Information on EC 2.3.1.85 - fatty-acid synthase and Organism(s) Homo sapiens

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
2.3.1.85
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RECOMMENDED NAME
GeneOntology No.
fatty-acid synthase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
acetyl-CoA + n malonyl-CoA + 2n NADPH + 2n H+ = a long-chain fatty acid + (n+1) CoA + n CO2 + 2n NADP+
show the reaction diagram
reaction mechanism; structure and regulation
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acyl group transfer
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decarboxylation
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redox reaction
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thioester hydrolysis
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
(5Z)-dodecenoate biosynthesis I
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fatty acid biosynthesis (plant mitochondria)
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fatty acid biosynthesis initiation I
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fatty acid biosynthesis initiation II
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fatty acid biosynthesis initiation III
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fatty acid elongation -- saturated
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mupirocin biosynthesis
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octanoyl-[acyl-carrier protein] biosynthesis (mitochondria, yeast)
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oleate biosynthesis IV (anaerobic)
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palmitate biosynthesis I (animals and fungi)
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palmitate biosynthesis II (bacteria and plants)
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superpathway of fatty acid biosynthesis initiation (E. coli)
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Fatty acid biosynthesis
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Metabolic pathways
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SYSTEMATIC NAME
IUBMB Comments
acyl-CoA:malonyl-CoA C-acyltransferase (decarboxylating, oxoacyl- and enoyl-reducing and thioester-hydrolysing)
The animal enzyme is a multi-functional protein catalysing the reactions of EC 2.3.1.38 [acyl-carrier-protein] S-acetyltransferase, EC 2.3.1.39 [acyl-carrier-protein] S-malonyltransferase, EC 2.3.1.41 3-oxoacyl-[acyl-carrier-protein] synthase, EC 1.1.1.100 3-oxoacyl-[acyl-carrier-protein] reductase, EC 4.2.1.59 3-hydroxyacyl-[acyl-carrier-protein] dehydratase, EC 1.3.1.39 enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) and EC 3.1.2.14 oleoyl-[acyl-carrier-protein] hydrolase. cf. EC 2.3.1.86, fatty-acyl-CoA synthase.
CAS REGISTRY NUMBER
COMMENTARY hide
9045-77-6
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
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FASN produces phospholipids for membrane microdomains that accommodate receptor tyrosine kinases including epidermal growth factor-receptor ErbB1 and ErbB2
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
additional information
?
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fatty acid synthase-dependent palmitoylation of epidermal growth factor receptor is required for epidermal growth factor receptor dimerization and kinase activation. Inhibition of fatty acid synthase or palmitoyl acyltransferases reduces the activity and down-regulated the levels of epidermal growth factor receptor, and sensitizes cancer cells to epidermal growth factor receptor tyrosine kinase inhibitors
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
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multifunctional enzyme, involved in animal fat synthesis
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?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4'-phosphopantetheine
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requirement, 1 mol associated with 1 mol subunit
NADPH
additional information
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no requirement for FMN
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(10E,12Z)-octadec-10,12-dienoic acid
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more potent inhibitor than (9Z,11E)-octadec-9,11-dienoic acid
(9Z,11E)-octadec-9,11-dienoic acid
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1,2,3,4,6-penta-O-galloyl-beta-D-glucose
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compound is transported across cancer cell membrane to further down-regulate FAS and activate caspase-3 in MDA-MB-231 cells. Compared with other FAS inhibitors, including catechin gallate and morin, 1,2,3,4,6-penta-O-galloyl-beta-D-glucose involves a higher reversible fast-binding inhibition with an irreversible slow-binding inhibition, i.e. saturation kinetics with a dissociation constant of 0.59 microM and a limiting rate constant of 0.16 per min. The major reacting site of PGG is on the beta-ketoacyl reduction domain of FAS. Compound exhibits different types of inhibitions against the three substrates in the FAS overall reaction
1,3-Dibromo-2-propanone
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2-[(Z)-[2-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]hydrazinylidene]methyl]pyridine
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good inhibition activity against two enzyme overexpressing cancer cell lines. IC50 value for MDA-MB-468 cell 0.0083 mM, for SW-480 cell 0.0015 mM
adriamycin
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cytotoxic activity against cancer cells, IC50 value for MCF-7 cell 0.0035 mM, for A-549 cell 0.0018 mM, for HL-60 cell 0.0008 mM
C75
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FASN inhibitor
cerulenin
diisopropylfluorophosphate
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dutasteride
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at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells
epigallocatechin-3-gallate
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ginkgolic acid C15:1
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DELTA8 and DELTA10 isomers, at ratio 1:2. Cytotoxic activity against cancer cells, IC50 value for MCF-7 cell 0.146 mM, for A-549 cell 0.066 mM, for HL-60 cell 0.005 mM
ginkgolic acid C17:1
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double bond positions not specified. Cytotoxic activity against cancer cells, IC50 value for MCF-7 cell 0.093 mM, for A-549 cell 0.050 mM, for HL-60 cell 0.004 mM
ginkgolic acid C17:2
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double bond positions not specified. Cytotoxic activity against cancer cells, IC50 value for MCF-7 cell 0.108 mM, for A-549 cell 0.056 mM, for HL-60 cell 0.004 mM
iodoacetamide
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beta-ketoacyl synthetase activity, acetyl-CoA but not malonyl-CoA protects
PMSF
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procyanidin
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procyanidins isolated from seeds of Hippophae rhamnoides inhibits the activity of FAS and reduces MDA-MB-231 cell viability with an IC50 value of 37.5 microg/ml. Procyanidins induce MDA-MB-231 cell apoptosis
pyridoxal 5'-phosphate
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enoyl reductase activity, NADPH protects
tetrahydrolipstatin
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i.e. orlistat
trans-4-carboxy-5-octyl-3-methylenebutyrolactone
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triclosan
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0005 - 0.008
acetyl-CoA
0.001 - 0.02
malonyl-CoA
0.005 - 0.4
NADPH
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.3 - 2.7
acetyl-CoA
0.3 - 2.7
malonyl-CoA
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0016
1,2,3,4,6-penta-O-galloyl-beta-D-glucose
Homo sapiens;
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37°C, pH not specified in the publication
0.0127
2-[(Z)-[2-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]hydrazinylidene]methyl]pyridine
Homo sapiens;
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pH not specified in the publication, temperature not specified in the publication
additional information
procyanidin
Homo sapiens;
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IC50 value is 0.087 microg/ml, 37°C, pH not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.6
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NADPH
additional information
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specific activities of subdomains
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 6.7
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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FAS is overexpressed significantly in pathologic and normal mucosa of patients with ulcerative colitis, mainly in the acute phase
Manually annotated by BRENDA team
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LNCaP prostate cancer cell
Manually annotated by BRENDA team
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oral squamous carcinoma cell lines SCC-4, SCC-9, SCC-15, SCC-25, differential expression of enzyme being highest in SCC-9 followed by SCC-25
Manually annotated by BRENDA team
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at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells
Manually annotated by BRENDA team
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
236000
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SDS-PAGE
265000
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SDS-PAGE
272000
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SDS-PAGE
272500
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calculated from nucleotide sequence
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
high-resolution crystal structure of a large part of human fatty acid synthase that encompasses the tandem domain of beta-oxoacyl synthase KS connected by a linker domain to the malonyltransferase domain MAT, to 2.15 A resolution. Hinge regions that allow for substantial flexibility of the subdomains are defined. The KS domain forms the canonical dimer, and its substrate-binding site geometry differs markedly from that of bacterial homologues but is similar to that of the porcine orthologue. The didomain structure reveals a possible way to generate a small and compact KS domain by omitting a large part of the linker and MAT domains, which could greatly aid in rapid screening of KS inhibitors. In the crystal, the MAT domain exhibits two closed conformations that differ significantly by rigid-body plasticity
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molecular dynamic simulation based binding free energy calculation and access tunnels analysis. The C16 acyl tail fatty acid, the major product of FAS, fits to the active site on beta-ketoacyl synthase domain better than any other substrates. The geometric shape of active site on beta-ketoacyl synthase domain might explain the product ratio of FAS
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of thioesterase domain, which comprises two dissimilar subdomains A and B
pharmacophore modeling based on crystal structure of 3-oxoacyl-[acyl-carrier-protein] synthase domain, PDB entry 3HHD
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
dissociation of native enzyme leads to loss of activity
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
0°C, inactivation after 12 h, reactivation after 2 h at 25°C in the presence of NADPH, not acetyl-CoA or NADH
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
fusion protein with maltose-binding protein
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near homogeneity
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
full length cDNA, cDNA encoding domain I and cDNA encoding domains II and III
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wild-type and mutant enzymes are expressed in Sf9 cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
(10E,12Z)-octadec-10,12-dienoic acid downregulates FAS expression in a concnetration-dependent manner, while (9Z,11E)-octadec-9,11-dienoic acid has no effect. (10E,12Z)-octadec-10,12-dienoic acid at 0.05 mM decreases FAS expression in MCF-7 cells by 52%, at 0.1 mM (10E,12Z)-octadec-10,12-dienoic acid, FAS protein is downregulated in MCF-7 (80%), LnCaP (27%), and HT-29 (61%) cells
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17beta-estradiol increases FAS expression, estrogen induces FAS expression
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C75 downregulates FASN mRNA in A2780 with an IC50 after 3d of 0.00525 mg/ml and an IT50 (time required for 50% inhibition) at 0.007 mg/ml of 21.5 h. This corresponds with FASN protein downregulation (IC50 = 0.00415 mg/ml), although the dynamics are slower (IT50 = 40 h). Pelitinib, given for 3d, abrogates FASN mRNA and protein in A-2780 cellsat doses as low as 0.003 mM
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fatty acid synthase is overexpressed in ovarian cancer
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isoleucine, whey, leucine, valine, skim milk, and casein downregulate the expression of fatty acid synthase in a concentration-dependent manner, a plateau is reached at 1.0% (w/v) skim milk and casein corresponding to about 40% inhibition of FAS expression, whey leads to 54% inhibition of FAS expression at 2.0%(w/v)
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mithramycin inhibits FAS expression, transfection of transcription factor Sp1 siRNA suppresses FAS expression
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the stromal cell-derived factor-1 alpha/CXCR4 axis induces the expression of fatty acid synthase via sterol regulatory element binding protein-1 activation in cancer cells. Sterol regulatory element-binding protein-1 is a major modulator of fatty acid synthase transcription. Also recombinant stromal cell-derived factor-1 alpha-induced phosphatidylinositol-3'-kinase/protein kinase B (Akt) phosphorylation is involved in the expression or activities of fatty acid synthase
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transcription factor Sp3 and Sp4 siRNAs do not affect FAS expression
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A2419L
97% reduction of thioesterase activity
A2419M
92% reduction of thioesterase activity
F2371W
20% reduction of thioesterase activity
F2423A
67% reduction of thioesterase activity
F2423W
24% reduction of thioesterase activity
I2250W
97% reduction of thioesterase activity
K1699A
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specific activity is 10% of wild-type value
K1699Q
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specific activity is 7.5% of wild-type value
K2426A
99% reduction of thioesterase activity
S2151A
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inactive enzyme
S2422A
7% reduction of thioesterase activity
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
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targeted liquid chromatography-mass spectroscopy method to directly measure endogenous levels of malonyl-CoA to drive a drug development structure-activity relationship screening cascade. The assay is amenable to multiplexing cellular endpoints, has a typical Z' of >0.6, and has high reproducibility of EC50 values
medicine