Primary metabolic pathways to high-energy molecules in yeasts

Abstract

A cell is the basic unit of life, where metabolism takes place. The three main purposes of metabolism are the conversion of fuel (food) to energy for cellular processes, conversion of nutrients to cellular building blocks, and also the generation of wastes and sometimes the recycle of valuable elements from those wastes. Metabolites, the (small) molecules circulating around in all cells, are not only the passive participants in metabolic reactions but also essential parts of metabolic pathway regulations. Commonly, due to experimental limitations, we extract metabolites and measure their concentrations as an average value of the same metabolite in different compartments. Similar to the Heisenberg’s uncertainty principle, now we have a accuracy dilemma in quantitative metabolomics: we “cannot” measure the immediate steady-state value of metabolites if we extract a certain cellular organelle for the spatial information of metabolite distributions. However, if we define our biological focus clearly and utilize the power of mathematics and chemistry (mostly linear algebra and isotopic labeling), we can resolve this dilemma in many compartmentalized reactions. The work described here demonstrates the power of stable isotopic tracing in deciphering unique metabolic phenomenon in different yeast chassis strains, covering major primary metabolic pathways (glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, and folate cycle). Moreover, scientific discoveries from this work will provide a base to unlock biomanufacturing potentials in these synthetic biology platforms. As NADPH production is the cellular powerhouse for biosynthesis and carbon economy is the hottest development of human society in 21th century, this work carefully explores the intrisic metabolic features on up-scaling NADPH supply and maximizing the carbon efficiency in yeasts with great industrialization potentials, namely, Saccharomyces cerevisae, Rhodosporidium toruloides, and Yarrowia Lipolytica.