(421d) Area 15C Bioengineering Plenary Award: Orthogonal Metabolism for Industrial Biomanufacturing

The bow-tie architecture of metabolism affords biological systems with inherent robustness and plasticity, which also appears to be the case for engineered systems like the power grid, manufacturing, and the Internet (Trends Biotechnol. 2004 22:446). This architecture allows microbial metabolic networks to catabolize a myriad of substrates to a small number of precursor metabolites, ATP and reducing equivalents, which in turn serve as the basis to biosynthesize the building blocks and macromolecules required to sustain life. Efforts to metabolically engineer microbial systems to produce small molecules have been almost exclusively based on harnessing the aforementioned bow-tie architecture and corresponding pathways (Cell 2016, 164:1185). However, a number of inherent drawbacks associated with the use of such an approach have motivated the development of pathways orthogonal to the host metabolism (Nat Commun. 2017, 8:15188). For example, despite the high efficiency of pathways involved in catabolic and central metabolic functions, native biosynthetic pathways typically suffer from energy, carbon, and catalytic inefficiencies (Biochemistry, 2011, 50:4402), which in turn limit product synthesis. In addition, exploitation of native metabolic architectures requires extensive understanding of the host metabolism and can cause problematic cross-talk between product-forming and growth-sustaining functions.

In recent years, our laboratory has focused on designing and engineering novel biosynthetic pathways with varying degrees of orthogonality. For example, we have repurposed a catabolic pathway, the b-oxidation cycle, to operate in a biosynthetic manner (Nature 2011, 476:355) and extended this concept to develop a biosynthetic platform that is orthogonal to the host anabolic network (Nat. Biotechnol. 2016, 34:556). More recently, we have developed a synthetic metabolic pathway that allows conversion of single-carbon (C1) substrates to multi-carbon products in a manner that is orthogonal to the universally accepted bow-tie architecture of metabolism. In this talk, I will highlight our recent work on engineering these pathways and its implication for industrial biomanufacturing.