title: Nonlinear dynamics of eucaryotic pyruvate dehydrogenase multienzyme complex: decarboxylation rate, oscillations, and multiplicity.
abstract: Pyruvate conversion to acetyl-CoA by the pyruvate dehydrogenase (PDH) multienzyme complex is known as a key node in affecting the metabolic fluxes of animal cell culture. However, its possible role in causing possible nonlinear dynamic behavior such as oscillations and multiplicity of animal cells has received little attention. In this work, the kinetic and dynamic behavior of PDH of eucaryotic cells has been analyzed by using both in vitro and simplified in vivo models. With the in vitro model the overall reaction rate (nu(1)) of PDH is shown to be a nonlinear function of pyruvate concentration, leading to oscillations under certain conditions. All enzyme components affect nu(1) and the nonlinearity of PDH significantly, the protein X and the core enzyme dihydrolipoamide acyltransferase (E2) being mostly predominant. By considering the synthesis rates of pyruvate and PDH components the in vitro model is expanded to emulate in vivo conditions. Analysis using the in vivo model reveals another interesting kinetic feature of the PDH system, namely, multiple steady states. Depending on the pyruvate and enzyme levels or the operation mode, either a steady state with high pyruvate decarboxylation rate or a steady state with significantly lower decarboxylation rate can be achieved under otherwise identical conditions. In general, the more efficient steady state is associated with a lower pyruvate concentration. A possible time delay in the substrate supply and enzyme synthesis can also affect the steady state to be achieved and leads to oscillations under certain conditions. Overall, the predictions of multiplicity for the PDH system agree qualitatively well with recent experimental observations in animal cell cultures. The model analysis gives some hints for improving pyruvate metabolism in animal cell culture.
authors.affiliation: GBF-Gesellschaft für Biotechnologische Forschung mbH, Biochemical Engineering Division, Mascheroder Weg 1, 38124 Braunschweig, Germany.
authors.forename: An-Ping
authors.initials: AP
authors.lastname: Zeng
authors.forename: Jayant
authors.initials: J
authors.lastname: Modak
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Deckwer
mesh_terms: D000105:Acetyl Coenzyme A / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D003653:Decarboxylation; D005057:Eukaryotic Cells / Q000201:enzymology*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D010507:Periodicity; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid