4.8 Article

Deciphering the Reaction Pathway of Mononuclear Iron Enzyme-Catalyzed NC Triple Bond Formation in Isocyanide Lipopeptide and Polyketide Biosynthesis

Journal

ACS CATALYSIS
Volume 12, Issue 4, Pages 2270-2279

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acscatal.1c04869

Keywords

isocyanide; oxygenase; natural product; reaction mechanism; desaturation; C-N bond formation

Funding

  1. National Institutes of Health [GM127588, GM040541]
  2. Welch Foundation [F-1511]
  3. National Natural Science Foundation of China [22122305]
  4. National Key Research and Development Program of China [2018YFA0901900]

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Researchers have investigated the catalytic mechanism of several Fe/2OG enzymes capable of catalyzing isocyanide formation, and found that the reaction likely involves two steps: the formation of an imine intermediate and decarboxylation-assisted desaturation.
Despite the diversity of reactions catalyzed by 2-oxoglutarate-dependent nonheme iron (Fe/2OG) enzymes identified in recent years, only a limited number of these enzymes have been investigated in mechanistic detail. In particular, several Fe/2OG-dependent enzymes capable of catalyzing isocyanide formation have been reported. While the glycine moiety has been identified as a biosynthon for the isocyanide group, how the actual conversion is effected remains obscure. To elucidate the catalytic mechanism, we characterized two previously unidentified (AecA and AmcA) along with two known (ScoE and SfaA) Fe/2OG-dependent enzymes that catalyze N C triple bond installation using synthesized substrate analogues and potential intermediates. Our results indicate that isocyanide formation likely entails a two-step sequence involving an imine intermediate that undergoes decarboxylation-assisted desaturation to yield the isocyanide product. Results obtained from the in vitro experiments are further supported by mutagenesis, the product-bound enzyme structure, and in silico analysis.

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