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IUBMB CommentsRequires Fe(II). The enzyme, found in actinobacterial species, participates in the biosynthesis of isonitrile-containing lipopeptides. The reaction comprises two catalytic cycles, each consuming an oxygen molecule and a 2-oxoglutarate molecule. In the first cycle the substrate is hydroxylated, while in the second cycle the enzyme catalyses a decarboxylation/oxidation reaction that produces an isonitrile group.
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(3R)-3-[(E)-(carboxymethylidene)amino]butanoate + 2-oxoglutarate + O2
(3R)-3-(methylidyneazaniumyl)butanoate + succinate + 2 CO2 + 2 H2O
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(R)-3-((carboxymethyl)amino)butanoate + 2-oxoglutarate + O2
(R)-3-isocyanobutanoate + CO2 + ?
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a (3R)-3-[(carboxylmethyl)amino]fatty acid + 2 2-oxoglutarate + 2 O2
a (3R)-3-isocyanyl-fatty acid + 2 succinate + 3 CO2 + 2 H2O
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a (3R)-3-[(carboxylmethyl)amino]fatty acid + 2-oxoglutarate + O2
a (3R)-3-[carboxy(hydroxy)methyl]amino fatty acid + succinate + CO2
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a (3R)-3-[carboxy(hydroxy)methyl]amino fatty acid + 2-oxoglutarate + O2
a (3R)-3-isocyanyl-fatty acid + succinate + 2 CO2 + 2 H2O
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additional information
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an 1:1:1 correlation exists between 2-oxoglutarate consumption, oxygen consumption, and succinate formation. The reaction does not produce H2O2
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metabolism
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-NC bond formation involves two cycles of Fe/2OG enzyme catalysis, each consuming an oxygen molecule and a 2-oxoglutarate molecule. The reaction starts with an Fe(IV)-oxo catalyzed hydroxylation
metabolism
-NC bond formation involves two cycles of Fe/2OG enzyme catalysis, each consuming an oxygen molecule and a 2-oxoglutarate molecule. The reaction starts with an Fe(IV)-oxo catalyzed hydroxylation
metabolism
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-NC bond formation involves two cycles of Fe/2OG enzyme catalysis, each consuming an oxygen molecule and a 2-oxoglutarate molecule. The reaction starts with an Fe(IV)-oxo catalyzed hydroxylation
metabolism
isonitrile can only be formed through two consecutive catalytic cycles that both use one molecule of dioxygen and 2-oxoglutarate. In both cycles the active species is an iron(IV)-oxo species that in the first reaction cycle reacts through two consecutive hydrogen atom abstraction steps, first from the N-H group and thereafter from the C-H group to desaturate the NH-CH2 bond. The electronic configurations along that pathway implicate an initial hydride transfer followed by proton transfer. A second catalytic cycle of the reaction of iron(IV)-oxo with desaturated substrate starts with hydrogen atom abstraction followed by decarboxylation to give isonitrile directly
metabolism
the ScoE reaction initiates with C5 hydroxylation of (R)-3-((carboxymethyl)amino)butanoic acid. The hydroxylated product undergoes dehydration presumably mediated by Tyr96 to synthesize the C5 imine in a trans configuration. (R)-3-isocyanobutanoic acid is finally generated through radical-based decarboxylation of the imine
metabolism
the ScoE-catalyzed reaction contains two decoupled parts, desaturation and decarboxylation. The FeIV-oxo-triggered desaturation includes two consecutive H-abstractions. In the second stage reaction, the decarboxylation of the substrate radical generated by H-abstraction is calculated to be quite easy. The electron transfer from the substrate to the iron center is the key factor for lowering the barrier of decarboxylation. The central iron ion is responsible for H-abstraction and also acts as an electron relay station for decarboxylation. This electron transfer is coupled with a proton transfer, in which R310 and the associated H-bonding network play a critical role. The first C-N desaturation is the rate-limiting step of the whole catalysis with an overall energy barrier of 17.6 or 16.9 kcal/mol in two competitive pathways
physiological function
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enzyme is involved in the biosynthesis of isonitrile lipopeptides (INLPs) through a thio-template mechanism. Deletion of INLP biosynthetic genes decreases the intracellular metal concentration
physiological function
enzyme is involved in the biosynthesis of isonitrile lipopeptides (INLPs) through a thio-template mechanism. Isonitrile is generated from a single precursor Gly by a thioesterase and nonheme iron(II)-dependent oxidase ScoE. ScoD catalyzes a Michael addition of Gly to the beta-position of an alpha,beta-unsaturated fatty acyl-ACP to yield an N-carboxymethyl-3-aminoacyl-ACP. ScoE catalyzes the subsequent oxidation and decarboxylation to yield a beta-isonitrile moiety
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Li, H.; Liu, Y.
Mechanistic investigation of isonitrile formation catalyzed by the nonheme iron/alpha-KG-dependent decarboxylase (ScoE)
ACS Catal.
10
2942-2957
2020
Streptomyces coeruleorubidus (A0A3B6UEU3)
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brenda
Harris, N.; Born, D.; Cai, W.; Huang, Y.; Martin, J.; Khalaf, R.; Drennan, C.; Zhang, W.
Isonitrile formation by a non-heme iron(II)-dependent oxidase/decarboxylase
Angew. Chem. Int. Ed. Engl.
57
9707-9710
2018
Streptomyces coeruleorubidus (A0A3B6UEU3)
brenda
Chen, T.; Chen, J.; Tang, Y.; Zhou, J.; Guo, Y.; Chang, W.
Pathway from N-alkylglycine to alkylisonitrile catalyzed by iron(II) and 2-oxoglutarate-dependent oxygenases
Angew. Chem. Int. Ed.Engl.
59
7367-7371
2020
Streptomyces avermitilis, Streptomyces thioluteus, Streptomyces coeruleorubidus (A0A3B6UEU3)
brenda
Del Rio Flores, A.; Kastner, D.; Du, Y.; Narayanamoorthy, M.; Shen, Y.; Cai, W.; Vennelakanti, V.; Zill, N.; Dell, L.; Zhai, R.; Kulik, H.; Zhang, W.
Probing the mechanism of isonitrile formation by a non-heme iron(II)-dependent oxidase/decarboxylase
J. Am. Chem. Soc.
144
5893-5901
2022
Streptomyces coeruleorubidus (A0A3B6UEU3)
brenda
Jonnalagadda, R.; Del Rio Flores, A.; Cai, W.; Mehmood, R.; Narayanamoorthy, M.; Ren, C.; Zaragoza, J.; Kulik, H.; Zhang, W.; Drennan, C.
Biochemical and crystallographic investigations into isonitrile formation by a nonheme iron-dependent oxidase/ decarboxylase
J. Biol. Chem.
296
100231
2021
Streptomyces coeruleorubidus (A0A3B6UEU3)
brenda
Harris, N.; Sato, M.; Herman, N.; Twigg, F.; Cai, W.; Liu, J.; Zhu, X.; Downey, J.; Khalaf, R.; Martin, J.; Koshino, H.; Zhang, W.
Biosynthesis of isonitrile lipopeptides by conserved nonribosomal peptide synthetase gene clusters in Actinobacteria
Proc. Natl. Acad. Sci. USA
114
7025-7030
2017
Mycobacterium marinum, Streptomyces coeruleorubidus (A0A3B6UEU3)
brenda
Ali, H.; Ghafoor, S.; de Visser, S.
Density functional theory study into the reaction mechanism of isonitrile biosynthesis by the nonheme iron enzyme ScoE
Top. Catal.
65
528-543
2022
Streptomyces coeruleorubidus (A0A3B6UEU3)
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brenda
1.14.11.78 (R)-3-[(carboxymethyl)amino]fatty acid dioxygenase/decarboxylase
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