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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. A few non-canonical chemical elements are already present in living systems, and their assimilation routes have been characterized; however, this represents only a fraction of the atoms that could be incorporated in biology. Nature holds a treasure trove of novel, sometimes elusive, mechanisms for blending non-canonical chemical elements into living cells through synthetic metabolism. Methylation and S-adenosyl-L-methionine (SAM) -mediated incorporation are only two examples of reactions that can be harnessed for introducing new-to-Nature elements for biotechnological purposes. Synthetic metabolism and enzyme engineering are promising techniques to update the periodic table of Life. Thermodynamic calculations based on bond-formation free-energy values and analysis of chemical reaction databases help identify element-and-organic substrate pairs suitable for biologization. [ABSTRACT FROM AUTHOR]

Plants produce a wide variety of pharmacologically active molecules classified as natural products. Derivatization of these natural products can modulate or improve the bioactivity of the parent compound. Unfortunately, chemical derivatization of natural products is often difficult or impractical. Here we use the newly discovered biosynthetic genes for two monoterpene indole alkaloids, alstonine and stemmadenine acetate, to generate analogs of these compounds. We reconstitute these biosynthetic genes in the heterologous host Nicotiana benthamiana along with an unnatural starting substrate to produce the corresponding new-to-nature alkaloid product. [ABSTRACT FROM AUTHOR]

Plants produce a wide variety of pharmacologically active molecules classified as natural products. Derivatization of these natural products can modulate or improve the bioactivity of the parent compound. Unfortunately, chemical derivatization of natural products is often difficult or impractical. Here we use the newly discovered biosynthetic genes for two monoterpene indole alkaloids, alstonine and stemmadenine acetate, to generate analogs of these compounds. We reconstitute these biosynthetic genes in the heterologous host Nicotiana benthamiana along with an unnatural starting substrate to produce the corresponding new-to-nature alkaloid product.