Basallo Oriol, Lucido Abel, Sorribas Albert, Marin-Sanguino Alberto, Vilaprinyo Ester, Martinez Emilce, Eleiwa Abderrahmane, Alves Rui
Systems Biology Group, Department Ciències Mèdiques Bàsiques, Faculty of Medicine, Universitat de Lleida, Lleida, Spain.
Institut de Recerca Biomédica IRBLleida (IRBLleida), Lleida, Spain.
Front Plant Sci. 2024 Nov 14;15:1465030. doi: 10.3389/fpls.2024.1465030. eCollection 2024.
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.
萜类化合物是制药、生物技术、化妆品和生物医学行业中具有重要价值的化学物质。这些化学物质的生物合成依赖于异戊烯基二磷酸（IPP）和/或二甲基烯丙基二磷酸（DMAPP）单体的聚合，植物通过细胞质甲羟戊酸（MVA）途径和质体甲基赤藓糖醇-4-磷酸（MEP）途径合成这些单体。昼夜节律调节在三个层面影响MVA和MEP途径的活性：底物可用性、途径酶的基因表达以及IPP和DMAPP用于合成复杂萜类化合物的利用情况。在理解昼夜节律与这两条途径的动态和调节之间的相互作用方面存在差距。在本文中，我们创建了一个植物中MVA和MEP途径的数学模型，该模型纳入了昼夜节律的影响。然后，我们使用该模型研究昼夜节律的年度和纬度变化如何影响IPP和DMAPP的生物合成。我们发现，尽管日照时长存在显著波动，但IPP和DMAPP浓度的振荡幅度保持稳定，突出了该系统的稳健性。我们还研究了从模型的不同部分去除昼夜节律调节对其动态行为的影响。我们发现，仅对途径底物可用性进行调节会导致对日照变化的更高敏感性，而仅对基因表达进行调节会导致IPP/DMAPP浓度振荡的稳健性较低。我们的结果表明，底物可用性、基因表达和产物利用的联合昼夜节律调节，以及MVA和MEP特异性调节环，创造了一种最佳运行状态。这种状态使途径通量紧密耦合到需求，并在广泛的日照时长范围内保持稳定，平衡了途径的动态行为，并确保了对细胞对IPP/DMAPP需求的响应的稳健性。
