Orthogonal tandem catalysis in terpene biosynthesis

If sequential reactions in a multistep reaction sequence can be catalyzed in one-pot fashion, synthetic efficiency typically improves. This phenomenon is described as orthogonal tandem catalysis and extends from chemical to biochemical reactions: “one pot” in the organic chemistry laboratory is analogous to “one compartment” in the cell. Covalent linkage of tandem catalysts can further enhance synthetic or biosynthetic efficiency through proximity, which is a form of substrate channeling. In recent years, bifunctional terpene cyclases have been discovered that contain two distinct catalytic domains, including class I-class II terpene cyclases, several class II terpene cyclase-phosphatases, and more than 1000 prenyltransferase-class I/II terpene cyclases. Structural analyses of these systems using X-ray crystallography and cryo-electron microscopy provide a framework for understanding orthogonal tandem catalysis and substrate channeling in the enzymology of natural product biosynthesis.