The Promiscuity of Squalene Synthase-Like Enzyme: Dehydrosqualene Synthase, a Natural Squalene Hyperproducer?

Zheng Guan, Yafeng Song, Marcel de Vries, Hjalmar Permentier, Pieter Tepper, Ronald van Merkerk, Rita Setroikromo, Wim J. Quax*

*Corresponding author for this work

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Dehydrosqualene synthase (CrtM), as a squalene synthase-like enzyme from Staphylococcus aureus, can naturally utilize farnesyl diphosphate to produce dehydrosqualene (C30H48). However, no study has documented the natural production of squalene (C30H50) by CrtM. Here, based on an HPLC-Q-Orbitrap-MS/MS study, we report that the expression of crtM in vitro or in Bacillus subtilis 168 both results in the output of squalene, dehydrosqualene, and phytoene (C40H64). Notably, wild-type CrtM exhibits a significantly higher squalene yield compared to squalene synthase (SQS) from Bacillus megaterium with an approximately 2.4-fold increase. Moreover, the examination of presqualene diphosphate’s stereostructures in both CrtM and SQS enzymes provides further understanding into the presence of multiple identified terpenoids. In summary, this study not only provides insights into the promiscuity demonstrated by squalene synthase-like enzymes but also highlights a new strategy of utilizing CrtM as a potential replacement for SQS in cell factories, thereby enhancing squalene production.

Original languageEnglish
Pages (from-to)3017-3024
Number of pages8
JournalJournal of Agricultural and Food Chemistry
Issue number6
Early online date5-Feb-2024
Publication statusPublished - 14-Feb-2024


  • CrtM
  • enzyme promiscuity
  • SQS
  • squalene
  • terpenoid

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