well being, would be
targeted."
SOURCE
