Structural and mechanistic insights into Quinolone Synthase to address its functional promiscuity.

Autor: Vijayanathan M; Transdisciplinary Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, India.; Department of Plant and Environment Sciences, University of Copenhagen, 1871, Frederiksberg C, Denmark., Vadakkepat AK; Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.; Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester, LE17HB, UK., Mahendran KR; Transdisciplinary Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, India., Sharaf A; SequAna Core Facility, Department of Biology, University of Konstanz, Konstanz, Germany.; Genetic Department, Faculty of Agriculture, Ain Shams University, Cairo, 11241, Egypt., Frandsen KEH; Department of Plant and Environment Sciences, University of Copenhagen, 1871, Frederiksberg C, Denmark., Bandyopadhyay D; Department of Biological Sciences, Birla Institute of Technology and Science, Hyderabad, India., Pillai MR; Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, India., Soniya EV; Transdisciplinary Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, India. evsoniya@rgcb.res.in.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2024 May 14; Vol. 7 (1), pp. 566. Date of Electronic Publication: 2024 May 14.
DOI: 10.1038/s42003-024-06152-2
Abstrakt: Quinolone synthase from Aegle marmelos (AmQNS) is a type III polyketide synthase that yields therapeutically effective quinolone and acridone compounds. Addressing the structural and molecular underpinnings of AmQNS and its substrate interaction in terms of its high selectivity and specificity can aid in the development of numerous novel compounds. This paper presents a high-resolution AmQNS crystal structure and explains its mechanistic role in synthetic selectivity. Additionally, we provide a model framework to comprehend structural constraints on ketide insertion and postulate that AmQNS's steric and electrostatic selectivity plays a role in its ability to bind to various core substrates, resulting in its synthetic diversity. AmQNS prefers quinolone synthesis and can accommodate large substrates because of its wide active site entrance. However, our research suggests that acridone is exclusively synthesized in the presence of high malonyl-CoA concentrations. Potential implications of functionally relevant residue mutations were also investigated, which will assist in harnessing the benefits of mutations for targeted polyketide production. The pharmaceutical industry stands to gain from these findings as they expand the pool of potential drug candidates, and these methodologies can also be applied to additional promising enzymes.
(© 2024. The Author(s).)
Databáze: MEDLINE
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