Bacterial Squalene Cyclase

Enzymatic Chemistry of Cyclopropane, Epoxide, and Aziridine Biosynthesis

“…One of the best studied cyclopropane-forming isoprenoid biosynthetic enzymes is squalene synthase (SQS, Scheme ), a prenyltransferase enzyme that catalyzes formation of the irregular 1′–1 linkage between two molecules of farnesyl pyrophosphate ( 20 ) to form squalene ( 33 ), a key triterpenoid intermediate in cholesterol biosynthesis. , In the first step of SQS catalysis, a tyrosine residue may assist in the protonation of the pyrophosphate leaving group of one FPP molecule, generating an allylic cation ( 27 ) that then alkylates the other FPP molecule bound in the same active site. , Deprotonation of the resulting carbocation (either 28 or 29 ) yields the cyclopropane-containing intermediate, presqualene pyrophosphate (PSPP, 30 ), which can be released from the enzyme and isolated from reaction mixtures lacking NADPH . In the second step of SQS catalysis, the pyrophosphate moiety of PSPP is cleaved to generate the primary cyclopropylcarbinyl cation ( 31 ), which undergoes alkyl rearrangement to the more stable tertiary carbocation, 32 , prior to stereospecific reduction by NADPH to complete the reaction cycle ( 32 → 33 ). , Formation of the highly reactive cation 31 may be facilitated by electrostatic interactions with the pyrophosphate leaving group.…”