Total (Bio)Synthesis: Strategies of Nature and of Chemists

Abstract

The biosynthetic pathways to a number of natural products have been reconstituted in vitro using purified enzymes. Many of these molecules have also been synthesized by organic chemists. Here we compare the strategies used by nature and by chemists to reveal the underlying logic and success of each total synthetic approach for some exemplary molecules with diverse biosynthetic origins.

Bacterial Alkaloids Prevent Amoebal Predation

“…These results led us to propose an NRPS-based biosynthesis for the pyreudiones (Figure 3). [31] TheAdomain selects l-proline and loads the adenylated amino acid onto the Tdomain. Amide bond formation occurs in asubsequent step between the secondary amine of proline and a b-ketoacid, presumably catalyzed by the Cdomain.…”

“…These results led us to propose an NRPS‐based biosynthesis for the pyreudiones (Figure ) . The A domain selects l ‐proline and loads the adenylated amino acid onto the T domain.…”

Quo vadis, enzymology?

“…A related challenge, albeit one at a different scale, pertains to understanding nature’s myriad strategies for complex molecule construction. Given the exquisite ability of metabolism to operate in a one-pot environment, such problems are most holistically approached through in vitro reconstitution of entire biosynthetic pathways [11,12]. More recently, the study of secondary metabolism has also been extended to commensal microorganisms.…”

A Promiscuous Bacterial P450: The Unparalleled Diversity of BM3 in Pharmaceutical Metabolism

“…There is also a commercial interest in reducing manufacturing costs. Due to these factors, efforts are being made to move future pharmaceutical synthesis towards alternative routes of production that focus on sustainability and cost efficiency [ 1 ]. One area of current interest is biosynthetic manufacture, which harnesses bacterial cells and enzymes for metabolite production as an organic synthesis replacement.…”