Structure of the Human Fatty Acid Synthase KS–MAT Didomain as a Framework for Inhibitor Design

Pappenberger, Florian; Benz, Jörg; Gsell, Bernard; Hennig, Michael; Ruf, A.; Stihle, M.; Thoma, Ralf; Rudolph, M.G.

doi:10.1016/j.jmb.2010.01.066

Cited by 60 publications

(77 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, our data show that no flexibility is observed in AT52 between the linkers and the ␣/␤-hydrolaselike subdomain, whereas the ferredoxin-like subdomain, helped by the two anchoring loops, can be considered as a flexible element of the protein. A similar observation has been reported in the x-ray structures of fungal, yeast, and mammalian FASs (4, 6, 7) and of both the KS-MAT didomain (42) and isolated MAT domain of human FAS (41). Pairwise superposition of Pks13 AT52, E. coli MCAT, KS-AT of module 5 from DEBS, and FAS structures also illustrates this flexibility (supplemental Fig.…”

Section: Production Of a Functionally Active Acyltransferasesupporting

confidence: 83%

“…The AT domain consists of a large ␣/␤-hydrolase-like subdomain delineated by residues 712-835 and 911-1035 and a smaller ferredoxin-like subdomain, which comprises residues 836 -910. Thus, the AT domain of the AT52 fragment adopts the canonical fold found in various individual AT enzymes, such as malonyl-CoA:ACP transferases (MCATs) (38 -41); in the AT domain associated with DEBS (7,13,41,42); and in malonyl-acetyltransferase (MAT) domains associated with FAS enzymes (7, 13, 41, 42) (Fig. 3).…”

Section: Production Of a Functionally Active Acyltransferasementioning

confidence: 99%

See 1 more Smart Citation

Biochemical and Structural Study of the Atypical Acyltransferase Domain from the Mycobacterial Polyketide Synthase Pks13

Bergeret

Gavalda

Chalut

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Pks13 is involved in the final biosynthesis step of mycolic acids. Results: We report the full characterization of a 52-kDa fragment containing the acyltransferase domain of Pks13. Conclusion: Pks13 is able to load unusually long chain acyl-CoAs through an unprecedented hydrophobic channel. Significance: This study could constitute a key step toward the development of new antibiotics against mycobacterial infections.

show abstract

Section: Production Of a Functionally Active Acyltransferasesupporting

confidence: 83%

Section: Production Of a Functionally Active Acyltransferasementioning

confidence: 99%

Biochemical and Structural Study of the Atypical Acyltransferase Domain from the Mycobacterial Polyketide Synthase Pks13

Bergeret

Gavalda

Chalut

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The three inhibitors were found to dock on the documented active sites of FASN, suggestive of predictive accuracy of the semi-flexible docking protocol [13][14][15][16]. Table 2 …”

Section: Docking Studies Of Fasn Inhibitorsmentioning

confidence: 83%

“…Cerulenin induces apoptosis in human cancer cells by inhibiting FASN and causing malonyl-CoA accumulation, CPT-1 inhibition and inhibition of fatty acid oxidation [23]. The crystal structure KS-MAT didomain of human FASN is already available [PDB ID:3HHD], and this structure was used for docking with cerulenin [13]. The docking results revealed the binding energy of the enzymeinhibitor complex to be −5.82 kcal/mol.…”

Section: Discussionmentioning

confidence: 99%

“…The docking grid was fixed to cover the respective catalytic domain of FASN pertaining to the inhibitor binding, as documented in in vitro and in in silico studies. The grid box size in x-, y-, and z-axis was normally set in accordance to the drug binding site [13][14][15][16]. The spacing between grid points was fixed as 0.375Ǻ.…”

Section: Docking Studies Of Fasn Inhibitorsmentioning

confidence: 99%

See 1 more Smart Citation

Chemical inhibition of fatty acid synthase: molecular docking analysis and biochemical validation in ocular cancer cells

Deepa

Vandhana

Muthukumaran³

et al. 2010

j ocul biol dis inform

View full text Add to dashboard Cite

anti-cancer therapeutics. The ocular cancer, retinoblastoma cells were treated with fatty acid synthase (FASN) enzyme inhibitors: cerulenin, triclosan and orlistat. The IC 50 and dose-dependent sensitivity of cancer cells to FASN inhibitors decrease in biologic enzyme activity, and cell morphology alterations were analysed. Molecular interactions of enzyme-inhibitor complexes were studied by molecular modelling and docking simulations. The crystal structures of ketoacyl synthase (PDB ID:3HHD) (cerulenin) and thioesterase (PDB ID:2PX6) (orlistat) domains of human FASN were utilized for docking, while for the non-crystallised human FASN enoyl reductase domain (triclosan), homology model was built and used for docking. All three inhibitors showed significant binding energy indicating stable complex formation with their respective FASN subunits. The predicted Ki value of the FASN inhibitors corroborated well with their corresponding anti-cancer effects.

show abstract

Die Kinetik der Kohlenstoff‐Kohlenstoff‐Bindungsbildung in der metazoischen Fettsäure Synthase und ihr Einfluss auf die Produktgenauigkeit

Gusenda,

Calixto,

Da Silva

et al. 2024

Angewandte Chemie

View full text Add to dashboard Cite

Fatty acid synthase (FAS) multienzymes are responsible for de novo fatty acid biosynthesis and crucial in primary metabolism. Despite extensive research, the molecular details of the FAS catalytic mechanisms are still poorly understood. For example, the b‐ketoacyl synthase (KS) catalyzes the fatty acid elongating carbon‐carbon‐bond formation, which is the key catalytic step in biosynthesis, but factors that determine the speed and accuracy of his reaction are still unclear. Here, we report enzyme kinetics of the KS‐mediated carbon‐carbon bond formation, enabled by a continuous fluorometric activity assay. We observe that the KS is likely rate‐limiting to the fatty acid biosynthesis, its kinetics are adapted to the length of the bound fatty acyl chain, and that the KS is also responsible for the fidelity of biosynthesis by preventing intermediates from undergoing KS‐mediated elongation. To provide mechanistic insight into KS selectivity, we performed computational molecular dynamics (MD) simulations. We identify positive cooperativity of the KS dimer, which we suggest to affect the conformational variability of the multienzyme. Advancing our knowledge about the KS molecular mechanism will pave the ground for engineering FAS for biotechnology applications and the design of new therapeutics targeting the fatty acid metabolism.

show abstract

Structure of the Human Fatty Acid Synthase KS–MAT Didomain as a Framework for Inhibitor Design

Cited by 60 publications

References 50 publications

Biochemical and Structural Study of the Atypical Acyltransferase Domain from the Mycobacterial Polyketide Synthase Pks13

Biochemical and Structural Study of the Atypical Acyltransferase Domain from the Mycobacterial Polyketide Synthase Pks13

Chemical inhibition of fatty acid synthase: molecular docking analysis and biochemical validation in ocular cancer cells

Die Kinetik der Kohlenstoff‐Kohlenstoff‐Bindungsbildung in der metazoischen Fettsäure Synthase und ihr Einfluss auf die Produktgenauigkeit

Contact Info

Product

Resources

About