The shape of human squalene epoxidase expands the arsenal against cancer

Nature Communications
Andrew J BrownNieng Yan

Abstract

Squalene epoxidase (also known as squalene monooxygenase, EC 1.14.99.7) is a key rate-limiting enzyme in cholesterol biosynthesis. Anil Padyana and colleagues report the long awaited structure of human squalene epoxidase (SQLE). They solved the crystal structure of the catalytic domain of human SQLE alone and in complex with two similar pharmacological inhibitors and elucidate their mechanism of action. SQLE is the target of fungicides and of increasing interest in human health and disease, particularly as a new anti-cancer target. Indeed, in a companion paper, Christopher Mahoney and colleagues performed an inhibitor screen with cancer cell lines and identified SQLE as an unique vulnerability in a subset of neuroendocrine tumours, where SQLE inhibition caused a toxic accumulation of the substrate squalene. The SQLE structure will facilitate the development of improved inhibitors. Here, we comment on these two studies in the wider context of the field and discuss possible future directions.

References

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Citations

Jul 11, 2019·Current Opinion in Lipidology·Rosa Chiara Paolicelli, Christian Widmann
Jan 19, 2021·Biophysical Journal·Alexandre SantinhoAbdou Rachid Thiam
Jan 19, 2021·Archives of Biochemistry and Biophysics·Renata A G ReisPablo Sobrado
Feb 16, 2021·Biotechnology Advances·Caroline E PaulWillem J H van Berkel
May 4, 2020·Progress in Lipid Research·Ngee Kiat ChuaAndrew J Brown
Jul 28, 2020·Cancer Letters·Sara FeltrinGabriele Zoppoli
Apr 6, 2021·Frontiers in Cell and Developmental Biology·Rosa VonaPaola Matarrese
May 20, 2021·Biochemical Pharmacology·Babita MadanDavid J Leaver
Oct 28, 2021·Analytical Chemistry·Tienan ZangXiaoling Zhang

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Software Mentioned

SQLE

Related Concepts

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Antifungals

An antifungal, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis, cryptococcal meningitis, and others. Discover the latest research on antifungals here.

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