Understanding the molecular production line

How natural polyketides are produced “in assembly lines”: HZI researchers decode the molecular structure of synthesizing enzymes

 Das funktionelle CinFDas funktionelle CinF ist aus vier CinF Molekülen aufgebaut, die sich gegenseitig bei der Bindung des Substrates unterstützen.From deadly toxins to curative antibiotics: The polyketides, a class of biologically active compounds, comprise a multitude of metabolites from plants, fungi, bacteria and other organisms.  How does nature produce this remarkably broad spectrum? Researchers of the Helmholtz Centre for Infection Research (HZI), Braunschweig, the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and Saarland University in Saarbrücken have now reached a milestone on the way to understanding these processes. They have decoded the structure and function of an enzyme that provides and prepares an important component for the stepwise assembly of a polyketide molecule. The team of scientists was the first to elucidate how the enzyme recognizes, binds and activates specific precursor components. The results of this study have now been published by the renowned scientific journal “Nature Chemical Biology”. The researchers hope that they soon will be able to “reprogram” the polyketide synthesis in cells – and thus yield new substances with pharmaceutical properties.

Polyketides make up one of the most extensive classes of natural products. Many of them have been discovered and isolated from microorganisms and plants. Their biological activities are remarkably manifold: they serve as signaling molecules, natural pigments and “defense weapons” against antagonists. The antibiotic Erythromycin, the chemotherapeutic agents Doxorubicin and Epothilon and the antiparasitic drug Avermectin are prominent examples. In spite of their diversity, polyketides are produced via a common biosynthetic pathway.

The stepwise linking of single precursor elements that leads to the formation of polyketides in microorganisms is accomplished by special enzyme complexes, the so-called polyketide synthases. “The production of polyketides is basically assembly line work”, explains Professor Rolf Müller, Director of HIPS as well as Professor for Pharmaceutical Biotechnology at Saarland University. “The polyketide synthase is an analogue to a factory’s production line. The enzyme accepts an element from a certain supplier unit and another element from a different one. Comparable to car production, where specific units provide only doors, others only engine hoods and so on. The polyketide synthase chemically links all elements in order to form a complete polyketide.”

Using the reference bacterium Streptomyces, the researchers focused their attention on the suppliers that provide the single elements. The suppliers studied represent a class of proteins assigned the complex name „crotonyl-CoA carboxylase/reductase“, short CCR. They fulfill the task of delivering elements to the synthases; each CCR is specialized to provide only certain elements. “The question now was: How do the CCRs help to accomplish the remarkable variety of polyketide structures?” 

The researchers analyzed the biochemistry and the molecular structure of one particular CCR. They chose the enzyme 2 octenoyl-CoA synthase, short CinF. „We were the first to see at atomic resolution how CinF binds its substrate”, says Dr. Nick Quade, scientist in the Department of Molecular Structural Biology at the HZI. A pocket in the supplier protein enables the binding partner to directly interact with CinF. Finally the researchers compared the CinF binding pocket structure to pocket structures of other CCRs that provide distinct substrates. 

Binding pockets of the latter are exactly complementary to their respective substrate, similar to the lock and key principle. The researchers found that CCRs choose their substrates depending on the pocket size: Some CCRs are specialized in short-chained molecules, others preferentially “fish” for long-chained elements, and then prepare them for the integration into the polyketide.

As polyketides often show interesting medical effects, the scientists hope to gain valuable information for the development of novel pharmaceutics. “We want to understand the way CCRs work and provide single elements”, explains Professor Dirk Heinz, Scientific Director at the HZI and co-author of the publication. “The long-term goal is to specifically regulate the assembly and modification of polyketide components and thus to produce customized medical products.” 

Original publication: 

Unusual Carbon Fixation Giving Rise to Diverse Polyketide Extender Units. Nick Quade, Liujie Huo, Shwan Rachid, Dirk W. Heinz, Rolf Müller.

Nature Chemical Biology,Advanced Online Publication, DOI: 10.1038/NChemBio.734


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