Enzyme Mechanisms for Polycyclic Triterpene Formation

Abstract

The mechanisms by which triterpene cyclases transform olefins into complex and biologically important polycyclic products have fueled nearly half a century of intense research. Recent chemical and biological studies, together with previous findings, provide intriguing new insights into the enzymatic mechanism of triterpene formation and form a surprisingly detailed picture of these elegant catalysts. It can be concluded that the role of the oxidosqualene cyclases involves protection of the intermediate carbocation against addition of water or deprotonation by base, thereby allowing the shift of the hydride and methyl groups along a thermodynamically and kinetically favorable cascade. Key questions in the areas of structural biology, site‐directed mutagenesis, and directed evolution are apparent, now that the first structure of a triterpene cyclase is known.

The use of 1H NMR for yield determination in the regioselective epoxidation of squalene

“…Squalene is a key intermediate in the biosynthesis of steroids such as lanosterol and cholesterol (2). The first step in this sequence consists of the formation of the terminal epoxide (2,3-oxidosqualene) by the squalene epoxidase enzyme (3).…”

Incorporating Linear Synchronous Transit Interpolation into the Growing String Method: Algorithm and Applications

“…This reaction is inspired by the much more complicated (and enzymatically catalyzed) reaction of 2,3-oxidosqualene to produce lanosterol during cholesterol synthesis. 41 Even though this reaction is simplified, it possesses four transition states on the path from linear reactant to final product at the gas-phase HF/ STO-3 g level of theory. Each of these transition states and the stable intermediates are depicted in Figure 7.…”

Substrate specificity of a novel squalene-hopene cyclase from Zymomonas mobilis

“…In particular, the family of squalene-hopene cyclases (SHC) has been widely used in mutational and biochemical analysis elucidating the highly complex mechanism by which these enzymes catalyze the reaction of the natural substrate squalene 1 to its pentacyclic products hopene 2 and hopanol 3 (Scheme 1). It was the pioneering work of both organic and biological chemists in this field, which led to a considerable understanding on the structural diversity and the cyclization process attained by a single enzyme [1][2][3][4][5][6][7][8][9][10][11][12]. Interestingly, other related molecules, like linear terpenoids of different chain lengths containing additional functional groups have also been shown to serve as substrates for the well investigated SHC from the thermophilic bacterium Alicyclobacillus acidocaldarius (AacSHC) in several studies [13][14][15][16][17][18].…”