Biosynthesis of triacsin featuring an N-hydroxytriazene pharmacophore.

Autor: Del Rio Flores A; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Twigg FF; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Du Y; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Cai W; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Aguirre DQ; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Sato M; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan., Dror MJ; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Narayanamoorthy M; Department of Chemistry, University of California Berkeley, Berkeley, CA, United States., Geng J; Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, CA, United States., Zill NA; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Zhai R; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States., Zhang W; Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA, United States. wjzhang@berkeley.edu.; Chan Zuckerberg Biohub, San Francisco, CA, United States. wjzhang@berkeley.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2021 Dec; Vol. 17 (12), pp. 1305-1313. Date of Electronic Publication: 2021 Nov 01.
DOI: 10.1038/s41589-021-00895-3
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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