Department of Chemical Engineering, Pennsylvania State University, University Park, Pennsylvania, United States of America.
Department of Biology, Washington University, St. Louis, Missouri, United States of America.
PLoS Comput Biol. 2019 Jan 24;15(1):e1006692. doi: 10.1371/journal.pcbi.1006692. eCollection 2019 Jan.
Phototrophic organisms such as cyanobacteria utilize the sun's energy to convert atmospheric carbon dioxide into organic carbon, resulting in diurnal variations in the cell's metabolism. Flux balance analysis is a widely accepted constraint-based optimization tool for analyzing growth and metabolism, but it is generally used in a time-invariant manner with no provisions for sequestering different biomass components at different time periods. Here we present CycleSyn, a periodic model of Synechocystis sp. PCC 6803 metabolism that spans a 12-hr light/12-hr dark cycle by segmenting it into 12 Time Point Models (TPMs) with a uniform duration of two hours. The developed framework allows for the flow of metabolites across TPMs while inventorying metabolite levels and only allowing for the utilization of currently or previously produced compounds. The 12 TPMs allow for the incorporation of time-dependent constraints that capture the cyclic nature of cellular processes. Imposing bounds on reactions informed by temporally-segmented transcriptomic data enables simulation of phototrophic growth as a single linear programming (LP) problem. The solution provides the time varying reaction fluxes over a 24-hour cycle and the accumulation/consumption of metabolites. The diurnal rhythm of metabolic gene expression driven by the circadian clock and its metabolic consequences is explored. Predicted flux and metabolite pools are in line with published studies regarding the temporal organization of phototrophic growth in Synechocystis PCC 6803 paving the way for constructing time-resolved genome-scale models (GSMs) for organisms with a circadian clock. In addition, the metabolic reorganization that would be required to enable Synechocystis PCC 6803 to temporally separate photosynthesis from oxygen-sensitive nitrogen fixation is also explored using the developed model formalism.
光养生物，如蓝细菌，利用太阳的能量将大气中的二氧化碳转化为有机碳，从而导致细胞代谢的昼夜变化。通量平衡分析是一种广泛接受的基于约束的优化工具，用于分析生长和代谢，但它通常以不变的方式使用，没有规定在不同时间间隔隔离不同的生物质成分。在这里，我们提出了CycleSyn，这是一种分段为 12 个时间点模型（TPM）的 Synechocystis sp. PCC 6803 代谢的周期性模型，每个 TPM 的持续时间为两小时，跨越了一个 12 小时的光/12 小时的暗周期。所开发的框架允许代谢物在 TPM 之间流动，同时记录代谢物水平，并且只允许利用当前或以前产生的化合物。这 12 个 TPM 允许纳入时间相关的约束条件，以捕捉细胞过程的周期性。根据时间分段的转录组数据对反应施加限制，可以模拟作为单个线性规划（LP）问题的光养生长。该解决方案提供了 24 小时周期内随时间变化的反应通量以及代谢物的积累/消耗。探讨了生物钟驱动的代谢基因表达的昼夜节律及其代谢后果。预测的通量和代谢物池与关于 Synechocystis PCC 6803 中光养生长的时间组织的已发表研究一致，为构建具有生物钟的生物体的时间分辨基因组规模模型（GSM）铺平了道路。此外，还使用开发的模型形式探索了使 Synechocystis PCC 6803 能够在时间上分离光合作用和对氧气敏感的氮固定所需的代谢重组。
