DataSheet1_Modeling the effect of daytime duration on the biosynthesis of terpenoid precursors.zip

Terpenoids are valued chemicals in the pharmaceutical, biotechnological, cosmetic, and biomedical industries. Biosynthesis of these chemicals relies on polymerization of Isopentenyl di-phosphate (IPP) and/or dimethylallyl diphosphate (DMAPP) monomers, which plants synthesize using a cytosolic mevalonic acid (MVA) pathway and a plastidic methyleritritol-4-phosphate (MEP) pathway. Circadian regulation affects MVA and MEP pathway activity at three levels: substrate availability, gene expression of pathway enzymes, and utilization of IPP and DMAPP for synthesizing complex terpenoids. There is a gap in understanding the interplay between the circadian rhythm and the dynamics and regulation of the two pathways. In this paper we create a mathematical model of the MVA and MEP pathways in plants that incorporates the effects of circadian rhythms. We then used the model to investigate how annual and latitudinal variations in circadian rhythm affect IPP and DMAPP biosynthesis. We found that, despite significant fluctuations in daylight hours, the amplitude of oscillations in IPP and DMAPP concentrations remains stable, highlighting the robustness of the system. We also examined the impact of removing circadian regulation from different parts of the model on its dynamic behavior. We found that regulation of pathway substrate availability alone results in higher sensitivity to daylight changes, while gene expression regulation alone leads to less robust IPP/DMAPP concentration oscillations. Our results suggest that the combined circadian regulation of substrate availability, gene expression, and product utilization, along with MVA- and MEP-specific regulatory loops, create an optimal operating regime. This regime maintains pathway flux closely coupled to demand and stable across a wide range of daylight hours, balancing the dynamic behavior of the pathways and ensuring robustness in response to cellular demand for IPP/DMAPP.萜类化合物（Terpenoids）是制药、生物技术、化妆品及生物医学产业中的高价值化学品。此类化合物的生物合成依赖于异戊烯基二磷酸（Isopentenyl di-phosphate, IPP）与/或二甲基烯丙基二磷酸（dimethylallyl diphosphate, DMAPP）单体的聚合；植物可通过胞质甲羟戊酸（mevalonic acid, MVA）途径与质体甲基赤藓醇-4-磷酸（methyleritritol-4-phosphate, MEP）途径合成这两类单体。昼夜节律调控可从三个层面影响MVA与MEP途径的活性：底物可用性、途径酶的基因表达水平，以及利用IPP与DMAPP合成复杂萜类化合物的过程。目前学界对昼夜节律与这两条途径的动态变化及调控之间的相互作用仍存在认知空白。本文构建了植物体内MVA与MEP途径的数学模型，该模型整合了昼夜节律的调控效应。随后，研究团队利用该模型探究了昼夜节律的年度及纬度差异如何影响IPP与DMAPP的生物合成过程。研究结果显示，尽管日照时长存在显著波动，但IPP与DMAPP浓度的振荡振幅仍保持稳定，这凸显了该系统的鲁棒性。此外，本研究还考察了移除模型不同模块的昼夜节律调控对其动态行为的影响。结果表明，仅对途径底物可用性进行调控会使系统对日照变化的敏感性显著升高，而仅通过基因表达实施调控则会导致IPP/DMAPP浓度振荡的鲁棒性下降。本研究结果提示，底物可用性、基因表达与产物利用的联合昼夜节律调控，结合MVA与MEP途径特异性的调控环路，共同构建了最优的运行模式。该模式可使途径代谢通量与细胞代谢需求紧密耦合，并在广泛的日照时长范围内保持稳定，同时平衡了两条途径的动态行为，确保了系统在响应IPP与DMAPP的细胞需求时具备鲁棒性。