Engineering specialized metabolic pathways—is there a room for enzyme improvements?

Recent advances in enzyme engineering enable dramatic improvements in catalytic efficiency and/or selectivity, as well as de novo engineering of enzymes to catalyze reactions where natural enzymes are not available. Can these capabilities be utilized to transform biosynthesis pathways? Metabolic engineering is traditionally based on combining existing enzymes to give new, or modified, pathways, within a new context and/or organism. How efficient, however, are the individual enzyme components? Is there room to improve pathway performance by enzyme engineering? We discuss the differences between enzymes in central versus specialized, or secondary metabolism and highlight unique features of specialized metabolism enzymes participating in the synthesis of natural products. We argue that, for the purpose of metabolic engineering, the catalytic efficiency and selectivity of many enzymes can be improved with the aim of achieving higher rates, yields and product purities. We also note the relative abundance of spontaneous reactions in specialized metabolism, and the potential advantage of engineering enzymes that will catalyze these steps. Specialized metabolism therefore offers new opportunities to integrate enzyme and pathway engineering, thereby achieving higher metabolic efficiencies, enhanced production rates and improved product purities.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (137 K)Download as PowerPoint slideHighlights► Specialized metabolism offers challenging engineering opportunities. ► Unlike central metabolism, specialized metabolism is slow, sluggish and messy. ► Spontaneous reactions are relatively common in specialized metabolism. ► Enzymes can be engineered for higher rate and substrate specificity. ► Enzymes can be engineered for naturally spontaneous reactions.