TY - JOUR T1 - A Systems-Level Model Reveals That 1,2-Propanediol Utilization Microcompartments Enhance Pathway Flux Through Intermediate Sequestration JF - bioRxiv DO - 10.1101/069542 SP - 069542 AU - Christopher M. Jakobson AU - Marilyn F. Slininger AU - Danielle Tullman-Ercek AU - Niall M. Mangan Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/08/14/069542.abstract N2 - The spatial organization of metabolism is common to all domains of life. Enteric and other bacteria use subcellular organelles known as bacterial microcompartments to spatially organize the metabolism of pathogenicity-relevant carbon sources, such as 1,2-propanediol. The organelles are thought to sequester a private cofactor pool, minimize the effects of toxic intermediates, and enhance flux through the encapsulated metabolic pathways. We develop a mathematical model of the function of the 1,2-propanediol utilization microcompartment of Salmonella enterica and use it to analyze the function of the microcompartment organelles in detail. Our model makes accurate predictions of doubling times based on an optimized compartment shell permeability determined by maximizing metabolic flux in the model. The compartments function primarily to decouple cytosolic intermediate concentrations from the concentrations in the microcompartment, allowing significant enhancement in pathway flux by the generation of large concentration gradients across the microcompartment shell. We find that selective permeability of the microcompartment shell is not absolutely necessary, but is often beneficial in establishing this intermediate-trapping function. Our findings also implicate active transport of the 1,2-propanediol substrate under conditions of low external substrate concentration, and we present a mathematical bound, in terms of external 1,2-proanediol substrate concentration and diffusive rates, on when active transport of the substrate is advantageous. By allowing us to predict experimentally inaccessible aspects of microcompartment function, such as intra-microcompartment metabolite concentrations, our model presents avenues for future research and underscores the importance of carefully considering changes in external metabolite concentrations and other conditions during batch cultures. Our results also suggest that the encapsulation of heterologous pathways in bacterial microcompartments might yield significant benefits for pathway flux, as well as for toxicity mitigation.Author Summary Many bacterial species, such as Salmonella enterica (responsible for over 1 million illnesses per year in the United States) and Yersinia pestis (the causative agent of bubonic plague), have a suite of unique metabolic capabilities allowing them to proliferate in the hostile environment of the host gut. Bacterial microcompartments are the subcellular organelles that contain the enzymes responsible for these special metabolic pathways. In this study, we use a mathematical model to explore the possible reasons why Salmonella enclose the 1,2-propanediol utilization metabolic pathway within these sophisticated organelle structures. Using our model, we can examine experimentally inaccessible aspects of the system and make predictions to be tested in future experiments. The metabolic benefits that bacteria gain from the microcompartment system may also prove helpful in enhancing bacterial production of fuels, pharmaceuticals, and specialty chemicals. ER -