title: Comparative Modeling and Molecular Dynamics Simulation of Substrate Binding in Human Fatty Acid Synthase: Enoyl Reductase and β-Ketoacyl Reductase Catalytic Domains.
abstract: Fatty acid synthase (FASN, EC 2.3.1.85), is a multi-enzyme dimer complex that plays a critical role in lipogenesis. This lipogenic enzyme has gained importance beyond its physiological role due to its implications in several clinical conditions-cancers, obesity, and diabetes. This has made FASN an attractive pharmacological target. Here, we have attempted to predict the theoretical models for the human enoyl reductase (ER) and β-ketoacyl reductase (KR) domains based on the porcine FASN crystal structure, which was the structurally closest template available at the time of this study. Comparative modeling methods were used for studying the structure-function relationships. Different validation studies revealed the predicted structures to be highly plausible. The respective substrates of ER and KR domains-namely, trans-butenoyl and β-ketobutyryl-were computationally docked into active sites using Glide in order to understand the probable binding mode. The molecular dynamics simulations of the apo and holo states of ER and KR showed stable backbone root mean square deviation trajectories with minimal deviation. Ramachandran plot analysis showed 96.0% of residues in the most favorable region for ER and 90.3% for the KR domain, respectively. Thus, the predicted models yielded significant insights into the substrate binding modes of the ER and KR catalytic domains and will aid in identifying novel chemical inhibitors of human FASN that target these domains.
authors: Centre for Bioinformatics, Vision Research Foundation, Sankara Nethralaya, Nungambakkam, Chennai 600-006, India.
authors: Arun
authors: A
authors: John
authors: Centre for Bioinformatics, Vision Research Foundation, Sankara Nethralaya, Nungambakkam, Chennai 600-006, India.
authors: Vetrivel
authors: V
authors: Umashankar
authors: Larsen and Toubro Department of Ocular Pathology, Vision Research Foundation, Sankara Nethralaya, Nungambakkam, Chennai 600-006, India.
authors: Subramanian
authors: S
authors: Krishnakumar
authors: Department of Biological Sciences, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
authors: Perinkulam Ravi
authors: PR
authors: Deepa
keywords: comparative modeling; docking; enoyl reductase; fatty acid synthase; β-ketoacyl reductase molecular dynamics simulation