Scientists studying the biosynthesis and production of
microbial natural products now have a greater insight into the
process. This research was conducted at the U.S. Department of
Energy's Argonne National Laboratory in collaboration with
scientists from the Scripps Research Institute and Rice
University.
Armed with this new information, researchers can use it to
manipulate nature's biosynthetic machinery to produce more
effective antibiotics and cancer-fighting drugs.
Streptomyces are Gram-positive bacteria that live in soil.
These bacteria possess a complex metabolism and are known to
naturally produce clinically useful compounds.
One large class of natural products, known as polyketides,
includes many drugs such as erythromycin (antibacterial) and
rapamycin (immunosuppressive), as well as promising drug
leads such as migrastatin and oxazolomycin reported in the
current study, which show important antibacterial, antitumor,
and anti-human immunodeficiency virus activity.
These antibiotics are synthesized by a set of enzymes that
are orchestrated into assembly-line-like biosynthetic machinery.
Researchers in this study focused on understanding the enzymes
specificity, which is responsible for generating the vast
chemical structural diversities known for migrastatin,
oxazolomycin and other polyketides.
Andrzej Joachimiak works in the biosciences division at
Argonne and was one of the authors of a paper published on the
topic in The Proceedings of the National Academy of Sciences
of the United States of America.
"If we understand the specificity of these processes, we
will be able to engineer the enzymes to accept other chemical
molecules, opening the door to new treatments for some of our
most challenging diseases," said Joachimiak, Director of the
5
New information about bacterial enzymes to
help scientists develop more effective antibiotics,
cancer drugs
Department of Energy's Structural Biology Center, which is
located at Argonne.
Antibiotics are made up of a set of multiple enzymes that
perform consecutive actions.
Scientists seek to modify these molecules chemically to
create new drugs with improved therapeutic properties.
"In order to do that we need to understand the specificity of
this "enzymatic assembly line," Dr. Ben Shen of the Scripps
Research Institute said. "We need to know which part we need to
place, and do it in a rational and specific manner, to synthesize the
designer compounds."
Manipulating enzymes that catalyze complex reactions that
alter natural product structures to create diverse novel compounds
with new biological activities is a key.
This work was done with the help of the Advanced Protein
Characterization Facility, which has greatly aided medical and
biomedical research by automating the production of protein and
protein crystals -- two key steps in solving the structure of
proteins, understanding how they operate and ultimately helping to
identify new and more effective drug treatments.
Proteins are long molecular chains that fold on themselves in
complex ways with many of those folds serving as docking sites
where other molecules, including those from pathogens, can
attach.
In protein structure research, snippets of the DNA code for a
protein are cloned. The clones are used to produce the proteins that
are isolated and exposed to various chemical environments with
the hope that one of them will cause the protein molecules to form
a crystal.
Researchers at Argonne, Scripps Research Institute and Rice
University provide greater insight into the process of manipulating
nature's biosynthetic machinery to produce more effective
antibiotics and cancer fighting drugs.
(Image Credit: Joachimiak et, al.)
This can take days, weeks or even months. But when it
happens, the protein molecules align to form a repeating
array. That repetitive configuration allows X-rays from the
Advanced Photon Source, a DOE Office of Science User
Facility located at Argonne, to analyze the three-dimensional
structure of the molecules by means of their different
signatures using crystallographic techniques.
This helps Joachimiak and his team to solve age-old
problems.
"This work would not be possible without the
technology and equipment available here at Argonne," he
said.
Source: www.sciencedaily.com
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