Abstract
AbstractDigoxin 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 P450sccthrough 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 P450CYP87Agene 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 P450sccis a crucial step toward completely elucidating digoxin biosynthesis and expanding the therapeutic applications of digoxin analogs in future work.
Funder
SUNY | Research Foundation for the State University of New York
National Science Foundation
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference57 articles.
1. Withering, W. An account of the foxglove, and some of its medical uses. (Swinney, 1785).
2. World Health Organization. WHO model list of essential medicines - 22nd list, 2021. Tech. Doc. (2021).
3. Medical Expenditure Panel Survey. Digoxin drug usage statistics, United States, 2013–2020. ClinCalc DrugStats Database (2022).
4. Mekhail, T. et al. Phase 1 trial of AnvirzelTM in patients with refractory solid tumors. Invest. N. Drugs 24, 423–427 (2006).
5. Srivastava, M. et al. Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from fibrosis lung epithelial cells. Proc. Natl Acad. Sci. USA 101, 7693–7698 (2004).
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