1. Biosynthesis of triacsin featuring an N-hydroxytriazene pharmacophore
- Author
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Moriel J. Dror, Michio Sato, Rui Zhai, Yongle Du, Jiaxin Geng, Antonio Del Rio Flores, Wenlong Cai, Frederick F. Twigg, Daniel Q. Aguirre, Maanasa Narayanamoorthy, Wenjun Zhang, and Nicholas A. Zill
- Subjects
Biochemistry & Molecular Biology ,Stereochemistry ,Glycine ,Article ,Catalysis ,Medicinal and Biomolecular Chemistry ,chemistry.chemical_compound ,Biosynthesis ,Coenzyme A Ligases ,Escherichia coli ,Moiety ,Molecular Biology ,Nitrites ,chemistry.chemical_classification ,Streptomyces aureofaciens ,Mutagenesis ,Lipid metabolism ,Cell Biology ,Bond formation ,Lipid Metabolism ,Lipids ,Hydrazines ,Enzyme ,chemistry ,Biocatalysis ,Biochemistry and Cell Biology ,Triazenes ,Pharmacophore - Abstract
Triacsins are an intriguing class of specialized metabolites possessing a conserved N-hydroxytriazene moiety not found in any other known natural products. Triacsins are notable as potent acyl-CoA synthetase inhibitors in lipid metabolism, yet their biosynthesis has remained elusive. Through extensive mutagenesis and biochemical studies, we here report all enzymes required to construct and install the N-hydroxytriazene pharmacophore of triacsins. Two distinct ATP-dependent enzymes were revealed to catalyze the two consecutive N–N bond formation reactions, including a glycine-utilizing, hydrazine-forming enzyme (Tri28) and a nitrite-utilizing, N-nitrosating enzyme (Tri17). This study paves the way for future mechanistic interrogation and biocatalytic application of enzymes for N–N bond formation. During the biosynthesis of triacsin, the two N–N bond formation reactions necessary to create the unique N-hydroxytriazene moiety are catalyzed by a glycine-utilizing hydrazine-forming enzyme and a nitrite-utilizing N-nitrosating enzyme.
- Published
- 2021