(72b) Rewriting Pathways to Life

In the first century of biochemical research, the focus has been on discovery and understanding of mechanisms for cellular reactions, signaling, and regulation. To date, the pathways and genes involved in cellular metabolism have largely been mapped out, along with reaction mechanisms in sufficient details. The time is ripe for re-designing metabolic networks for a specific purpose, say, replacing petroleum, which serves as the raw material for the majority of fuels and chemicals used today. However, the primary metabolic pathways, such as glycolysis and the Calvin cycle, are evolved for the purpose of cell growth and survival, rather than for biochemical productions. Glycolysis, or its variations, is a fundamental metabolic pathway in life that exists in almost all organisms to decompose external or intracellular sugars.  The pathway proceeds through partial oxidation and splitting of sugars to pyruvate, which in turn is decarboxylated to produce acetyl-coenzyme A (CoA) for various biosynthetic purposes.  The decarboxylation of pyruvate loses a carbon equivalent, and limits the theoretical carbon yield to only two moles of two-carbon (C2) metabolites per mole of hexose. This native route is a major source of carbon loss in biorefining and microbial carbon metabolism. Here we design and construct a non-oxidative, cyclic pathway that allows the production of stoichiometric amounts of C2 metabolites from hexose, pentose, and triose phosphates without carbon loss. This pathway, termed Non-Oxidative Glycolysis (NOG) enables complete carbon conservation in sugar catabolism to acetyl-CoA, and can be used in conjunction with CO₂ fixationand other one-carbon (C1) assimilation pathways to achieve 100% carbon yield to desirable fuels and chemicals.  In this talk, we will discuss how NOG was designed and the role of Systems Biology in this effort.