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Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis
Yi-Qiang Cheng1, Gong-Li Tang, Ben Shen
1Division of Pharmaceutical Sciences, Department of Chemistry, University of Wisconsin, 777 Highland Avenue, Madison, WI 53705, USA.
Summary
Researchers discovered a novel polyketide synthase (PKS) architecture in leinamycin (LNM) biosynthesis. A separate acyltransferase (AT) protein loads extender units in trans to AT-less PKS modules, enabling LNM production and offering engineering opportunities.
Area of Science:
- Biochemistry
- Molecular Biology
- Synthetic Biology
Background:
- Type I polyketide synthases (PKSs) are modular enzymes crucial for producing diverse natural products.
- Each PKS module typically contains a beta-ketoacyl synthase, acyltransferase (AT), and acyl carrier protein.
Purpose of the Study:
- To elucidate the PKS architecture involved in leinamycin (LNM) biosynthesis.
- To investigate the role of a discrete AT protein in this process.
Main Methods:
- Analysis of the leinamycin (LNM) biosynthetic gene cluster from Streptomyces atroolivaceus S-140.
- Gene inactivation studies (lnmG, lnmI, lnmJ) in vivo.
- In vitro biochemical characterization of the LnmG protein.
Main Results:
- The LNM gene cluster contains two PKS genes (lnmI, lnmJ) encoding six AT-less PKS modules.
- A discrete AT protein, LnmG, was identified as the sole AT activity within the cluster.
- Inactivation of lnmG, lnmI, or lnmJ abolished LNM production.
- LnmG efficiently loaded malonyl CoA to all six PKS modules in vitro.
Conclusions:
- A novel PKS architecture was revealed, featuring a trans-acting, iterative AT protein (LnmG) that complements AT-less PKS modules.
- This unique PKS structure facilitates polyketide biosynthesis and presents avenues for PKS engineering, such as enhancing LNM production via LnmG overexpression.