TY - JOUR

T1 - Biosynthesis and biotechnological production of the anti-obesity agent celastrol

AU - Zhao, Yong

AU - Hansen, Nikolaj L.

AU - Duan, Yaotao

AU - Prasad, Meera

AU - Motawia, Mohammed S.

AU - Møller, Birger L.

AU - Pateraki, Irini

AU - Staerk, Dan

AU - Bak, Søren

AU - Miettinen, Karel

AU - Kampranis, Sotirios C.

N1 - Funding Information: We thank F. Geu-Flores (University of Copenhagen), V. Roussis and E. Ioannou (National and Kapodistrian University of Athens, Greece) for critical reading of the manuscript, and H. Chen (Kunming University of Science and Technology, China) and H. Zhang (Swiss Federal Institute of Technology Lausanne, Switzerland) for discussions on the chemical mechanism. We also thank D. R. Nelson (University of Tennessee, USA) for assigning the CYP names. We thank J. Olsen, M. Ramirez, D. Pattison, I. Ovejero-Lopez and L. Kjærulff (University of Copenhagen) for their assistance in running analytical instruments. This work was financially supported by the Novo Nordisk Foundation (grants NNF17OC0027646 to S.B. and S.C.K. and NNF16OC0021760 and NNF19OC0055204 to S.C.K.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

PY - 2023

Y1 - 2023

N2 - Obesity is a major health risk still lacking effective pharmacological treatment. A potent anti-obesity agent, celastrol, has been identified in the roots of Tripterygium wilfordii. However, an efficient synthetic method is required to better explore its biological utility. Here we elucidate the 11 missing steps for the celastrol biosynthetic route to enable its de novo biosynthesis in yeast. First, we reveal the cytochrome P450 enzymes that catalyse the four oxidation steps that produce the key intermediate celastrogenic acid. Subsequently, we show that non-enzymatic decarboxylation-triggered activation of celastrogenic acid leads to a cascade of tandem catechol oxidation-driven double-bond extension events that generate the characteristic quinone methide moiety of celastrol. Using this acquired knowledge, we have developed a method for producing celastrol starting from table sugar. This work highlights the effectiveness of combining plant biochemistry with metabolic engineering and chemistry for the scalable synthesis of complex specialized metabolites. [Figure not available: see fulltext.].

AB - Obesity is a major health risk still lacking effective pharmacological treatment. A potent anti-obesity agent, celastrol, has been identified in the roots of Tripterygium wilfordii. However, an efficient synthetic method is required to better explore its biological utility. Here we elucidate the 11 missing steps for the celastrol biosynthetic route to enable its de novo biosynthesis in yeast. First, we reveal the cytochrome P450 enzymes that catalyse the four oxidation steps that produce the key intermediate celastrogenic acid. Subsequently, we show that non-enzymatic decarboxylation-triggered activation of celastrogenic acid leads to a cascade of tandem catechol oxidation-driven double-bond extension events that generate the characteristic quinone methide moiety of celastrol. Using this acquired knowledge, we have developed a method for producing celastrol starting from table sugar. This work highlights the effectiveness of combining plant biochemistry with metabolic engineering and chemistry for the scalable synthesis of complex specialized metabolites. [Figure not available: see fulltext.].

U2 - 10.1038/s41557-023-01245-7

DO - 10.1038/s41557-023-01245-7

M3 - Journal article

C2 - 37365337

AN - SCOPUS:85162900174

VL - 15

SP - 1236

EP - 1246

JO - Nature Chemistry

JF - Nature Chemistry

SN - 1755-4330

ER -