Solution Structure and Conformational Flexibility of a Polyketide Synthase Module
Maja Klaus1, Emanuele Rossini2, Andreas Linden3,4
1Institute of Organic Chemistry and Chemical Biology, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Max-von-Laue Strasse 15, Frankfurt am Main 60438, Germany.
JACS Au
|January 3, 2022
Summary
Polyketide synthases (PKSs) are crucial for drug synthesis. This study reveals the structure and dynamics of a PKS module, uncovering electrostatic interactions guiding substrate transfer.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Polyketide synthases (PKSs) are essential enzymes in producing polyketide compounds, a family including vital drugs like erythromycin and lovastatin.
- Understanding the structural properties and dynamics of PKSs is critical for harnessing their potential in custom compound synthesis.
- Key domains within modular PKSs are poorly understood in their arrangement and interplay within the quaternary structure.
Purpose of the Study:
- To characterize the solution structure and conformational dynamics of module 2 from the 6-deoxyerythronolide B synthase.
- To investigate the interplay of domains and the quaternary structure of cis-AT type PKS modules.
- To elucidate the mechanism of substrate shuttling mediated by the acyl carrier protein (ACP).
Main Methods:
- Small-angle X-ray scattering (SAXS) was employed to determine the low-resolution structure in solution.
- Cross-linking mass spectrometry (XL-MS) provided insights into domain proximity and interactions.
- Coarse-grained structural modeling was used to integrate SAXS and XL-MS data.
- Directed evolution was applied to probe functional aspects of the PKS module.
Main Results:
- The study determined the solution structure and conformational dynamics of a cis-AT type PKS module.
- Analysis revealed the arrangement and interplay of domains within the PKS module's quaternary structure.
- Evidence suggests that acyl carrier protein (ACP)-mediated substrate shuttling is guided by a network of nonspecific electrostatic interactions.
Conclusions:
- The hybrid approach provides valuable insights into the structural and dynamic properties of modular PKSs.
- Understanding these properties is key to advancing the engineering of PKSs for novel drug discovery.
- Nonspecific electrostatic interactions play a significant role in directing substrate transfer within PKSs.
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