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Structure-based Tailoring of the First Coumarins-Specific Bergaptol O-methyltransferase to Synthesize Bergapten for Depigmentation Disorder Treatment

Structure-based Tailoring of the First Coumarins-Specific Bergaptol O-methyltransferase to Synthesize Bergapten for Depigmentation Disorder Treatment

Yucheng Zhao, Nana Wang, Huali Wu, Yuanze Zhou, Chuanlong Huang, Jun Luo, Zhixiong Zeng, Lingyi Kong

J Adv Res. 2019 Oct 10;21:57-64.

PMID: 31666994

Abstract:

Bergapten has long been used in combination with ultraviolet A irradiation to treat depigmentation disorder. However, extremely low bergapten contents in plants and difficulties in synthesizing bergapten have limited its application. Here, we developed an alternative bergapten-production method. We first determined the crystal structures of bergaptol O-methyltransferase from Peucedanum praeruptorum (PpBMT) and the ternary PpBMT-S-adenosyl-L-homocysteine (SAH)-bergaptol complex to identify key residues involved in bergaptol binding. Then, structure-based protein engineering was performed to obtain PpBMT mutants with improved catalytic activity towards bergaptol. Subsequently, a high-activity mutant was used to produce bergapten for pharmacological-activity analysis. Key PpBMT amino acids involved in bergaptol binding and substrate specificity were identified, such as Asp226, Asp246, Ser265, and Val320. Site-directed mutagenesis and biochemical analysis revealed that the V320I mutant efficiently transformed bergaptol to produce bergapten. Pharmacological-activity analysis indicated that bergapten positively affected hair pigmentation in mice and improved pigmentation levels in zebrafish embryos. This report provides the first description of the catalytic mechanism of coumarins-specific O-methyltransferase. The high-activity V320I mutant protein could be used in metabolic engineering to produce bergapten in order to treat depigmentation disorder. This structure-function study provides an alternative synthesis method and important advances for treating depigmentation disorders.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP486602	Bergaptol		486-60-2	Price

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