Evolution of Sterol and Triterpene Cyclases

Squalene- and oxidosqualene cyclase enzymes catalyze remarkable and complex cyclization/rearrangement reactions. Recently, two cyclase genes have been cloned and sequenced, making it possible to address questions of cyclase evolution and mechanistic enzymology. A comparison of the predicted amino acid sequences of the squalene-hopene cyclase from Bacillus acidocaldarius and the oxidosqualene-lanosterol cyclase from Candida albicans is presented. These enzymes have different substrate and product specificities but share four regions of substantial amino acid identity, consistent with a divergent evolutionary relationship. These cyclases also share a general richness in tryptophan and tyrosine residues. This feature, the cationic nature of the cyclization/rearrangement reactions, and literature precedents have led to formulation of the aromatic hypothesis--that electron-rich aromatic sidechains from tryptophan, tyrosine, and perhaps phenylalanine are essential features of cyclase active sites, where they direct the folding of substrate and stabilize positively charged transition states and/or high-energy intermediates during cyclization/rearrangement.