Structure and function of animal fatty acid synthase

  title={Structure and function of animal fatty acid synthase},
  author={Subrahmanyam S. Chirala and Salih J. Wakil},
Fatty acid synthase (FAS; EC of animal tissues is a complex multifunctional enzyme consisting of two identical monomers. The FAS monomer (∼270 kDa) contains six catalytic activities and from the N-terminus the order is β-ketoacyl synthase (KS), acetyl/malonyl transacylase (AT/MT), β-hydroxyacyl dehydratase (DH), enoyl reductase (ER), β-ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE). Although the FAS monomer contains all the activities needed for palmitate… 
A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site.
The identification of GSK2194069, a potent and specific inhibitor of the β-ketoacyl reductase (KR) activity of hFAS is described; the characterization of its enzymatic and cellular mechanism of action; and its inhibition of human tumor cell growth are described.
Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat
The details of these interactions reveal the molecular basis for inhibition and suggest a mechanism for acyl-chain length discrimination during the FAS catalytic cycle, and provide a foundation for the development of new cancer drugs that target FAS.
Mechanism of Orlistat Hydrolysis by the Thioesterase of Human Fatty Acid Synthase
It is found that the hexyl tail of the covalently bound orlistat undergoes a conformational transition, which is accompanied by destabilization of a hydrogen bond between a hydroxyl moiety of orlistsat and the catalytic His2481 of TE that in turn leads to an increased hydrogen bonding between water molecules and his2481 and increased chance for water activation to hydrolyze thecovalent bond between orlist at and Ser2308.
Synthesis of novel beta-lactone inhibitors of fatty acid synthase.
The syntheses and activity of novel inhibitors of the thioesterase domain of FAS are reported on, supporting the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.
Mammalian fatty acid synthase: X-ray structure of a molecular assembly line.
A recently published X-ray structure of FAS reveals, for the first time, the organization of all active sites involved in acyl chain elongation and provides a structural framework for interpretation of extensive functional studies.
Molecular docking study of the interactions between the thioesterase domain of human fatty acid synthase and its ligands
Comparison of the binding modes of five fatty acids with chain lengths ranging from 12 to 20 carbons confirmed that the ligand binding pocket of TE domain is a decisive factor in chain length specificity.
Fatty Acid Biosynthesis in Chromerids
A full-scale description of the biosynthesis of fatty acids and their derivatives provides important insights into the reductive evolutionary transition of a phototropic algal ancestor to obligate parasites.
Inhibitors of Fatty Acid Synthase for Prostate Cancer. Revision
This report summarizes the immense amount of structure-activity-relationships for new compounds developed and reports on a new click-chemistry approach to derive novel FASN inhibitors.


Animal fatty acid synthase: functional mapping and cloning and expression of the domain I constituent activities.
It is found that kallikrein cleavage sites occur in the least conserved regions of the FAS polypeptide subunit, and the order of the component activities in domain I is confirmed, paving the way for successful expression and characterization of the remaining activities.
Structural and functional organization of the animal fatty acid synthase.
Mapping of functional interactions between domains of the animal fatty acid synthase by mutant complementation in vitro.
The current model for the animal FAS must be revised to reflect the finding that the two constituent polypeptides are not simply positioned side-by-side in a fully extended conformation but are coiled in a manner that allows the dehydrase domain to access the beta-hydroxyacyl-ACP located more than 1100 residues distant on the same subunit.
Human fatty acid synthase: assembling recombinant halves of the fatty acid synthase subunit protein reconstitutes enzyme activity.
The successful reconstitution of the human FAS activity from its domain I and domains II and III fully supports the model for the structure-function relationship of FAS in animal tissues.
The animal fatty acid synthase: one gene, one polypeptide, seven enzymes
  • Stuart Smith
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 1994
The animal fatty acid synthase comprises two multifunctional polypeptide chains, each containing seven discrete functional domains, juxtaposed head‐to‐tail such that two separate centers for fatty
The malonyl/acetyltransferase and beta-ketoacyl synthase domains of the animal fatty acid synthase can cooperate with the acyl carrier protein domain of either subunit.
The results of this study reveal an unanticipated element of redundancy in the FAS reaction mechanism in that the amino-terminal KS and MAT domains can make functional contact with the penultimate carboxy-Terminal ACP domain of either subunit.
Human fatty acid synthase: Role of interdomain in the formation of catalytically active synthase dimer
It is shown that the fatty acid synthase activity could not be reconstituted when the ID sequences present in the two recombinant halves are deleted, suggesting that these ID sequences are essential for fatty Acid synthase dimer formation.
Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain.
The structure revealed the presence of a hydrophobic groove with a distal pocket at the interface of the two subdomains, which constitutes the candidate substrate binding site and is consistent with the high selectivity of the thioesterase for palmitoyl acyl substrate.
Human fatty acid synthase: properties and molecular cloning.
  • A. Jayakumar, M. Tai, S. Wakil
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1995
All the partial activities of human FAS are comparable to those of other animal FASs, except for the beta-ketoacyl synthase, whose significantly lower activity is attributable to the low 4'-phosphopantetheine content of HepG2 FAS.
Construction, expression, and characterization of a mutated animal fatty acid synthase deficient in the dehydrase function.