Modelling of metabolic control by Short Chain Fatty Acids at the level of the functional proteome

ABSTRACT Background: Fibre fermentation by bacteria in the luminal colon leads to the production of short chain fatty acids (SCFAs), which have been thought to alter global protein acetylation patterns depending on their concentration levels through their role as lysine deacetylase inhibitors. Aim: Perform a representation analysis on a proteomic dataset. Model the action of increasing concentrations of acetate, butyrate, propionate and glucose on acetyl-CoA and CoA and to simulate the effect of a time course on the levels of butyryl-CoA, propionyl-CoA, acetyl-CoA and CoA. Methods: An existing mitochondrial proteomic dataset was examined to detect which metabolic enzymes in glycolysis, the TCA cycle, β-oxidation and pyruvate metabolism are acetylated. Free access software (DAVID, Uniprot identifier, KEGG, and Reactome) was used to generate a representation and acetylation map of these metabolic pathways. Enrichment scores of functional annotations in gene ontology terms, pathway percentage coverage and matching representation of these pathways were also elucidated by using this software. Two models developed by Bernard Corfe, butyrate_v3-1 and SCFA uptake and oxidation v4, were used to simulate the effect of a time course and to model the action of increasing concentrations of SCFAs and glucose in COPASI. Results: Changes in the acetylation patterns of metabolic enzymes were reflected in terms of enrichment scores, percentage coverage, and matching representation. The best model to simulate the effect of a time course was SCFA Uptake and Oxidation v4 model, whereas butyrate_v3-1 model was the best to simulate the action of increasing concentrations of SCFAs and glucose. Conclusions: SCFAs produce changes in the acetylation patterns of metabolic enzymes. There is an effect of a time course on the levels of butyryl-CoA, propionyl-CoA, acetyl-CoA and CoA. Increasing concentrations of SCFAs and glucose also have an effect on CoA and acetyl-CoA levels. Since there are discrepancies between the simulations and in vitro data, further studies are needed to elucidate the role of a time course and increasing concentrations of SCFAs and to validate the models used