Structural analysis unravels the functional promiscuity of Quinolone synthase-mediated polyketide biosynthesis in Aegle marmelos Correa

Abstract

Quinolone synthase from Aegle marmelos (AmQNS) is a type III polyketide synthase that yields therapeutically effective quinolone and acridone compounds. Based on the high-resolution protein structure of AmQNS, this study provided a mechanistic explanation of the structure to synthetic selectivity. Additionally, it displays the comparatively wide active site entry that allows the catalytic pocket to accommodate bulky substrates, which affects the enzyme catalysis. We also develop a model framework for comprehending the structural constraints on ketide insertion, and postulate that AmQNS synthetic diversity is owing to its steric and electrostatic selectivity, which allows it to bind to a variety of core substrates. We further establish that AmQNS is structurally biased toward quinolone synthesis and only synthesizes acridone when malonyl-CoA concentrations are significantly high. In a nutshell, we anticipate that addressing the structural and molecular underpinnings of AmQNS-substrate interaction in terms of its high selectivity and specificity can aid in the development of numerous novel compounds. Besides, the approaches can also be expanded to other potential enzymes, which will help the pharmaceutical sector by expanding the pool of potential medication leads.