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A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis

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 (P450_scc), which catalyzes the first and rate-limiting step. Here we identify the long-speculated foxglove P450_scc 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 P450_scc. Protein structural analysis reveals two amino acids in the active site critical for the foxglove P450_scc's sterol cleavage ability. Identifying the foxglove P450_scc is a crucial step toward completely elucidating digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work.

INSTRUMENT(S): Liquid Chromatography MS - positive - reverse phase, Gas Chromatography MS - positive

PROVIDER: MTBLS7993 | MetaboLights | 2025-07-03

REPOSITORIES: MetaboLights

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A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis.

Carroll Emily E Ravi Gopal Baradwaj B Raghavan Indu I Mukherjee Minakshi M Wang Zhen Q ZQ

Nature communications 20230708 1

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 (P450<sub>scc</sub>), which catalyzes the first and rate-limiting step. Here we identify the long-speculated foxglove P450<sub>scc</sub> through differential transcriptomic analysis. ...[more]

PMID: 37422531

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			Action	DRS
	FS5_S11_26_11_1.mzML	Mzml
	FS5_S11_26_11_2.mzML	Mzml
	FS5_S11_26_11_3.mzML	Mzml
	FS5_S11_26_E_1.mzML	Mzml
	FS5_S11_26_E_2.mzML	Mzml