A view of the flavin-dependent thymidylate synthase enzyme used by many deadly bacteria in complex with the methylenetetrahydrofolate (yellow) and several other substances it needs. Image: Proceedings of the National Academy of Sciences |
A
small team of researchers has used the brilliant X-rays of the Stanford
Synchrotron Radiation Laboratory to pin down the crystalline structure
of an enzyme complex that scientists had spent nearly a decade trying to
resolve. Their discovery could lead to anti-microbial agents for a host
of deadly bacteria, including anthrax, tuberculosis, leprosy and
diphtheria.
These
bacteria use the enzyme, called flavin-dependent thymidylate synthase
(FDTS), to synthesize a nucleotide they need to produce DNA. Other
organisms, including humans, rely on a different version of the enzyme
to accomplish this vital process; and the two versions of the enzyme
differ significantly enough that targeting the bacterial form via drug
therapies should not interfere with the human enzyme’s work.
In
other words, there’s a low probability that drugs targeting the
bacterial version of the enzyme will cause side effects in people.
According to SSRL Staff Scientist Irimpan Mathews, a corresponding author of the study published online last week by the Proceedings of the National Academy of Sciences,
the difficulty in solving the enzyme’s structure lay in crystallizing a
version of the enzyme that could show them precisely what part of it a
drug would need to target.
The
target researchers had been trying to isolate is the site where FDTS
binds with a compound called methylenetetrahydrofolate during nucleotide
synthesis. “No one could get a structure of FDTS bound with that or
with similar compounds,” Mathews said. This was akin to knowing what
door researchers wanted to create a key for, but not being able to find
the lock.
Advances
in growing crystals for analysis, coupled with X-rays from SSRL
beamlines 9-2 and 12-2, have given them the lock. “Our work represents
the first structures of FDTS with methylenetetrahydrofolate and its
mimics,” Mathews said.
Mathews
sees in the discovery a novel avenue for designing drugs that inhibit a
wide variety of harmful bacteria. “Many of the microbes that use FTDS
are deadly, and some of them are biological warfare agents,” he said.
Many on the list also cause the opportunistic infections that often
strike suffers of autoimmune diseases. “If we can make a good inhibitor
for the FDTS enzyme, it could in principle kill more than 20 different
microbes,” he said.
Folate binding site of flavin-dependent thymidylate synthase
