Information on EC 2.3.1.85 - fatty-acid synthase

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

EC NUMBER
COMMENTARY
2.3.1.85
-
RECOMMENDED NAME
GeneOntology No.
fatty-acid synthase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
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
-
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
-
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
-
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
-
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
structure and regulation
-
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
structure and regulation
-
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
-
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
scheme of functional interactions between constituent domains. A single subunit, in context of a dimer, is able to catalyze the entire biosynthetic pathway
-
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 TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Acyl group transfer
-
-
-
-
decarboxylation
-
-
-
-
redox reaction
-
-
-
-
thioester hydrolysis
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
cis-dodecenoyl biosynthesis
-
Fatty acid biosynthesis
-
fatty acid biosynthesis (plant mitochondria)
-
fatty acid biosynthesis initiation I
-
fatty acid biosynthesis initiation II
-
fatty acid biosynthesis initiation III
-
fatty acid elongation -- saturated
-
Metabolic pathways
-
octanoyl-ACP biosynthesis (mitochondria, yeast)
-
palmitate biosynthesis I (animals and fungi)
-
palmitate biosynthesis II (bacteria and plants)
-
superpathway of fatty acid biosynthesis initiation (E. coli)
-
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.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
F09E10.3 protein
-
-
FAS
-
-
-
-
FASN
-
-
fatty acid synthase
-
-
fatty acid synthase
-
-
fatty acid synthase
-
-
fatty acid synthase
-
-
fatty acid synthase
-
-
fatty acid synthase
-
-
fatty acid synthase I
-
-
fatty acid synthase II
-
-
fatty acid synthase type 2
-
3-oxoacyl-acyl carrier protein reductase FabG1/Rv1483 is a component of the fatty acid synthase type 2 system
type 2 dissociative FAS
-
-
type 2 fatty acid synthase
-
3-oxoacyl-acyl carrier protein reductase is a component of the type 2 fatty acid synthase system
type 2 fatty acid synthase
-
-
type II fatty acid synthase
-
-
yeast fatty acid synthase
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9045-77-6
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
goose
-
-
Manually annotated by BRENDA team
goat, female
-
-
Manually annotated by BRENDA team
modulation of enzyme expression by siRNA
-
-
Manually annotated by BRENDA team
thioesterase domain of enzyme
Uniprot
Manually annotated by BRENDA team
male FVB-N
-
-
Manually annotated by BRENDA team
Mus musculus FVB-N
male FVB-N
-
-
Manually annotated by BRENDA team
animals fed with semipurified diets containing either 1% w/w corn oil or 10% each of beef tallow, corn oil, perilla oil, and fish oil. Enzyme activity is reduced in the polyunsaturated fat-fed group in the order of fish oil, perilla oil, and corn oil
-
-
Manually annotated by BRENDA team
female wistar rat
-
-
Manually annotated by BRENDA team
Fischer rats
-
-
Manually annotated by BRENDA team
male Sprague-Dawley
-
-
Manually annotated by BRENDA team
Sprague-Dawley
-
-
Manually annotated by BRENDA team
wild-type and mutant
-
-
Manually annotated by BRENDA team
Rattus norvegicus Sprague-Dawley
Sprague-Dawley
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
Fas2 KO strains are unable to form normal biofilms and are more efficiently killed by murine-like macrophages, J774.16, than the wild type, heterozygous and reconstituted strains, Fas2 KO strains are hypersensitive to human serum, and inhibition of Fas2 in wild type Candida parapsilosis by cerulenin significantly decreases fungal growth in human serum
metabolism
-
FASII supplies the C8 substrate for lipoic acid synthesis
physiological function
-
FASN produces phospholipids for membrane microdomains that accommodate receptor tyrosine kinases including epidermal growth factor-receptor ErbB1 and ErbB2
physiological function
-
fatty acid synthase is a key enzyme regulating de novo fatty acid synthesis
physiological function
-
the Fas2 gene is essential for fungal growth in fatty acid-free medium, but dispensable in medium with fatty acids
physiological function
-
mice with fatty acid synthase knockout in the myocardium, FASKard, develop normally, manifest normal resting heart function, and have normal cardiac PPARalpha signaling as well as fatty acid oxidation. Mutant mice decompensate with stress. Most die within 1 h of transverse aortic constriction, probably due to arrhythmia. Voltage clamp measurements of FASKard cardiomyocytes show hyperactivation of L-type calcium channel current that can not be reversed with palmitate supplementation.Ca2+/calmodulin-dependent protein kinase II but not protein kinase A signaling is activated in FASKard hearts, and knockdown of fatty acid synthase in cultured cells activates Ca2+/calmodulin-dependent protein kinase II. In addition to being intolerant of the stress of acute pressure, FASKard hearts are also intolerant of the stress of aging, reflected as persistent CaMKII hyperactivation, progression to dilatation, and premature death by 1 year of age. Ca2+/calmodulin-dependent protein kinase II signaling appears to be pathogenic in FASKard hearts
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
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
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
P49327
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
FAS-A mainly synthesizes the C18 fatty acids oleate and stearate with only traces of palmitate, the major product of FAS-B is pamitate
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
lactating mammary gland thioesterase II of fatty acid synthetase: products are medium chain fatty acids from C8 to C12
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
C20 and C22 fatty acids in the absence of thioesterase activity
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
methylmalonyl-CoA instead of malonyl-CoA yields branched fatty acid, e.g. 2,4,6,8-tetramethyldecanoic acid
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
products are fatty acid chains from C14 to C20
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
-
in the absence of NADPH the product is triacetic acid lactone
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
acetoacetyl-CoA can substitute for acetyl-CoA
small amounts of stearate and myristate are also produced
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
decanoyl-CoA, acetyl-CoA, butyryl-CoA and malonyl-CoA are bound to the same active site
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
specific for malonyl-CoA, acetyl-CoA can be replaced by propionyl-CoA or butyryl-CoA
in the absence of NADPH the product is triacetic acid lactone
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
participates in energy metabolism in vivo which is related to adiposis and cancer
-
-
?
acetyl-CoA + malonyl-CoA + NADH
palmitate + CoA + CO2 + NAD+
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
carries acetyl- and malonyl-CoA transacylase, condensing enzyme, beta-ketoacyl reductase, beta-hydroxyacyl dehydrase, enoylacyl reductase, palmitoyl-CoA thioesterase activities on each multifunctional subunit
-
-
-
additional information
?
-
-
fatty acid synthetases of vertebrates and yeast are stable enzyme complexes of multifunctional polypeptide chains, the fatty acid synthetases of plants and E. coli consist of non-associated individual enzymes
-
-
-
additional information
?
-
-
synthesizes equal amounts of C14 and C16 fatty acids
-
-
-
additional information
?
-
-
enzyme generated signals are needed to support preadipocyte differentiation
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
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
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
multifunctional enzyme, involved in animal fat synthesis
-
-
?
acetyl-CoA + 7 malonyl-CoA + 14 NADPH + 14 H+
palmitate + 8 CoA + 7 CO2 + 14 NADP+ + 6 H2O
show the reaction diagram
-
participates in energy metabolism in vivo which is related to adiposis and cancer
-
-
?
additional information
?
-
-
enzyme generated signals are needed to support preadipocyte differentiation
-
-
-
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
4'-phosphopantetheine
-
no covalently bound subunit component; requirement, 1 mol associated with 1 mol subunit
4'-phosphopantetheine
-
location of active site; present in substoichiometric amounts
4'-phosphopantetheine
-
location of active site
4'-phosphopantetheine
-
-
4'-phosphopantetheine
-
-
NADH
-
requirement, 10% as effective as NADPH
NADPH
-
requirement, high specificity
4'-phosphopantetheine
-
-
additional information
-
no requirement for FMN
-
additional information
-
no requirement for FMN
-
additional information
-
NADP+ does not act as cofactor
-
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
(+)-catechin
-
50% inhibition of overall enzyme reaction at 1.6 mM, 50% inhibition of ketoacyl reduction reaction at 7.4 mM
(+-)-taxifolin
-
50% inhibition at 0.041163 mM
(-)-catechin gallate
-
50% inhibition at 0.0015 mg/ml, B ring, C ring and gallate ring of inhibitor react with acyl transferase domain
(-)-epicatechin
-
50% inhibition of overall enzyme reaction at 3.8 mM, 50% inhibition of ketoacyl reduction reaction at 9.38 mM
(-)-epicatechin gallate
-
50% inhibition of overall enzyme reaction at 0.042 mM, 50% inhibition of ketoacyl reduction reaction at 0.068 mM, two-step inhibition mechanism with reversible initial inhibition and irreversible subsequent inactivation
(-)-epigallocatechin gallate
-
0.5 mM, 20% residual activity, 50% inhibition of overall enzyme reaction at 0.052 mM, 50% inhibition of ketoacyl reduction reaction at 0.1 mM
(10E,12Z)-octadec-10,12-dienoic acid
-
more potent inhibitor than (9Z,11E)-octadec-9,11-dienoic acid
(9Z,11E)-octadec-9,11-dienoic acid
-
-
1,1'-[methanediylbis(2,4,6-trihydroxy-5-methylbenzene-3,1-diyl)]dibutan-1-one
-
IC50: 0.0254 mM
1,3-Dibromo-2-propanone
-
acetyl-CoA, not malonyl-CoA, protects against inactivation, both protect against cross-linking of the subunits
1,3-Dibromo-2-propanone
-
acetyl-CoA, not malonyl-CoA, protects against inactivation, both protect against cross-linking of the subunits; covalently cross-links subunits, inactivates beta-ketoacyl synthetase- and overall-fatty acid synthase reaction
1-(2,6-dihydroxy-4-methoxy-3-methylphenyl)butan-1-one
-
IC50: 0.0491 mM
2,2'-methanediylbis(3,5-dihydroxy-4,4-dimethyl-6-propanoylcyclohexa-2,5-dien-1-one)
-
IC50: 0.0602 mM
2,3-Butanedione
-
-
2,3-trans-octenoyl-CoA
-
competitively inhibits malonyl-transferase reaction
2-(3-butanoyl-2,4,6-trihydroxy-5-methylbenzyl)-3,5-dihydroxy-4,4-dimethyl-6-propanoylcyclohexa-2,5-dien-1-one
-
IC50: 0.0231 mM
2-acetyl-6-(3-butanoyl-2,4,6-trihydroxy-5-methylbenzyl)-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0287 mM
2-acetyl-6-(3-butanoyl-2,4,6-trihydroxybenzyl)-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0297 mM
2-acetyl-6-[(2,4-dihydroxy-3,3-dimethyl-6-oxo-5-propanoylcyclohexa-1,4-dien-1-yl)methyl]-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0717 mM
2-acetyl-6-{3-butanoyl-5-[(2,4-dihydroxy-3,3-dimethyl-6-oxo-5-propanoylcyclohexa-1,4-dien-1-yl)methyl]-2,4,6-trihydroxybenzyl}-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.031 mM
2-butanoyl-6-(3-butanoyl-2,6-dihydroxy-4-methoxy-5-methylbenzyl)-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0326 mM
2-butanoyl-6-[(2,4-dihydroxy-3,3-dimethyl-6-oxo-5-propanoylcyclohexa-1,4-dien-1-yl)methyl]-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0561 mM
2-[(Z)-[2-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]hydrazinylidene]methyl]pyridine
-
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
3,4-dihydroxybenzoic acid
-
50% inhibition of overall enzyme reaction at 9.0 mM, 50% inhibition of ketoacyl reduction reaction at 30 mM
3-Oxooctanoyl-CoA
-
competitively inhibits malonyl-transferase reaction
4',6,7-trihydroxylisoflavone
-
IC50: 0.0295 mM
5-chloropyrazinamide
-
IC50: 0.151 mM
adriamycin
-
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
apigenin
-
IC50: 0.0176 mM
aryl-acyl-beta-alanyl NADP+
-
inhibits beta-ketoacyl-reductase
-
avicularin
-
IC50: 0.00615 mM
baicalein
-
50% inhibition at 0.11169 mM
Benzamide
-
100 mM, 15% inhibition
C75
-
0.05 mM, 90% reduction of enzyme activity, dramatic reduction of visible lipid droplet accumulation, reduction of enzyme mRNA
C75
-
inactivation of beta-ketoacyl synthase, enoyl reductase and thioesterase partial activites, mechanism
C75
-
i.e. 3-carboxy-4-octyl-2-methylenebutyrolactone, 50% inhibition of enzyme at 0.2 mM
C75
-
FASN inhibitor
catechin gallate
-
very potent inhibitor, acts mainly on an acyl transferase domain. IC50 of 0.0015 mg/ml
catechol
-
50% inhibition of overall enzyme reaction at 7.4 mM, 50% inhibition of ketoacyl reduction reaction at 21 mM
cerulenin
-
acetyl-CoA protects
cerulenin
-
0.01 mM, 75% reduction of enzyme activity, dramatic reduction of visible lipid droplet accumulation, reduction of enzyme mRNA
cerulenin
-
significant reduction of proliferation of cell lines
cerulenin
-
no inhibitory at 3 mM, 62% inhibition at 6.0 mM
cerulenin
-
IC50: 0.013 mM
cerulenin
-
-
cerulenin
-
specific inhibitor
cerulenin
-
-
Chloroacetyl-CoA
-
-
CoA
-
competitive inhibition
crotonyl-CoA
-
dehydrase activity
daidzein
-
IC50: 0.0732 mM
dutasteride
-
at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells
epigallocatechin-3-gallate
-
-
fisetin
-
50% inhibition at 0.01877 mM
galangin
-
50% inhibition above 0.1 mM
galangin
-
poor inhibition
Gallic acid
-
50% inhibition of overall enzyme reaction at 21 mM, 50% inhibition of ketoacyl reduction reaction at 26 mM
genistein
-
0.0287 mM
ginkgolic acid C15:1
-
DELTA8 and DELTA10 isomers, at ratio 1:2
-
ginkgolic acid C15:1
-
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
-
double bond positions not specified
-
ginkgolic acid C17:1
-
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
-
double bond positions not specified
-
ginkgolic acid C17:2
-
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
-
hesperetin
-
50% inhibition at 0.06886 mM
hyperoside
-
IC50: 0.0746 mM
iodoacetamide
-
kinetics, 50% inactivation after 5 min at 1 mM and after 0.5 min at 20 mM
iodoacetamide
-
beta-ketoacyl synthetase activity, acetyl-CoA but not malonyl-CoA protects
iodoacetamide
-
inhibition of elongation processs
iodoacetamide
-
inhibits beta-ketoacyl synthetase activity, acetyl-CoA but not malonyl CoA protects
iso-liquiritigenin
-
IC50: 0.0088 mM
isoquercitrin
-
IC50: 0.108 mM
kaempferol
-
50% inhibition at 0.01038 mM
kaempferol
-
50% inhibition at 0.00298 mg/ml
long-chain acyl-CoA
-
malonyl-transferase reaction
luteolin
-
50% inhibition at 0.00252 mM
luteolin
-
IC50: 0.0625 mM
Malonyl pantetheine
-
malonyl-transferase reaction
morin
-
50% inhibition at 0.00233 mM
myricetin
-
50% inhibition at 0.02718 mM
N-ethylmaleimide
-
inhibition of elongation process and malonyl transfer at 10 mM
nordihydroguaiaretic acid
-
inhibits competitively with respect to acetyl-CoA, noncompetitively with respect to malonyl-CoA, and in a mixed manner with respect toNADPH.IC50 = 0.093 mM
Octanoyl-CoA
-
competitively inhibits malonyl-transferase reaction
Phenylglyoxal
-
-
phloretin
-
0.0261 mM
propyl gallate
-
50% inhibition of overall enzyme reaction at 0.5 mM, 50% inhibition of ketoacyl reduction reaction at 1.4 mM
propyl p-hydroxylbenzoate
-
50% inhibition of overall enzyme reaction at 1.1 mM, 50% inhibition of ketoacyl reduction reaction at 2.6 mM
-
Pyrazinamide
-
IC50: 8.9 mM
quercetin
-
50% inhibition at 0.00429 mM
quercetin
-
50% inhibition at 0.0024 mg/ml, mixed type inhibition for substrate NADPH, competitive with substrate acetyl-CoA, noncompetitive with malonyl-CoA
quercitrin
-
IC50: 0.0456 mM
resveratrol
-
IC50: 0.0085 mM
S-(4-Bromo-2,3-dioxobutyl)-CoA
-
irreversible, acetyl transacetylase and beta-ketoacyl synthase activity, 4 mol inhibitor per mol enzyme complex, mechanism, dithiothreitol protects
S-(4-Bromo-2,3-dioxobutyl)-CoA
-
irreversible, 50% inhibition after 10 s at 0.02 mM, 6.5 s at 0.06 mM and 4.5 s at 0.09 mM, specific for acetyl transacetylase and beta-ketoacyl synthase activity, 4 mol inhibitor per mol enzyme complex, acetyl-CoA, malonyl-CoA, cysteine and pantetheine protect
sodium dodecylsulfate
-
causes conformational changes at higher concentrations
tetrahydrolipstatin
-
i.e. orlistat
trans-4-carboxy-5-octyl-3-methylenebutyrolactone
-
-
triclosan
-
0.05 mM, 70% reduction of enzyme activity, dramatic reduction of visible lipid droplet accumulation, reduction of enzyme mRNA
triclosan
-
inititation of mammary carcinogenesis is reduced in animals fed with triclosan, triclosan also inhibits enzyme activity in tumor cell homogenates
triclosan
-
-
Urea
-
enzyme forms inactive aggregates in the presence of urea, cyclodextrins prevent aggregation
Urea
-
non-competitive inhibitor for NADPH, competitive inhibitor for acetyl-CoA and malonyl-CoA, complete inactivation occurs at lower concentration than obvious conformational changes, aggregation occurs at 3-4 M
Zn2+
-
80% loss of activity at 0.008 mM, interacts with SH groups, substrates of the reaction protect, malonyl-CoA being the most effective, addition of dithiothreitol leads to a recovery of 70% enzyme activity; below 0.004 mM, rapid and irreversible inactivation, above 0.004 mM, cross-linking of enzyme involving phosphopantheine SH group. All three substrates, acetyl-CoA, malonyl-CoA, NADPH, protect. Renaturation by dithiothreitol
malonyl-CoA
-
competitive, malonyl-transferase reaction
additional information
-
the enzyme is potently inhibited by green tea extract
-
additional information
-
inhibition by extract from rhizome of Alpinia officinarum, i.e. galangal. Inhibition consists of both reversible inhibition with an IC50-value of 0.0017 mg dried extract per ml, and biphasic slow-binding inactivation
-
additional information
-
a common model is proposed that is possibly shared by all FAS polyphenol inhibitors. The model includes two almost planar aromatic rings with their respective hydroxyl groups, and a proper ester linkage between the two rings that possibly causes the inhibition of FAS by irreversibly inhibiting the beta-ketoacyl reductase domain
-
additional information
-
black tea extract shows more potent inhibitory activity on fatty acid synthase than green tea extract. Inhibitory ability of the black tea extract depends on the extracting solvent and the conditions used. Only 1023% of the inhibitory activity from the black tea is extracted by the general method of boiling with water. The results suggest that the main fatty acid synthase inhibitors in black tea might be theaflavins
-
additional information
-
FAS is potently inhibited by extracts of Taxillus chinensis Danser. Potent, reversible and a fast irreversible inhibition. IC50: 480 ng/ml
-
additional information
-
not inhibitory: NAD+ or NADP+ up to 5 mM
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0005
-
acetyl-CoA
-
25C, pH 7.0, mutant enzyme K1699Q
0.0018
-
acetyl-CoA
-
R606A mutant
0.0029
-
acetyl-CoA
-
R606K mutant
0.0039
-
acetyl-CoA
-
wild-type enzyme
0.0043
-
acetyl-CoA
-
-
0.007
-
acetyl-CoA
-
25C, pH 7.0, mutant enzyme K1699A; 25C, pH 7.0, wild-type enzyme
0.008
-
acetyl-CoA
-
-
0.001
-
malonyl-CoA
-
25C, pH 7.0, mutant enzyme K1699Q
0.0013
-
malonyl-CoA
-
R606K mutant
0.0019
-
malonyl-CoA
-
wild-type enzyme
0.003
-
malonyl-CoA
-
25C, pH 7.0, mutant enzyme K1699A
0.005
-
malonyl-CoA
-
-
0.006
-
malonyl-CoA
-
25C, pH 7.0, wild-type enzyme
0.0162
-
malonyl-CoA
-
R606A mutant
0.02
-
malonyl-CoA
-
-
0.096
-
malonyl-CoA
-
-
0.121
-
NADH
-
wild-type, enoylreductase activity
0.0041
-
NADPH
-
-
0.005
-
NADPH
-
25C, pH 7.0, wild-type enzyme
0.0065
-
NADPH
-
wild-type, enoylreductase activity
0.00796
-
NADPH
-
-
0.02
-
NADPH
-
wild-type, beta-ketoreductase activity
0.025
-
NADPH
-
-
0.37
-
NADPH
-
25C, pH 7.0, mutant enzyme K1699A
0.4
-
NADPH
-
25C, pH 7.0, mutant enzyme K1699Q
0.5
-
NADPH
-
wild-type, beta-ketoreductase activity
0.9
-
NADPH
-
mutant G1888A, beta-ketoreductase activity
2.7
-
NADPH
-
mutant G1886F, beta-ketoreductase activity
0.1
-
malonyl-CoA
-
alcohol-fed animals
additional information
-
additional information
-
Km-values for various partial activities of fatty acid synthetase
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0317
-
acetyl-CoA
-
wild-type enzyme
0.0567
-
acetyl-CoA
-
R606K mutant
0.237
-
acetyl-CoA
-
R606A mutant
0.3
-
acetyl-CoA
-
mutant enzyme K1699Q
0.32
-
acetyl-CoA
-
mutant enzyme K1699A
2.7
-
acetyl-CoA
-
wild-type enzyme
0.0002
-
malonyl-CoA
-
R606K mutant
0.00167
-
malonyl-CoA
-
R606A mutant
0.02
-
malonyl-CoA
-
wild-type enzyme
0.3
-
malonyl-CoA
-
mutant enzyme K1699Q
0.32
-
malonyl-CoA
-
mutant enzyme K1699A
2.7
-
malonyl-CoA
-
wild-type enzyme
0.12
-
NADH
-
wild-type, enoylreductase activity
1.1
-
NADH
-
wild-type, beta-ketoreductase activity
1.1
-
NADPH
-
mutant G1886F, beta-ketoreductase activity
7.3
-
NADPH
-
mutant G1888A, beta-ketoreductase activity
9.8
-
NADPH
-
wild-type, enoylreductase activity
73
-
NADPH
-
wild-type, beta-ketoreductase activity
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.055
0.059
5-chloropyrazinamide
-
37C, pH 7.4
0.0012
-
luteolin
-
pH 7.0, 37C, substrate acetyl-CoA
0.00415
-
luteolin
-
pH 7.0, 37C, substrate NADPH
0.0098
-
luteolin
-
pH 7.0, 37C, substrate malonyl-CoA
1.04
-
Malonyl pantetheine
-
-
0.00205
-
morin
-
pH 7.0, 37C, substrate NADPH
0.00246
-
morin
-
pH 7.0, 37C, substrate malonyl-CoA
0.00357
-
morin
-
pH 7.0, 37C, substrate acetyl-CoA
2.6
-
Pyrazinamide
-
37C, pH 7.4
0.00183
-
quercetin
-
substrate NADPH, pH 7.0, 37C
0.00301
-
quercetin
-
substrate acetyl-CoA, pH 7.0, 37C
0.14
-
sodium dodecylsulfate
-
-
0.02053
-
taxifolin
-
pH 7.0, 37C, substrate acetyl-CoA
0.03796
-
taxifolin
-
pH 7.0, 37C, substrate NADPH
0.094
-
taxifolin
-
pH 7.0, 37C, substrate malonyl-CoA
210
-
Urea
-
substrate NADPH
570
-
Urea
-
substrate malonyl-CoA
580
-
Urea
-
substrate acetyl-CoA
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0254
-
1,1'-[methanediylbis(2,4,6-trihydroxy-5-methylbenzene-3,1-diyl)]dibutan-1-one
-
IC50: 0.0254 mM
0.0491
-
1-(2,6-dihydroxy-4-methoxy-3-methylphenyl)butan-1-one
-
IC50: 0.0491 mM
0.0602
-
2,2'-methanediylbis(3,5-dihydroxy-4,4-dimethyl-6-propanoylcyclohexa-2,5-dien-1-one)
-
IC50: 0.0602 mM
0.0231
-
2-(3-butanoyl-2,4,6-trihydroxy-5-methylbenzyl)-3,5-dihydroxy-4,4-dimethyl-6-propanoylcyclohexa-2,5-dien-1-one
-
IC50: 0.0231 mM
0.0287
-
2-acetyl-6-(3-butanoyl-2,4,6-trihydroxy-5-methylbenzyl)-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0287 mM
0.0297
-
2-acetyl-6-(3-butanoyl-2,4,6-trihydroxybenzyl)-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0297 mM
0.0717
-
2-acetyl-6-[(2,4-dihydroxy-3,3-dimethyl-6-oxo-5-propanoylcyclohexa-1,4-dien-1-yl)methyl]-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0717 mM
0.031
-
2-acetyl-6-{3-butanoyl-5-[(2,4-dihydroxy-3,3-dimethyl-6-oxo-5-propanoylcyclohexa-1,4-dien-1-yl)methyl]-2,4,6-trihydroxybenzyl}-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.031 mM
0.0326
-
2-butanoyl-6-(3-butanoyl-2,6-dihydroxy-4-methoxy-5-methylbenzyl)-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0326 mM
0.0561
-
2-butanoyl-6-[(2,4-dihydroxy-3,3-dimethyl-6-oxo-5-propanoylcyclohexa-1,4-dien-1-yl)methyl]-3,5-dihydroxy-4,4-dimethylcyclohexa-2,5-dien-1-one
-
IC50: 0.0561 mM
0.0127
-
2-[(Z)-[2-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]hydrazinylidene]methyl]pyridine
-
pH not specified in the publication, temperature not specified in the publication
0.0295
-
4',6,7-trihydroxylisoflavone
-
IC50: 0.0295 mM
0.151
-
5-chloropyrazinamide
-
IC50: 0.151 mM
0.0176
-
apigenin
-
IC50: 0.0176 mM
0.00615
-
avicularin
-
IC50: 0.00615 mM
0.013
-
cerulenin
-
pH 7.0, 37C
0.0732
-
daidzein
-
IC50: 0.0732 mM
0.017
-
ginkgolic acid C15:1
-
pH 7.0, 37C
-
0.01
-
ginkgolic acid C17:1
-
pH 7.0, 37C
-
0.009
-
ginkgolic acid C17:2
-
pH 7.0, 37C
-
0.0746
-
hyperoside
-
IC50: 0.0746 mM
0.0088
-
iso-liquiritigenin
-
IC50: 0.0088 mM
0.108
-
isoquercitrin
-
IC50: 0.108 mM
0.062
-
luteolin
-
pH 7.0, 37C
0.093
-
nordihydroguaiaretic acid
-
inhibits competitively with respect to acetyl-CoA, noncompetitively with respect to malonyl-CoA, and in a mixed manner with respect toNADPH.IC50 = 0.093 mM
8.9
-
Pyrazinamide
-
IC50: 8.9 mM
0.0456
-
quercitrin
-
IC50: 0.0456 mM
0.0085
-
resveratrol
-
IC50: 0.0085 mM
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.015
-
-
for malonyl-CoA, R606A mutant
0.078
0.1
-
palmitate
0.14
0.16
-
-
0.154
-
-
for malonyl-CoA, R606K mutant
0.6
-
-
NADPH
1.12
1.4
-
NADPH, 30C
1.13
2.77
-
various tagged wild-type enzyme
1.2
1.6
-
NADPH
1.2
-
-
NADPH
1.3
-
-
NADPH
1.61
-
-
for malonyl-CoA, wild-type enzyme
2.049
-
-
wild-type enzyme, activity in mutants is less than 0.5%
2.6
-
-
NADPH
2.68
-
-
for acetyl-CoA, wild-type enzyme
4.53
-
-
for acetyl-CoA, R606K mutant
17.8
-
-
for acetyl-CoA, R606A mutant
additional information
-
-
specific activities of subdomains
additional information
-
-
specific activity in liver and fat cells
additional information
-
-
specific activity of recombinant domain I and its subdomains
additional information
-
-
specific activities of subdomains
additional information
-
-
-
additional information
-
-
specific activities after diet with sesamin
additional information
-
-
increase after exposure of animals to cold temperatures for 48 h
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6.5
6.7
-
-
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
-
-
assay at
25
-
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
epididymal fat pads
Manually annotated by BRENDA team
-
brown adipose tissue
Manually annotated by BRENDA team
Mus musculus FVB-N
-
brown adipose tissue
-
Manually annotated by BRENDA team
Rattus norvegicus Sprague-Dawley
-
epididymal fat pads
-
Manually annotated by BRENDA team
-
mammary adenocarcinoma cell, expression of high levels of enzyme
Manually annotated by BRENDA team
-
FAS is overexpressed significantly in pathologic and normal mucosa of patients with ulcerative colitis, mainly in the acute phase
Manually annotated by BRENDA team
-
cultured hepatocytes
Manually annotated by BRENDA team
-
hepatoma cell line HepG2
Manually annotated by BRENDA team
-
insulin acutely decreases hepatic fatty acid synthase activity
Manually annotated by BRENDA team
-
feeding wild-type mice a chow diet supplemented with the natural FXR agonist chenodeoxycholic acid results in a significant induction of FAS mRNA expression
Manually annotated by BRENDA team
Rattus norvegicus Sprague-Dawley
-
-
-
Manually annotated by BRENDA team
-
at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells
Manually annotated by BRENDA team
-
fetal epithelial cells
Manually annotated by BRENDA team
-
positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells
Manually annotated by BRENDA team
-
at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells
Manually annotated by BRENDA team
-
LNCaP prostate cancer cell
Manually annotated by BRENDA team
-
transgenic adenocarcinoma of mouse prostate model, TRAMP
Manually annotated by BRENDA team
-
high-level expression of fatty acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB
Manually annotated by BRENDA team
-
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
-
at clinically relevant levels, inhibits FASN mRNA, protein expression and enzymatic activity in prostate cancer cells
Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
236000
-
-
SDS-PAGE
265000
-
-
SDS-PAGE
270000
-
-
subunit, SDS-PAGE
272000
-
-
SDS-PAGE
272500
-
-
calculated from nucleotide sequence
310000
-
-
SDS-PAGE
324900
-
-
calculated from nucleotide sequence
400000
-
-
value above 400000 Da, polymer, SDS-PAGE
425000
-
-
sedimentation equilibrium method
431000
-
-
calculated from amino acid sequence
434000
-
-
ultracentrifugation in 0.5-0.8 M phosphate buffer
450000
-
-
-
450000
-
-
SDS-PAGE
480000
-
-
SDS-PAGE
additional information
-
-
molecular weight of fragments after proteolytic cleavage
additional information
-
-
amino acid composition; sedimentation coefficients of centrifugation of active enzyme
additional information
-
-
molecular weight of fragments after proteolytic cleavage
additional information
-
-
active-site mapping of isolated acetyl/malonyl transferase activity domain
additional information
-
-
molecular weight of fragments after proteolytic cleavage
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
dimer
-
2 identical subunits, SDS-PAGE
dimer
-
2 * 244000, ultracentrifugation in 6 M guanidinium chloride
dimer
-
2 * 250000, SDS-PAGE
dimer
-
2 * 240000, SDS-PAGE
dimer
-
2 * 220000, SDS-PAGE
dimer
Rattus norvegicus Sprague-Dawley
-
2 * 244000, ultracentrifugation in 6 M guanidinium chloride
-
hexamer
-
homohexamer
additional information
-
fatty acid synthetases of vertebrates and yeast are stable enzyme complexes of multifunctional polypeptide chains, the fatty acid synthetases of plants and Escherichia coli consist of non-associated individual enzymes
additional information
-
-
additional information
-
-
additional information
-
-
additional information
-
alpha2-dimer of multifunctional subunits: each subunit contains up to seven active centres required for palmitate synthesis
additional information
-
alpha2-dimer of multifunctional subunits: each subunit contains up to seven active centres required for palmitate synthesis and an acyl carrier site, arranged in three domains but dimer is the only catalytically active form of fatty acid synthase
additional information
-
condensing enzyme activity requires both subunits
additional information
-
alpha2-dimer of multifunctional subunits: each subunit contains up to seven active centres required for palmitate synthesis and an acyl carrier site, arranged in three domains
additional information
-
identical subunits, SDS-PAGE
additional information
-
structural analysis by electron microscopy, enzyme monomers in the dimeric form adopt a coiled conformation that allows for a variety of intra- and intermonomer functional domain interactions
additional information
Rattus norvegicus Sprague-Dawley
-
alpha2-dimer of multifunctional subunits: each subunit contains up to seven active centres required for palmitate synthesis and an acyl carrier site, arranged in three domains but dimer is the only catalytically active form of fatty acid synthase
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
phosphoprotein
-
condensing activities of the Mycobacterium tuberculosis type II fatty acid synthase are differentially regulated by phosphorylation
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
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
-
of thioesterase domain, which comprises two dissimilar subdomains A and B
P49327
pharmacophore modeling based on crystal structure of 3-oxoacyl-[acyl-carrier-protein] synthase domain, PDB entry 3HHD
-
three-dimensional map of yeast fatty acid synthase at 5.9 A resolution, obtained by electron cryomicroscopy of single particles. Distinct density regions in the reaction chambers next to each of the catalytic domains fitted the substrate-binding acyl carrier protein domain. In each case, this results in the expected distance of about 18 A from the acyl carrier protein substrate-binding site to the active site of the catalytic domains. The multiple, partially occupied positions of the acyl carrier protein within the reaction chamber provide direct structural insight into the substrate-shuttling mechanism. The acyl carrier protein domain is mobile within the fatty acid synthase barrel, enabling it to visit successive catalytic sites
-
structure at 4.5 A resolution. The dimeric synthase adopts an asymmetric X-shaped conformation with two reaction chambers on each side formed by a full set of enzymatic domains required for fatty acid elongation, which are separated by considerable distances
-
pH STABILITY
pH STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
8.4
-
-
inactivation, decreased by 0.2 M KCl or 0.02 mM NADP(H)
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
-
-
50% loss of activity in dilute, mildly alkaline solution within 3.5 h, high ionic strength together with DTT reactivates
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
dissociation of native enzyme leads to loss of activity
-
dithiothreitol stabilizes
-
foaming leads to surface inactivation
-
low ionic strength leads to dissociation of native enzyme and inactivation
-
dissociation of native enzyme leads to loss of activity
-
phosphate buffer, 0.5 M, reassociates enzyme subunits
-
ORGANIC SOLVENT
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
acetonitrile
-
up to 10% v/v, stable to
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
0C, inactivation after 12 h, reactivation after 2 h at 25C in the presence of NADPH, not acetyl-CoA or NADH
-
-20C, at least a month in the presence of DTT
-
-20C, under nitrogen at least 1-2 months
-
0C, inactivation after 12 h, reactivation after 2 h at 25C in the presence of NADPH, not acetyl-CoA or NADH
-
4C, 90% loss of activity in 8 days with 40% dissociation of native enzyme, incubation at 38C with 10 mM DTT restores activity
-
0C, inactivation after 12 h, reactivation after 2 h at 25C in the presence of NADPH, not acetyl-CoA or NADH
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
homogeneity
-
partial
-
purification of 2 structurally related but functionally differentiated fatty acid synthases: FAS-A and FAS-B, homogeneity
-
2 beta-ketoacyl reductase containing fragments after sequential proteolysis
-
domain I with acetyl and malonyl transacetylase activity and beta-hydroxyacyl dehydratase activity after expression in E. coli
-
homogeneity
-
fusion protein with maltose-binding protein
-
near homogeneity
-
680fold, erythrocyte enzyme immunologically not related to liver enzyme
-
95% pure, transacyclase domain
-
homogeneity
-
isolation of modified dimers containing independently mutated subunits
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
gene sequences
-
expressed in Saccharomyces cerevisiae oar1DELTA cells
-
individual overexpression of all components of fatty acid synthase in Escherichia coli
-
domain I with acetyl and malonyl transacetylase activity and beta-hydroxyacyl dehydratase activity
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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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expressed in Saccharomyces cerevisiae oar1DELTA cells
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transacyclase domain
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EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
relative FASN mRNA expression is upregulated by 9 and 5fold, respectively, for high-concentrate diet (85% concentrate: 15% roughage) and diet on endophyte-free tall fescue pastures with corn grain supplement compared with pasture diet, grain feeding upregulates FASN mRNA expression
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oleic acid and Tween 80 downregulate the expression of the fatty acid synthase while myristic acid, stearic acid, and Tween 40 do not
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expression of Fas1 and Fas2 is significantly elevated by the presence of glucose
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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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mithramycin inhibits FAS expression, transfection of transcription factor Sp1 siRNA suppresses FAS expression
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(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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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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transcription factor Sp3 and Sp4 siRNAs do not affect FAS expression
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fatty acid synthase is overexpressed in ovarian cancer
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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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17beta-estradiol increases FAS expression, estrogen induces FAS expression
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FAS expression is reduced by 25% in Ki-ras-induced actin-interacting protein-deficient liver
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hepatic fatty acid synthase activity is significantly higher after week 1 of refeeding
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ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
S36T
-
mutant in acyl carrier protein, mutant is incapable of undergoing phosphopantetheinylation. The S36T mutant is a weaker inhibitor of the fatty acid synthase than holo-acyl carrier protein, suggesting that the prostheticgroup of the acyl carrier protein contributes directly to its inhibitory characteristics at high concentrations
A2419L
P49327
97% reduction of thioesterase activity
A2419M
P49327
92% reduction of thioesterase activity
F2371W
P49327
20% reduction of thioesterase activity
F2423A
P49327
67% reduction of thioesterase activity
F2423W
P49327
24% reduction of thioesterase activity
I2250W
P49327
97% reduction of thioesterase activity
K1699A
-
specific activity is 10% of wild-type value
K1699Q
-
specific activity is 7.5% of wild-type value
K2426A
P49327
99% reduction of thioesterase activity
S2151A
-
inactive enzyme
C161A
-
no beta-ketoacyl synthase activity
C161Q
-
mutation of ketoacyl synthase, less conformational variability than wild-type
C161T
-
defective in beta-ketoacyl synthase, no overall fatty acid synthase activity
G1886F
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beta-ketoreductase activity, 130fold increase in Km-value
G1888A
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beta-ketoreductase activity, 25fold increase in Km-value
G1888A
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mutation of beta-ketoacyl reductase, less conformational variability than wild-type
K326A
-
no beta-ketoacyl synthase activity
K326A
-
defective in beta-ketoacyl synthase, no overall fatty acid synthase activity
R1508A
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similar activity as wild-type in overall reaction, analysis of partial reactions
R1508D
-
14% of wild-type activity in overall reaction, analysis of partial reactions
R1508K
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58% of wild-type activity in overall reaction, analysis of partial reactions
R606A
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reduced malonyl/acetyltransferase activity, increased transacylase activity, 16000fold increased selectivity for acetyl-CoA, 8.5fold increase of Km for malonyl-CoA
R606K
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reduced malonyl/acetyltransferase activity, increased transacylase activity, 16fold increased selectivity for acetyl-CoA
S215A
-
defective in acyl carrier protein
S2302A
-
mutation of thioesterase, less conformational variability than wild-type
S518A
-
no malonyl/acetyltransferase activity
S2422A
P49327
7% reduction of thioesterase activity
additional information
-
enzyme knockout mutants, heterozygous mutant animals are ostensibly normal, with about 50% reduction in enzyme mRNA and 35% reduction in enzyme activity. Partial haploid insufficieny in heterozygous animals, most embryos die at various stages of development. No production of enzyme homozygous mutant animals
K326A
-
mutation of ketoacyl synthase, less conformational variability than wild-type
additional information
-
engineering of a enzyme containing one wild-type subunit and one subunit comprised by mutations in all seven functional domains. Mutant enzyme is active
Renatured/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
reconstitution of fatty acid synthase using purified protein components. When all ketosynthases are present at 1 microM, the maximum rate of free fatty acid synthesis of the fatty acid synthase exceeds 100 microM/min. The steady-state turnover frequency is not significantly inhibited at high concentrations of any substrate or cofactor. Fatty acid synthase activity is saturated with respect to most individual protein components when their concentrations exceeded 1 microM. The exceptions are protein components FabI and FabZ, which increase fatty acid synthase activity up to concentrations of 10 microM, FabH and FabF, which decrease fatty acid synthase activity at concentrations higher than 1 microM, and holo-acyl carrier protein and TesA, which give maximum fatty acid synthase activity at 30 microM concentrations
-
complete renaturation of enzyme inactivated by Zn2+ using dithiothreitol
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APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
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the enzyme is a potential therapeutic target to treat cancer and obesity. Acylphloroglucinol derivatives could be considered to be a promising class of FAS inhibitors
medicine
-
in cancer cells, enzyme plays a major role in the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Link between enzyme overexpression and dysregulation of membrane composition and functioning in tumor cells
medicine
-
androgen-independent expression of enzyme in oral SSC cells, enzyme activity is necessary for their proliferation
medicine
-
FAS is a target for drug development against obesity and related diseases, and FAS inhibitors have antitumor activity
medicine
-
FAS could be a useful signal for early detection of ulcerative coliti
medicine
-
TRAMP mouse prostate adenocarcinoma cells show high enzyme expression and activity compared to nontransgenic littermates. Inhibition of enzyme expression and activity results in dose-dependent reduction in cell survival
medicine
-
triclosan suppresses mammary carcinogenesis by inhibiting enzyme
medicine
-
anorectic effect of C75 is independent of its inhibition of enzyme in the hypothalamus
nutrition
-
animals fed with semipurified diets containing either 1% w/w corn oil or 10% each of beef tallow, corn oil, perilla oil, and fish oil. Enzyme activity is reduced in the polyunsaturated fat-fed group in the order of fish oil, perilla oil, and corn oil