Elucidation of the biosynthetic pathway of hydroxysafflor yellow A

Zi-Long Wang, Hao-Tian Wang, Guowei Chang, Guo Ye, Meng Zhang, Jiang Chen and Min Ye ()
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Zi-Long Wang: 38 Xueyuan Road
Hao-Tian Wang: 38 Xueyuan Road
Guowei Chang: Chinese Academy of Sciences
Guo Ye: 38 Xueyuan Road
Meng Zhang: 38 Xueyuan Road
Jiang Chen: Chengdu University of Traditional Chinese Medicine
Min Ye: 38 Xueyuan Road

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Hydroxysafflor yellow A (HSYA) is a clinical investigational new drug for the treatment of acute ischemic stroke. It has a unique quinochalcone di-C-glycoside structure and is exclusively found in the flowers of safflower (Carthamus tinctorius). To date, little is known about the biosynthesis of HSYA. In this work, we characterize four key biosynthetic enzymes from C. tinctorius: CtF6H (6-hydroxylation of naringenin to produce carthamidin), CtCHI1 (isomerization between carthamidin and isocarthamidin), CtCGT (flavonoid di-C-glycosyltransferase), and Ct2OGD1 (2-oxoglutarate-dependent dioxygenase). Notably, Ct2OGD1 coordinates with CtCGT to convert carthamidin or isocarthamidin to HSYA. Functions of these genes are confirmed by VIGS (virus-induced gene silencing) in C. tinctorius, de novo biosynthesis of HSYA in Nicotiana benthamiana, semi-synthesis in yeast, and in vitro enzyme assays. We further find that the simultaneous presence and high expression of the above four key genes, together with the absence of F2H (flavanone 2-hydroxylase) genes, are essential for the biosynthesis of HSYA, and thus interpret mechanisms for the unique presence of HSYA in safflower. This work elucidates the biosynthetic pathway of HSYA and provides a foundation for the green and efficient production of this valuable medicinal natural product.

Date: 2025
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DOI: 10.1038/s41467-025-59774-3

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