Challenges and opportunities in bringing nonbiological atoms to life with synthetic metabolism.

The relatively narrow spectrum of chemical elements within the microbial 'biochemical palate' limits the reach of biotechnology, because several added-value compounds can only be produced with traditional organic chemistry. Synthetic biology offers enabling tools to tackle this issue by facilitating 'biologization' of non-canonical chemical atoms. The interplay between xenobiology and synthetic metabolism multiplies routes for incorporating nonbiological atoms into engineered microbes. In this review, we survey natural assimilation routes for elements beyond the essential biology atoms [i.e., carbon (C), hydrogen (H), nitrogen (N), oxygen (O), phosphorus (P), and sulfur (S)], discussing how these mechanisms could be repurposed for biotechnology. Furthermore, we propose a computational framework to identify chemical elements amenable to biologization, ranking reactions suitable to build synthetic metabolism. When combined and deployed in robust microbial hosts, these approaches will offer sustainable alternatives for smart chemical production.