Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models

Abstract

Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.

Figure 1

A schematic representation of the reactions included in the computer model of glycolysis in Trypanosoma brucei [18]. Reaction numbers indicate: 1. glucose transport; 2. hexokinase; 3. phosphoglucose isomerase; 4. phosphofructokinase; 5. aldolase; 6. triose-phosphate isomerase; 7. glyceraldehyde-3-phosphate dehydrogenase; 8. phosphoglycerate kinase; 9. phosphoglycerate mutase; 10. enolase; 11. pyruvate kinase; 12. pyruvate transport; 13. glycerol-3-phosphate dehydrogenase; 14. glycerol-3-phosphate oxidase (a combined process of mitochondrial glycerol-3-phosphate dehydrogenase and trypanosome alterative oxidase; 15. glycerol kinase; 16. combined ATP utilization; 17. glycosomal adenylate kinase; 18. cytosolic adenylate kinase. Question marks indicate uncharacterized transport processes. Abbreviations of metabolite names: Glc-6-P: glucose 6-phosphate; Fru-6-P: fructose 6-phosphate; Fru-1,6-BP: fructose 1,6-bisphosphate; DHAP: dihydroxyacetone phosphate; Gly-3-P: glycerol 3-phosphate; GA-3-P: glyceraldehyde 3-phosphate; 1,3-BPGA: 1,3-bisphosphoglycerate; 3-PGA: 3-phosphoglycerate; 2-PGA: 2-phosphoglycerate; PEP: phospho-enolpyruvate.

Figure 2

A schematic representation of the reactions included in the computer model of glycolysis in Saccharomyces cerevisiae [10]. Reaction numbers and metabolite abbreviations have the same meaning as in Fig. 1. Additional reactions included are pyruvate decarboxylase (19), alcohol dehydrogenase (20) and branches consisting of multiple enzymes towards trehalose (21), glycogen (22), glycerol (23) and succinate (24). AcAld denotes acetaldehyde.

Figure 3

A schematic representation of the reactions included in the computer model of glycolysis in skeletal muscle in the original version by Lambeth and Kushmerick [12]. Reaction numbers and metabolite abbreviations have the same meaning as in Fig. 1. Additional reactions included are glycogen phosphorylase (25), phosphoglucomutase (26), lactate dehydrogenase (27) and creatine kinase (28).