Researchers unravel the elusive source of
sulfur in an antibiotic
15 January 2015, by Bob Yirka
Ball-and-stick model of lincomycin. Credit:
Jynto/Wikipedia
genes were disrupted. Doing so led to the discovery
that disruption of lmbE led to intermediates that
looked a lot like lincomycin—that led them to study
lambV, a gene that also shows up in lincomycin,
which led to the discovery of another intermediary.
The team also tested other enzymes and found a
way to prove that there were at least three of them
that incorporated sulfur into parts of the antibiotic,
which was the original goal, of course. More
specifically, they found that two bacterial thiols
played a constructive role in the biosynthesis of
lincomycin A. The team then went further, isolating
the materials that were produced due to the genes
involved, along with the functions of enzymes that
were part of the process.
Work done by the team should help provide a
(Phys.org)—A team of researchers working at the pathway for other researchers attempting to find the
Chinese Academy of Sciences in Shanghai has for source of sulfur atoms in other molecules, perhaps
leading to new types of materials for use in a
the first time found the source of sulfur atoms in
variety of medical purposes, from antibiotics to
lincomycin A, a lincosamide widely used as an
cancer fighting agents.
antibiotic agent. In their paper published in the
journal Nature, the team describes their research
More information: Metabolic coupling of two
efforts and results. Charles Melancon with the
University of New Mexico outlines and comments small-molecule thiols programs the biosynthesis of
on the work done by the team in the same journal lincomycin A, Nature (2015) DOI:
10.1038/nature14137
issue.
Abstract
Low-molecular-mass thiols in organisms are well
known for their redox-relevant role in protection
against various endogenous and exogenous
stresses1, 2, 3. In eukaryotes and Gram-negative
bacteria, the primary thiol is glutathione (GSH), a
cysteinyl-containing tripeptide. In contrast,
mycothiol (MSH), a cysteinyl pseudo-disaccharide,
is dominant in Gram-positive actinobacteria,
including antibiotic-producing actinomycetes and
pathogenic mycobacteria. MSH is equivalent to
GSH, either as a cofactor or as a substrate, in
numerous biochemical processes4, most of which
To find the sulfur source, the researchers used
modern whole genome sequencing techniques to have not been characterized, largely due to the
work backwards through likely pathways looking to dearth of information concerning MSH-dependent
proteins. Actinomycetes are able to produce
isolate intermediaries that tended to build up as
As Melancon notes, there are a host of molecules
vital for biological processes that have sulfur as a
component—their metabolic origins can be
predicted as a matter of course. Sulfur atoms on
the other hand have been much more difficult to
predict. Overcoming such obstacles for some
molecules could have benefits such as helping to
develop new medicines. In this new effort the
researchers set their sights on lincomycin A, an
antibacterial agent that has been used to treat
Gram-positive bacterial infections for many years.
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another thiol, ergothioneine (EGT), a histidine
betaine derivative that is widely assimilated by
plants and animals for variable physiological
activities5. The involvement of EGT in enzymatic
reactions, however, lacks any precedent. Here we
report that the unprecedented coupling of two
bacterial thiols, MSH and EGT, has a constructive
role in the biosynthesis of lincomycin A, a sulfurcontaining lincosamide (C8 sugar) antibiotic that
has been widely used for half a century to treat
Gram-positive bacterial infections6, 7, 8, 9. EGT
acts as a carrier to template the molecular
assembly, and MSH is the sulfur donor for
lincomycin maturation after thiol exchange. These
thiols function through two unusual S-glycosylations
that program lincosamide transfer, activation and
modification, providing the first paradigm for EGTassociated biochemical processes and for the
poorly understood MSH-dependent
biotransformations, a newly described model that is
potentially common in the incorporation of sulfur, an
element essential for life and ubiquitous in living
systems.
© 2015 Phys.org
APA citation: Researchers unravel the elusive source of sulfur in an antibiotic (2015, January 15)
retrieved 17 June 2017 from https://phys.org/news/2015-01-unravel-elusive-source-sulfur-antibiotic.html
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