Understanding
how antibiotic scaffolds are constructed in nature can help scientists prospect
for new classes of antibiotics through DNA sequencing and genome mining.
Researchers have used this knowledge to help solve the X-ray crystal structure
of the enzyme that makes obafluorin -- a broad spectrum antibiotic agent made
by a fluorescent strain of soil bacteria. The new work is from Washington
University in St. Louis and the University at Buffalo.
A
multi-part enzyme called a nonribosomal peptide synthetase produces the highly
reactive beta-lactone ring that is responsible for obafluorin's antimicrobial
activity. These chemicals could be used as next-generation antibiotics for
humans, or even to benefit the agriculture sector.
The
new work provides a useful road map that shows how individual protein domains
in the ObiF1 enzyme are stitched together in three-dimensional space. An
enzyme's structure is fundamental to almost every function it performs.
Obafluorin
is made by a fluorescent strain of soil bacteria that forms biofilms on plant
roots. Like penicillin, obafluorin has a four-membered ring -- sometimes called
an enchanted ring. A four-membered ring puts strain on bond angles that carbon
prefers to adopt. But because a four-member ring is unstable, these molecules
are also short-lived and difficult to make. For example, it took years for
chemists to learn how to synthesize penicillin from chemicals and then figure
out how fungi make it. This ultimately led to the global production of
penicillin by fermentation.
Researchers were
able to fast-track
the discovery process using genetics to zero in on the biosynthetic machinery
that bacteria use to make obafluorin, and then to reconstruct that multi-step,
enzyme-catalyzed process in the laboratory.
The
result is a comprehensive, detailed molecular structure at 3 Angstrom
resolution that allows one to identify the atoms in the protein chain, see
their location and points of contact along the chain, and determine how the
pieces are assembled to produce useful molecules from start to finish.
One
particular component -- something called an MbtH-like protein, or MLP, because
it was first identified in a related system to produce mycobactin in the
bacteria that causes tuberculosis -- was shown to play a critical role in
facilitating protein-to-protein interactions between catalytic domains.
See:
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology
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