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| | <StructureSection load='3tjm' size='340' side='right'caption='[[3tjm]], [[Resolution|resolution]] 1.48Å' scene=''> | | <StructureSection load='3tjm' size='340' side='right'caption='[[3tjm]], [[Resolution|resolution]] 1.48Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3tjm]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TJM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TJM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3tjm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TJM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TJM FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7FA:METHYL+(R)-(6Z,9Z,12Z)-OCTADECA-6,9,12-TRIEN-1-YLPHOSPHONOFLUORIDATE'>7FA</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.48Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FAS, FASN ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7FA:METHYL+(R)-(6Z,9Z,12Z)-OCTADECA-6,9,12-TRIEN-1-YLPHOSPHONOFLUORIDATE'>7FA</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3tjm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tjm OCA], [http://pdbe.org/3tjm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3tjm RCSB], [http://www.ebi.ac.uk/pdbsum/3tjm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3tjm ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3tjm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tjm OCA], [https://pdbe.org/3tjm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tjm RCSB], [https://www.ebi.ac.uk/pdbsum/3tjm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tjm ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FAS_HUMAN FAS_HUMAN]] Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein. | + | [https://www.uniprot.org/uniprot/FAS_HUMAN FAS_HUMAN] Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Florante, A Q]] | + | [[Category: Florante AQ]] |
| - | [[Category: Zhang, W]] | + | [[Category: Zhang W]] |
| - | [[Category: Zheng, F]] | + | [[Category: Zheng F]] |
| - | [[Category: Fatty acid synthesis]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Thioesterase domain]]
| + | |
| Structural highlights
Function
FAS_HUMAN Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein.
Publication Abstract from PubMed
Human fatty acid synthase (hFAS) is a homodimeric multidomain enzyme that catalyzes a series of reactions leading to the de novo biosynthesis of long-chain fatty acids, mainly palmitate. The carboxy-terminal thioesterase (TE) domain determines the length of the fatty acyl chain and its ultimate release by hydrolysis. Because of the upregulation of hFAS in a variety of cancers, it is a target for antiproliferative agent development. Dietary long-chain polyunsaturated fatty acids (PUFAs) have been known to confer beneficial effects on many diseases and health conditions, including cancers, inflammations, diabetes, and heart diseases, but the precise molecular mechanisms involved have not been elucidated. We report the crystal structure of the hFAS TE domain covalently modified and inactivated by methyl gamma-linolenylfluorophosphonate. Whereas the structure confirmed the phosphorylation by the phosphonate head group of the active site serine, it also unexpectedly revealed the binding of the 18-carbon polyunsaturated gamma-linolenyl tail in a long groove-tunnel site, which itself is formed mainly by the emergence of an alpha helix (the "helix flap"). We then found inhibition of the TE domain activity by the PUFA dihomo-gamma-linolenic acid; gamma- and alpha-linolenic acids, two popular dietary PUFAs, were less effective. Dihomo-gamma-linolenic acid also inhibited fatty acid biosynthesis in 3T3-L1 preadipocytes and selective human breast cancer cell lines, including SKBR3 and MDAMB231. In addition to revealing a novel mechanism for the molecular recognition of a polyunsaturated fatty acyl chain, our results offer a new framework for developing potent FAS inhibitors as therapeutics against cancers and other diseases.
Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-{gamma}-linolenic acid.,Zhang W, Chakravarty B, Zheng F, Gu Z, Wu H, Mao J, Wakil SJ, Quiocho FA Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15757-62. Epub 2011 Sep 9. PMID:21908709[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhang W, Chakravarty B, Zheng F, Gu Z, Wu H, Mao J, Wakil SJ, Quiocho FA. Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-{gamma}-linolenic acid. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15757-62. Epub 2011 Sep 9. PMID:21908709 doi:10.1073/pnas.1112334108
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