Cortassa Sonia, Caceres Viviane, Bell Lauren N, O'Rourke Brian, Paolocci Nazareno, Aon Miguel A
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Metabolon, Inc., Durham, North Carolina.
Biophys J. 2015 Jan 6;108(1):163-72. doi: 10.1016/j.bpj.2014.11.1857.
We describe a believed-novel procedure for translating metabolite profiles (metabolome) into the set of metabolic fluxes (fluxome) from which they originated. Methodologically, computational modeling is integrated with an analytical platform comprising linear optimization, continuation and dynamic analyses, and metabolic control. The procedure was tested with metabolite profiles obtained from ex vivo mice Langendorff-heart preparations perfused with glucose. The metabolic profiles were analyzed using a detailed kinetic model of the glucose catabolic pathways including glycolysis, pentose phosphate (PP), glycogenolysis, and polyols to translate the glucose metabolome of the heart into the fluxome. After optimization, the ability of the model to simulate the initial metabolite profile was confirmed, and metabolic fluxes as well as the structure of control and regulation of the glucose catabolic network could be calculated. We show that the step catalyzed by phosphofructokinase together with ATP demand and glycogenolysis exert the highest control on the glycolytic flux. The negative flux control exerted by phosphofructokinase on the PP and polyol pathways revealed that the extent of glycolytic flux directly affects flux redirection through these pathways, i.e., the higher the glycolytic flux the lower the PP and polyols. This believed-novel methodological approach represents a step forward that may help in designing therapeutic strategies targeted to diagnose, prevent, and treat metabolic diseases.
我们描述了一种据信新颖的方法，用于将代谢物谱（代谢组）转化为其起源的代谢通量集（通量组）。在方法上，计算建模与一个分析平台相结合，该平台包括线性优化、连续和动态分析以及代谢控制。该方法用从灌注葡萄糖的离体小鼠Langendorff心脏制剂获得的代谢物谱进行了测试。使用包括糖酵解、磷酸戊糖（PP）、糖原分解和多元醇的葡萄糖分解代谢途径的详细动力学模型分析代谢谱，以将心脏的葡萄糖代谢组转化为通量组。优化后，证实了模型模拟初始代谢物谱的能力，并能够计算代谢通量以及葡萄糖分解代谢网络的控制和调节结构。我们表明，磷酸果糖激酶催化的步骤与ATP需求和糖原分解一起对糖酵解通量施加最高控制。磷酸果糖激酶对PP和多元醇途径施加的负通量控制表明，糖酵解通量的程度直接影响通过这些途径的通量重定向，即糖酵解通量越高，PP和多元醇越低。这种据信新颖的方法学方法是向前迈出的一步，可能有助于设计针对代谢疾病诊断、预防和治疗的治疗策略。
