Vijayanathan, M and Vadakkepat, AK and Mahendran, KR and Sharaf, A and Frandsen, KEH and Bandyopadhyay, D and Pillai, MR and Soniya, EV (2024) Structural and mechanistic insights into Quinolone Synthase to address its functional promiscuity. In: Communications Biology, 7 (1).
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Abstract
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. © The Author(s) 2024.
| Item Type: | Journal Article |
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| Publication: | Communications Biology |
| Publisher: | Nature Research |
| Additional Information: | The copyright for this article belongs to Nature Research. |
| Keywords: | polyketide synthase; quinolone derivative, chemistry; enzyme active site; enzyme specificity; genetics; metabolism; molecular model; protein conformation; X ray crystallography, Catalytic Domain; Crystallography, X-Ray; Models, Molecular; Polyketide Synthases; Protein Conformation; Quinolones; Substrate Specificity |
| Department/Centre: | Division of Biological Sciences > Molecular Biophysics Unit |
| Date Deposited: | 07 Jun 2024 14:01 |
| Last Modified: | 07 Jun 2024 14:01 |
| URI: | http://eprints.iisc.ac.in/id/eprint/85093 |
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