A radical S-adenosyl-L-methionine enzyme and a methyltransferase catalyze cyclopropane formation in natural product biosynthesis

Nature Communications
Wen-Bing JinGong-Li Tang

Abstract

Cyclopropanation of unactivated olefinic bonds via addition of a reactive one-carbon species is well developed in synthetic chemistry, whereas natural cyclopropane biosynthesis employing this strategy is very limited. Here, we identify a two-component cyclopropanase system, composed of a HemN-like radical S-adenosyl-L-methionine (SAM) enzyme C10P and a methyltransferase C10Q, catalyzes chemically challenging cyclopropanation in the antitumor antibiotic CC-1065 biosynthesis. C10P uses its [4Fe-4S] cluster for reductive cleavage of the first SAM to yield a highly reactive 5'-deoxyadenosyl radical, which abstracts a hydrogen from the second SAM to produce a SAM methylene radical that adds to an sp2-hybridized carbon of substrate to form a SAM-substrate adduct. C10Q converts this adduct to CC-1065 via an intramolecular SN2 cyclization mechanism with elimination of S-adenosylhomocysteine. This cyclopropanation strategy not only expands the enzymatic reactions catalyzed by the radical SAM enzymes and methyltransferases, but also sheds light on previously unnoticed aspects of the versatile SAM-based biochemistry.

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Citations

Jul 11, 2019·Natural Product Reports·Wen-Bing JinGong-Li Tang
Nov 22, 2019·Molecular Microbiology·Tianning PuZhijun Wang
Nov 27, 2018·Journal of Industrial Microbiology & Biotechnology·Linquan BaiEung-Soo Kim
Feb 9, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jie LiuDongfeng Chen
Mar 30, 2021·Acta Pharmaceutica Sinica. B·Qiu SunYuquan Wei
Oct 28, 2019·Biochemistry·Liju G MathewWilliam N Lanzilotta
Dec 4, 2021·Natural Product Reports·Suze MaQi Zhang
Nov 13, 2021·Chembiochem : a European Journal of Chemical Biology·Hayama TsutsumiYasuo Ohnishi

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Methods Mentioned

BETA
nuclear-magnetic
resonance
isothermal titration calorimetry
NMR
PCR
affinity purification

Software Mentioned

Clustal Omega

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