Improving 10-deacetylbaccatin III-10-β-O-acetyltransferase catalytic fitness for Taxol production

Nature Communications
Bing-Juan LiPing Zhu

Abstract

The natural concentration of the anticancer drug Taxol is about 0.02% in yew trees, whereas that of its analogue 7-β-xylosyl-10-deacetyltaxol is up to 0.5%. While this compound is not an intermediate in Taxol biosynthetic route, it can be converted into Taxol by de-glycosylation and acetylation. Here, we improve the catalytic efficiency of 10-deacetylbaccatin III-10-O-acetyltransferase (DBAT) of Taxus towards 10-deacetyltaxol, a de-glycosylated derivative of 7-β-xylosyl-10-deacetyltaxol to generate Taxol using mutagenesis. We generate a three-dimensional structure of DBAT and identify its active site using alanine scanning and design a double DBAT mutant (DBATG38R/F301V) with a catalytic efficiency approximately six times higher than that of the wild-type. We combine this mutant with a β-xylosidase to obtain an in vitro one-pot conversion of 7-β-xylosyl-10-deacetyltaxol to Taxol yielding 0.64 mg ml-1 Taxol in 50 ml at 15 h. This approach represents a promising environmentally friendly alternative for Taxol production from an abundant analogue.

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Citations

Dec 7, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jing-Jing ChenPing Zhu
Jan 18, 2018·International Journal of Molecular Sciences·Ana M L Seca, Diana C G A Pinto
May 26, 2018·Applied Biochemistry and Biotechnology·Lin-Feng YouJia-Jun Huang
May 26, 2018·Molecular Biotechnology·Shu-Ling LinPing-Lan Ouyang
Dec 28, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jing-Jing ChenPing Zhu
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tao WangZhong Wang
Jun 25, 2021·The Plant Journal : for Cell and Molecular Biology·Aashish KumarSumit Ghosh
Jun 10, 2021·Chemistry : a European Journal·Weijin WangHans Renata

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Datasets Mentioned

BETA
EU107143.1
AF456342.1
EU107134.1
EU107140.1
AY452666.1
ABO47805.1
CAD89104.2

Methods Mentioned

BETA
acetylation
nuclear magnetic resonance
PCR
molecular
Protein Assay

Software Mentioned

Swissmodel
Autodock
DBAT
Discovery Studio
Procheck
Autodock Vina
Chimera

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