Total Biosynthesis of Triacsin Featuring an N-hydroxytriazene Pharmacophore

Del Rio Flores, A.; Twigg, F. F.; Du, Y.; Cai, W.; Aguirre, D. Q.; Sato, M.; Dror, M. J.; Narayanamoorthy, M.; Geng, J.; Zill, N. A.; Zhang, W.

doi:10.1101/2021.05.12.443849

bioRxiv · 10.1101/2021.05.12.443849

Total Biosynthesis of Triacsin Featuring an N-hydroxytriazene Pharmacophore

Del Rio Flores, A.·Twigg, F. F.·Du, Y.·Cai, W.·Aguirre, D. Q.·Sato, M.·Dror, M. J.·Narayanamoorthy, M.·Geng, J.·Zill, N. A.·Zhang, W.

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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 nitrous acid-utilizing N-nitrosating enzyme, Tri17. This study paves the way for future mechanistic interrogation and biocatalytic application of enzymes for N-N bond formation.

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Del Rio Flores, A., Twigg, F. F., Du, Y., Cai, W., Aguirre, D. Q., Sato, M., Dror, M. J., Narayanamoorthy, M., Geng, J., Zill, N. A., Zhang, W.. 2021-05-13. Total Biosynthesis of Triacsin Featuring an N-hydroxytriazene Pharmacophore. https://doi.org/10.1101/2021.05.12.443849

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