The shape of human squalene epoxidase expands the arsenal against cancer

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.

Fig. 1

Simplified scheme of the cholesterol biosynthesis pathway featuring the shunt pathway. In the shunt pathway SQLE acts a second time to lead to the production of a potent oxysterol regulator, 24(S),25-epoxycholesterol. The oxygen atoms from the epoxidation are shown in red

Fig. 2

SQLE structure. a Linear view of SQLE protein with known structural features. b Structure of the catalytic domain of human SQLE. The FAD binding domain is shown in green, the substrate-binding domain in magenta, and the C-terminal membrane-associated helical domain is coloured orange. FAD (yellow) and the inhibitor NB-598 (blue) are shown in stick representation. Schematic model of SQLE partially embedded in the endoplasmic reticulum membrane including a representation of the N-terminal domain based on our previous work