Optimal growth of microbes on mixed carbon sources

A classic problem in microbiology is that bacteria display two types of growth behavior when cultured on a mixture of two carbon sources: in certain mixtures the bacteria consume the two carbon sources sequentially (diauxie) and in other mixtures the bacteria consume both sources simultaneously (co-utilization). The search for the molecular mechanism of diauxie led to the discovery of the lac operon and gene regulation in general. However, why microbes would bother to have different strategies of taking up nutrients remained a mystery. Here we show that diauxie versus co-utilization can be understood from the topological features of the metabolic network. A model of optimal allocation of protein resources to achieve maximum growth quantitatively explains why and how the cell makes the choice when facing multiple carbon sources. Our work solves a long-standing puzzle and sheds light on microbes' optimal growth in different nutrient conditions. 3 During the course of evolution, biological systems have acquired a myriad of strategies to adapt to their environments. A great challenge is to understand the rationale of these strategies on quantitative bases. It has long been discovered that the production of digestive enzymes in a microorganism depends on (adapts to) the composition of the medium (1). More precisely, in the 1940s Jacques Monod observed two distinct strategies in bacteria (E. coli and B. subtilis) to take up nutrients. He cultured these bacteria on a mixture of two carbon sources, and found that for certain mixtures the bacteria consume both nutrients simultaneously while for other mixtures they consume the two nutrients one after another (2, 3). The latter case resulted a growth curve consisted of two consecutive exponentials, for which he termed this phenomenon " diauxie ". Subsequent studies revealed that the two types of growth behavior, diauxic-and co-utilization of carbon sources are common in microorganisms (4-8). The regulatory mechanism responsible for diauxie, that is the molecular mechanism for the microbes to express only the enzymes for the preferred carbon source even when multiple sources are present, is commonly ascribed to catabolite repression (5, 9-13). In bacteria it is exemplified by the lac operon and the cAMP-Crp system (14-17). In yeast, the molecular implementation of catabolite repression differs, but the logic and the outcome are similar (5). Why have microbes evolved to possess the two strategies and what are the determining factors for them to choose one versus the other? For unicellular organisms, long term …