Biological factories: How do bacteria build up natural products?
X-ray structure analysis gives detailed insights into molecular factory


Date:
July 6, 2020
Source:
Technical University of Munich (TUM)
Summary:
The active agents of many drugs are natural products, so called
because often only microorganisms are able to produce the complex
structures.

Similar to the production line in a factory, large enzyme complexes
put these active agent molecules together. Biologists have now
succeeded in investigating the basic mechanisms of one of these
molecular factories.



FULL STORY ==========================================================================
The active agents of many drugs are natural products, so called
because often only microorganisms are able to produce the complex
structures. Similar to the production line in a factory, large enzyme
complexes put these active agent molecules together. A team of the
Technical University of Munich (TUM) and the Goethe University Frankfurt
has now succeeded in investigating the basic mechanisms of one of these molecular factories.


==========================================================================
Many important drugs such as antibiotics or active agents against cancer
are natural products which are built up by microorganisms for example
bacteria or fungi. In the laboratory, these natural products can often
be not produced at all or only with great effort. The starting point
of a large number of such compounds are polyketides, which are carbon
chains where every second atom has a double bound to an oxygen atom.

In a microbial cell such as in the Photorhabdus luminescens bacterium,
they are produced with the help of polyketide synthases (PKS). In order
to build up the desired molecules step by step, in the first stage of
PKS type II systems, four proteins work together in changing "teams."
In a second stage, they are then modified to the desired natural product
by further enzymes. Examples of bacterial natural products which are
produced that way are, inter alia, the clinically used Tetracyclin
antibiotics or Doxorubicin, an anti-cancer drug.

Interdisciplinary cooperation While the modified steps of the second stage
are well studied for many active agents, there have up to now hardly been
any insights into the general functioning of the first stage of these
molecular factories where the highly reactive polyketide intermediate
product is bound to the enzyme complex and protected so that it cannot
react spontaneously.

This gap is now closed by the results of the cooperation between the
working groups of Michael Groll, professor of biochemistry at the
Technical University of Munich, and Helge Bode, professor of molecular biotechnology at Goethe University Frankfurt, which are published in
the scientific journal Nature Chemistry.

Findings inspire to new syntheses of active agents "In the context of
this work, we were for the first time able to analyze complexes of the different partner proteins of type II polyketide synthase with the help
of X-ray structure analysis and now understand the complete catalytic
cycle in detail," Michael Groll explains.

"Based on these findings, it will be possible in the future to manipulate
the central biochemical processes in a targeted manner and thus change the basic structures instead of being restricted to the decorating enzymes,"
Helge Bode adds.

Although it is a long way to develop improved antibiotics and other drugs,
both groups are optimistic that now also the structure and the mechanism
of the missing parts of the molecular factory can be explained. "We
already have promising data of the further protein complexes," says
Maximilian Schmalhofer, who was involved in the study as a doctoral
candidate in Munich.


========================================================================== Story Source: Materials provided by
Technical_University_of_Munich_(TUM). Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Alois Bra"uer, Qiuqin Zhou, Gina L. C. Grammbitter, Maximilian
Schmalhofer, Michael Ru"hl, Ville R. I. Kaila, Helge B. Bode,
Michael Groll. Structural snapshots of the minimal PKS system
responsible for octaketide biosynthesis. Nature Chemistry, 2020;
DOI: 10.1038/s41557-020- 0491-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200706140848.htm

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