Inside Back Cover: Stereoselective Directed Cationic Cascades Enabled by Molecular Anchoring in Terpene Cyclases (Angew. Chem. Int. Ed. 24/2021)

Abstract

Designed hydrogen bonds …… in the active site of terpene cyclases enable the control of cationic cyclization cascades by molecular anchoring of a substrates polar functional group. As a result, it is possible to replace multi-step synthetic routes by one enzymatic step and manufacture valuable apocarotenoids in a highly product-and stereoselective manner on gram scale, as reported by Bernhard Hauer and co-workers in their Research Article on page 13251.

Controlling Monoterpene Isomerization by Guiding Challenging Carbocation Rearrangement Reactions in Engineered Squalene‐Hopene Cyclases

“…In addition to focusing on the positions identified during the initial substrate screening, we also conducted iterative saturation mutagenesis targeting the second shell positions surrounding these amino acids. Furthermore, we saturated four positions along the substrate tunnel, as they displayed activity‐enhancing characteristics for other promiscuous reactions [42,43] . Given our anticipation of a complex interplay among amino acids to selectively terminate carbocation 6 , we consistently revisited active pocket positions that showed promising trends during saturation mutagenesis, aiming to address potential epistatic effects.…”

Class II terpene cyclases: structures, mechanisms, and engineering

“…This, in turn, affords greater exibility to M600, enabling homofarnesol to adopt a more favorable pre-folded conformation. 156 To augment the substrate range of SHC, TelSHC, a homolog of AaSHC from Thermosynechococcus vestitus, was identied from 450 SHC variants including several SHC homologues and AaSHC mutants. 157 TelSHC facilitated the conversion of allylic alcohols into spiro-containing products through a semipinacol rearrangement mechanism (Fig.…”

“…20C). 156 Molecular dynamics simulations and tunnel analyses elucidated that W169G generates sufficient space for the G600M side-chain, while M132R appears to interact with F434, causing the loop encompassing F437 to flip. This, in turn, affords greater flexibility to M600, enabling homofarnesol to adopt a more favorable pre-folded conformation.…”

“…This, in turn, affords greater flexibility to M600, enabling homofarnesol to adopt a more favorable pre-folded conformation. 156…”

Novel Biocatalysts from Specialized Metabolism

“…However, the use of such enzymes for synthesis has been limited because they are membrane proteins. A squalene‐hopene‐cyclase (SHC) was transformed into a 400‐fold faster catalyst for ambroxide (27) formation by engineering the membrane‐facing substrate entrance tunnel [50] . The recently discovered class II terpene cyclase MstE is soluble and holds promise for enabling synthetically useful biotransformations.…”