UB研究室が心不全治療薬ジゴキシンの鍵となる酵素を特定(UB lab identifies key enzyme for heart failure drug digoxin)

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2023-07-17 バッファロー大学(UB)

◆バッファロー大学の研究者たちは、キツネノギク植物に心不全治療薬ジゴキシンを生成する酵素を初めて特定しました。この発見により、ジゴキシンの効率的な生産が可能になり、またより毒性の低い代替薬の開発にも寄与する見込みです。これにより、心臓病治療に限定されていたジゴキシンの応用範囲が拡大し、他の疾患への治療法にも応用される可能性が示唆されています。

<関連情報>

シトクロムP450 CYP87A4がジゴキシンの生合成においてステロール側鎖の切断を行う。 A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis

Emily Carroll,Baradwaj Ravi Gopal,Indu Raghavan,Minakshi Mukherjee & Zhen Q. Wang
Nature Communications  Published:08 July 2023
DOI:https://doi.org/10.1038/s41467-023-39719-4

UB研究室が心不全治療薬ジゴキシンの鍵となる酵素を特定(UB lab identifies key enzyme for heart failure drug digoxin)

Abstract

Digoxin extracted from the foxglove plant is a widely prescribed natural product for treating heart failure. It is listed as an essential medicine by the World Health Organization. However, how the foxglove plant synthesizes digoxin is mostly unknown, especially the cytochrome P450 sterol side chain cleaving enzyme (P450scc), which catalyzes the first and rate-limiting step. Here we identify the long-speculated foxglove P450scc through differential transcriptomic analysis. This enzyme converts cholesterol and campesterol to pregnenolone, suggesting that digoxin biosynthesis starts from both sterols, unlike previously reported. Phylogenetic analysis indicates that this enzyme arises from a duplicated cytochrome P450 CYP87A gene and is distinct from the well-characterized mammalian P450scc. Protein structural analysis reveals two amino acids in the active site critical for the foxglove P450scc’s sterol cleavage ability. Identifying the foxglove P450scc is a crucial step toward completely elucidating digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work.

有機化学・薬学
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