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acetoacetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methyl triacetic acid lactone + CoA + NADP+
-
-
-
?
acetoacetyl-CoA + malonyl-CoA
6-methyl triacetic acid lactone + CoA
-
5% of the rate of 6-methylsalicylic acid synthesis
-
?
acetoacetyl-CoA + malonyl-CoA + NADPH
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
acetyl-CoA + malonyl-CoA
triacetic lactone
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
acetyl-CoA + malonyl-CoA + NADPH + H+
6-methylsalicylate + CoA + CO2 + NADP+ + H2O
-
-
-
?
acetyl-CoA + N-acetylcysteamine + NADPH
?
-
-
-
-
?
acetyl-CoA + pantetheine
acetyl pantetheine + CoA
butyryl-CoA + malonyl-CoA
6-propyl triacetic acid lactone + CoA
-
5% of the rate of 6-methylsalicylic acid synthesis
-
?
crotonyl-CoA + malonyl-CoA
6-(2-propene) triacetic acid lactone + CoA
-
5% of the rate of 6-methylsalicylic acid synthesis
-
?
heptanoyl-CoA + malonyl-CoA
6-hexyl triacetic acid lactone + CoA
-
5% of the rate of 6-methylsalicylic acid synthesis
-
?
hexanoyl-CoA + malonyl-CoA
6-pentyl triacetic acid lactone + CoA
-
5% of the rate of 6-methylsalicylic acid synthesis
-
?
propionyl-CoA + malonyl-CoA
6-ethyl triacetic acid lactone + CoA
-
5% of the rate of 6-methylsalicylic acid synthesis
-
?
propionyl-CoA + malonyl-CoA + NADPH
6-ethylsalicylate + CoA + CO2 + NADP+
propionyl-CoA + pantetheine
propionyl pantetheine + CoA
valeryl-CoA + malonyl-CoA
6-butyl triacetic acid lactone + CoA
-
5% of the rate of 6-methylsalicylic acid synthesis
-
?
additional information
?
-
acetoacetyl-CoA + malonyl-CoA + NADPH
?
-
-
-
-
?
acetoacetyl-CoA + malonyl-CoA + NADPH
?
-
-
-
-
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
-
-
-
-
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
-
-
-
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
-
-
-
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
-
-
-
-
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
-
ATX by itself can synthesize tetraketide and release 6-methylsalicylate as the free acid without involvement of serine protease-type thioesterase, the product 6-methylsalicylate is retained on the acyl-carrier-protein until its release from ATX, product-releasing mechanism, overview
-
-
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
-
-
-
?
acetyl-CoA + 3 malonyl-CoA + NADPH + H+
6-methylsalicylate + 4 CoA + 3 CO2 + NADP+ + H2O
-
-
-
?
acetyl-CoA + malonyl-CoA
triacetic lactone
-
-
-
?
acetyl-CoA + malonyl-CoA
triacetic lactone
-
exclusive product in the absence of NADPH, 5:1 ratio of 6-methylsalicylic acid to triacetic acid lactone at 0.0005 mM NADPH, less than 1% triacetic acid lactone at 0.012 mM NADPH
-
?
acetyl-CoA + malonyl-CoA
triacetic lactone
-
exclusive product in the absence of NADPH, 5:1 ratio of 6-methylsalicylic acid to triacetic acid lactone at 0.0005 mM NADPH, less than 1% triacetic acid lactone at 0.012 mM NADPH
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
-
ir
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
first enzyme of patulin biosynthetic pathway
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
first enzyme of patulin biosynthetic pathway
-
?
acetyl-CoA + malonyl-CoA + NADPH
6-methylsalicylate + CoA + CO2 + NADP+
-
-
-
?
acetyl-CoA + pantetheine
acetyl pantetheine + CoA
-
-
-
?
acetyl-CoA + pantetheine
acetyl pantetheine + CoA
-
-
-
?
propionyl-CoA + malonyl-CoA + NADPH
6-ethylsalicylate + CoA + CO2 + NADP+
-
-
-
?
propionyl-CoA + malonyl-CoA + NADPH
6-ethylsalicylate + CoA + CO2 + NADP+
-
-
-
?
propionyl-CoA + pantetheine
propionyl pantetheine + CoA
-
13 times slower rate compared to acetyl-CoA
-
?
propionyl-CoA + pantetheine
propionyl pantetheine + CoA
-
13 times slower rate compared to acetyl-CoA
-
?
additional information
?
-
-
the truncated enzyme, THID mutant, hydrolyzes the model substrate 6-methylsalicylic acid-N-acetylcysteamine
-
-
?
additional information
?
-
no enzymatic dehydration takes place at a triketide stage of 6-MSA assembly, so loss of water must occur at the tetraketide stage. The enzyme is able to accept malonate surrogates of different chain lengths and bearing various functionalities (including alkyne and fluorine moieties) at different positions and for every round of chain extension, and also to generate novel pentaketide products
-
-
?
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(2S,3R)-2,3-epoxy-4-oxo-7,10-dodecadienoylamide
1,3-dibromo-propane-2-one
5,5'-dithiobis(2-nitrobenzoic acid)
-
0.01 mM, rapid inactivation, inactivation half-life: approx. 15 s, both acetyl-CoA and malonyl-CoA protect
NAD+
-
0.3 mM, 21% inhibition in crude extracts
NADH
-
0.3 mM, 26% inhibition in crude extracts
NADP+
-
0.3 mM, 21% inhibition in crude extracts
nicotinamide hypoxanthine dinucleotide phosphate
-
reduced form, 0.3 mM, 32% inhibition in crude extracts, oxidized form, 0.3 mM, 24% inhibition in crude extracts
additional information
-
no inhibition by phenylmethylsulfonyl fluoride, a serine protease-type thioesterase inhibitor at 1 mM
-
(2S,3R)-2,3-epoxy-4-oxo-7,10-dodecadienoylamide
-
mycotoxin produced by Cephalosporium caerulens, trivial name cerulenin, 0.2 mM, complete inactivation after approx. 30 min, second-order rate constant for the reaction with 6-methylsalicylic acid synthase: 13.8 M/s, acetyl-CoA protects, site of modification: Cys204
(2S,3R)-2,3-epoxy-4-oxo-7,10-dodecadienoylamide
-
0.0014 mM, complete inactivation after 40 min, acetyl-CoA protects
1,3-dibromo-propane-2-one
-
0.02 mM, complete inactivation after 40 min, acetyl-CoA protects
1,3-dibromo-propane-2-one
-
very rapid inactivation, inactivation half-life: 7 s
iodoacetamide
-
0.5 mM, complete inactivation of synthetase activity after 15 min at 0°C, enzyme is then able to decarboxlate malonyl-CoA
iodoacetamide
-
100 mM, complete inactivation after 45 min, site of modification: Cys204
iodoacetamide
-
100fold molar excess, complete inactivation after 30 min
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Dimroth, P.; Ringelmann, E.; Lynen, F.
6-Methylsalicylic acid synthetase from Penicillium patulum. Some catalytic properties of the enzyme and its relation to fatty acid synthetase
Eur. J. Biochem.
68
591-596
1976
Penicillium griseofulvum, Penicillium griseofulvum NRRL 2159A
brenda
Lam, K.S.; Neway, J.O.; Gaucher, G.M.
In vitro stabilization of 6-methylsalicylic acid synthetase from Penicillium urticae
Can. J. Microbiol.
34
30-37
1988
Penicillium griseofulvum, Penicillium griseofulvum NRRL 2159A
brenda
Spencer, J.B.; Jordan, P.M.
Purification and properties of 6-methylsalicylic acid synthase from Penicillium patulum
Biochem. J.
288
839-846
1992
Penicillium griseofulvum, Penicillium griseofulvum NRRL 2159A
-
brenda
Spencer, J.B.; Jordan, P.M.
Investigation of the mechanism and steric course of the reaction catalyzed by 6-methylsalicylic acid synthase from Penicillium patulum using (R)-[1-13C;2-2H] and (S)-[1-13C; 2-2H]malonates
Biochemistry
31
9107-9116
1992
Penicillium griseofulvum
brenda
Child, C.J.; Shoolingin-Jordan, P.M.
Inactivation of the polyketide synthase, 6-methylsalicylic acid synthase, by the specific modification of Cys-204 of the beta-ketoacyl synthase by the fungal mycotoxin cerulenin
Biochem. J.
330
933-937
1998
Penicillium griseofulvum
-
brenda
Child, C.J.; Spencer, J.B.; Bhogal, P.; Shoolingin-Jordan, P.M.
Structural similarities between 6-methylsalicylic acid synthase from Penicillium patulum and vertebrate type I fatty acid synthase: evidence from thiol modification studies
Biochemistry
35
12267-12274
1996
Penicillium griseofulvum
brenda
Campuzano, I.D.G.; Shoolingin-Jordan, P.M.
Incubation of 6-methylsalicylic acid synthase with alternative starter units in the absence of NADPH and the identification of the resulting triaceticacid lactones
Biochem. Soc. Trans.
26
S284
1998
Penicillium griseofulvum
brenda
Richardson, M.T.; Pohl, N.L.; Kealey, J.T.; Khosla, C.
Tolerance and specificity of recombinant 6-methylsalicylic acid synthase
Metab. Eng.
1
180-187
1999
Penicillium griseofulvum
brenda
Shao, L.; Qu, X.; Jia, X.; Zhao, Q.; Tian, Z.; Wang, M.; Tang, G.; Liu, W.
Cloning and characterization of a bacterial iterative type I polyketide synthase gene encoding the 6-methylsalicyclic acid synthase
Biochem. Biophys. Res. Commun.
345
133-139
2006
Streptomyces antibioticus
brenda
Wattanachaisaereekul, S.; Lantz, A.E.; Nielsen, M.L.; Andresson, O.S.; Nielsen, J.
Optimization of heterologous production of the polyketide 6-MSA in Saccharomyces cerevisiae
Biotechnol. Bioeng.
97
893-900
2006
Penicillium griseofulvum, Penicillium griseofulvum (P22367)
brenda
Moriguchi, T.; Ebizuka, Y.; Fujii, I.
Analysis of subunit interactions in the iterative type I polyketide synthase ATX from Aspergillus terreus
Chembiochem
7
1869-1874
2006
Aspergillus terreus
brenda
Lu, P.; Zhang, A.; Dennis, L.M.; Dahl-Roshak, A.M.; Xia, Y.Q.; Arison, B.; An, Z.; Tkacz, J.S.
A gene (pks2) encoding a putative 6-methylsalicylic acid synthase from Glarea lozoyensis
Mol. Genet. Genomics
273
207-216
2005
Glarea lozoyensis (Q58K76), Glarea lozoyensis
brenda
Puel, O.; Tadrist, S.; Delaforge, M.; Oswald, I.P.; Lebrihi, A.
The inability of Byssochlamys fulva to produce patulin is related to absence of 6-methylsalicylic acid synthase and isoepoxydon dehydrogenase genes
Int. J. Food Microbiol.
115
131-139
2007
Paecilomyces niveus (Q96X07), Paecilomyces niveus, Paecilomyces niveus NRRL 2615 (Q96X07)
brenda
Panagiotou, G.; Andersen, M.R.; Grotkjaer, T.; Regueira, T.B.; Nielsen, J.; Olsson, L.
Studies on the production of fungal polyketides in Aspergillus nidulans using systems biology tools
Appl. Environ. Microbiol.
75
2212-2220
2009
Penicillium griseofulvum
brenda
Moriguchi, T.; Ebizuka, Y.; Fujii, I.
Domain-domain interactions in the iterative type I polyketide synthase ATX from Aspergillus terreus
ChemBioChem
9
1207-1212
2008
Aspergillus terreus, Penicillium griseofulvum
brenda
Sanzani, S.; Schena, L.; Nigro, F.; de Girolamo, A.; Ippolito, A.
Effect of quercetin and umbelliferone on the transcript level of Penicillium expansum genes involved in patulin biosynthesis
Eur. J. Plant Pathol.
125
223-233
2009
Penicillium expansum (Q4JIM3)
brenda
Bacha, N.; Dao, H.P.; Atoui, A.; Mathieu, F.; OCallaghan, J.; Puel, O.; Liboz, T.; Dobson, A.D.; Lebrihi, A.
Cloning and characterization of novel methylsalicylic acid synthase gene involved in the biosynthesis of isoasperlactone and asperlactone in Aspergillus westerdijkiae
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46
742-749
2009
Aspergillus westerdijkiae
brenda
Wattanachaisaereekul, S.; Lantz, A.E.; Nielsen, M.L.; Nielsen, J.
Production of the polyketide 6-MSA in yeast engineered for increased malonyl-CoA supply
Metab. Eng.
10
246-254
2008
Penicillium griseofulvum
brenda
Moriguchi, T.; Kezuka, Y.; Nonaka, T.; Ebizuka, Y.; Fujii, I.
Hidden function of catalytic domain in 6-methylsalicylic acid synthase for product release
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285
15637-15643
2010
Aspergillus terreus
brenda
Parascandolo, J.S.; Havemann, J.; Potter, H.K.; Huang, F.; Riva, E.; Connolly, J.; Wilkening, I.; Song, L.; Leadlay, P.F.; Tosin, M.
Insights into 6-methylsalicylic acid bio-assembly by using chemical probes
Angew. Chem. Int. Ed. Engl.
55
3463-3467
2016
Penicillium griseofulvum (P22367)
brenda
Holm, D.K.; Petersen, L.M.; Klitgaard, A.; Knudsen, P.B.; Jarczynska, Z.D.; Nielsen, K.F.; Gotfredsen, C.H.; Larsen, T.O.; Mortensen, U.H.
Molecular and chemical characterization of the biosynthesis of the 6-MSA-derived meroterpenoid yanuthone D in Aspergillus niger
Chem. Biol.
21
519-529
2014
Aspergillus niger (G3Y419), Aspergillus niger, Aspergillus niger ATCC 1015 (G3Y419)
brenda
Petersen, L.; Holm, D.; Gotfredsen, C.; Mortensen, U.; Larsen, T.
Investigation of a 6-MSA synthase gene cluster in Aspergillus aculeatus reveals 6-MSA-derived aculinic acid, aculins A-B and epi-Aculin A
ChemBioChem
16
2200-2204
2015
Aspergillus aculeatus
brenda
Kallscheuer, N.; Kage, H.; Milke, L.; Nett, M.; Marienhagen, J.
Microbial synthesis of the type I polyketide 6-methylsalicylate with Corynebacterium glutamicum
Appl. Microbiol. Biotechnol.
103
9619-9631
2019
Streptomyces antibioticus (Q0R4P8), Streptomyces antibioticus
brenda
Hitschler, J.; Boles, E.
De novo production of aromatic m-cresol in Saccharomyces cerevisiae mediated by heterologous polyketide synthases combined with a 6-methylsalicylic acid decarboxylase
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9
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2019
Penicillium griseofulvum (P22367), Penicillium griseofulvum
brenda