Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload.

Karen van Eunen, Sereh M J Simons, Albert Gerding, Aycha Bleeker, Gijs den Besten, Catharina M L Touw, Sander M Houten, Bert K Groen, Klaas Krab, Dirk-Jan Reijngoud, Barbara M Bakker

PLoS computational biology 2013

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Fatty-acid metabolism plays a key role in acquired and inborn metabolic diseases. To obtain insight into the network dynamics of fatty-acid β-oxidation, we constructed a detailed computational model of the pathway and subjected it to a fat overload condition. The model contains reversible and saturable enzyme-kinetic equations and experimentally determined parameters for rat-liver enzymes. It was validated by adding palmitoyl CoA or palmitoyl carnitine to isolated rat-liver mitochondria: without refitting of measured parameters, the model correctly predicted the β-oxidation flux as well as the time profiles of most acyl-carnitine concentrations. Subsequently, we simulated the condition of obesity by increasing the palmitoyl-CoA concentration. At a high concentration of palmitoyl CoA the β-oxidation became overloaded: the flux dropped and metabolites accumulated. This behavior originated from the competition between acyl CoAs of different chain lengths for a set of acyl-CoA dehydrogenases with overlapping substrate specificity. This effectively induced competitive feedforward inhibition and thereby led to accumulation of CoA-ester intermediates and depletion of free CoA (CoASH). The mitochondrial [NAD⁺]/[NADH] ratio modulated the sensitivity to substrate overload, revealing a tight interplay between regulation of β-oxidation and mitochondrial respiration.

Citation

Karen van Eunen, Sereh M J Simons, Albert Gerding, Aycha Bleeker, Gijs den Besten, Catharina M L Touw, Sander M Houten, Bert K Groen, Klaas Krab, Dirk-Jan Reijngoud, Barbara M Bakker. Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload. PLoS computational biology. 2013;9(8):e1003186