title: Regulating effect of β-ketoacyl synthase domain of fatty acid synthase on fatty acyl chain length in de novo fatty acid synthesis.
abstract: Fatty acid synthase (FAS) is a multifunctional homodimeric protein, and is the key enzyme required for the anabolic conversion of dietary carbohydrates to fatty acids. FAS synthesizes long-chain fatty acids from three substrates: acetyl-CoA as a primer, malonyl-CoA as a 2 carbon donor, and NADPH for reduction. The entire reaction is composed of numerous sequential steps, each catalyzed by a specific functional domain of the enzyme. FAS comprises seven different functional domains, among which the β-ketoacyl synthase (KS) domain carries out the key condensation reaction to elongate the length of fatty acid chain. Acyl tail length controlled fatty acid synthesis in eukaryotes is a classic example of how a chain building multienzyme works. Different hypotheses have been put forward to explain how those sub-units of FAS are orchestrated to produce fatty acids with proper molecular weight. In the present study, molecular dynamic simulation based binding free energy calculation and access tunnels analysis showed that the C16 acyl tail fatty acid, the major product of FAS, fits to the active site on KS domain better than any other substrates. These simulations supported a new hypothesis about the mechanism of fatty acid production ratio: the geometric shape of active site on KS domain might play a determinate role.
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: cuiwei@ucas.ac.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: School of Kinesiology and Health, Capital University of Physical Education and Sports, No. 11 Beisanhuanxi Road, Beijing 100191, China. Electronic address: yanliang@cupes.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: tianweixi@ucas.ac.cn.
authors.forename: Weixi
authors.initials: W
authors.lastname: Tian
authors.affiliation: School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: jmj@ucas.ac.cn.
authors.forename: Mingjuan
authors.initials: M
authors.lastname: Ji
authors.affiliation: College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China. Electronic address: maxiaofeng@ucas.ac.cn.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Ma
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D064429:Fatty Acid Synthases / Q000737:chemistry / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis* / Q000737:chemistry; D008316:Malonyl Coenzyme A / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D005227:Fatty Acids; D008316:Malonyl Coenzyme A; D009249:NADP; D000105:Acetyl Coenzyme A; D064429:Fatty Acid Synthases
keywords: Binding free energy calculation; Chain length; Fatty acid production ratio; Fatty acid synthase (FAS); β-Ketoacyl synthase (KS)