Computational structural enzymology methodologies for the study and engineering of fatty acid synthases, polyketide synthases and nonribosomal peptide synthetases

Abstract

Various computational methodologies can be applied to enzymological studies on enzymes in the fatty acid, polyketide, and non-ribosomal peptide biosynthetic pathways. These multi-domain complexes are called fatty acid synthases, polyketide synthases, and non-ribosomal peptide synthetases. These mega-synthases biosynthesize chemically diverse and complex bioactive molecules, with the intermediates being chauffeured between catalytic partners via a carrier *

Production, Biosynthesis, and Commercial Applications of Fatty Acids From Oleaginous Fungi

“…The synthesis of some special FAs in microorganisms may be related to PKS. PKS is a sophisticated molecular machine responsible for synthesizing polyketides, which are natural products from the secondary metabolism with similarities to FA ( 115 – 117 ).…”

Probing the structure and function of acyl carrier proteins to unlock the strategic redesign of type II polyketide biosynthetic pathways

“…Integrating these advances with computational simulations allows for deeper insight into the biochemical behavior of ACPs in type II PKSs in at least four ways: (1) facilitating data interpretation; (2) modeling transient interactions that evade structural analyses; (3) assessing the effects of mimetic and mechanism-based probe approaches; and (4) generating models that can be tested experimentally. MD simulations are particularly powerful when used in conjunction with structural techniques such as X-ray crystallography, cryoelectron microscopy, and NMR spectroscopy because the ability to simulate information at faster and varying time scales extends the scope of traditional structural techniques ( 83 ).…”

“…Despite the promise of MD simulations, the application of this methodology to study type II PKS ACPs has been stymied by challenges associated with modeling the long, flexible Ppant arm and Ppant arm-bound intermediates ( 83 ). For this reason, early MD simulations on type II PKS systems did not focus on ACPs.…”

“…Tsai et al. recently developed a force field to model the Ppant arm and Ppant-bound intermediates, starter units, and extender units ( 83 , 87 ). Together, these advances provide an exciting framework for applying force fields capable of modeling ACPs in their holo - and acyl -states.…”

“…Recent progress toward the parameterization of the Ppant arm and its cargo has paved the way for a new era of type II PKS ACP research in which MD simulations can be used hand-in-hand with structural and biochemical approaches. Tsai et al recently developed a force field to model the Ppant arm and Ppant-bound intermediates, starter units, and extender units (83,87). Together, these advances provide an exciting framework for applying force fields capable of modeling ACPs in their holoand acyl-states.…”