131 5 Establishing a peroxisomal β-oxidation computational kinetic model to understand the effects of amino-acid restriction INTRODUCTION Peroxisomes are small organelles, found in practically all eukaryotic cells and highly abundant in the liver of mammals1. These single-membrane organelles present a wide range of functions, including hydrogen peroxide and lipid metabolism2. Given the importance of peroxisomes, impairments in these organelles lead to metabolic disorders3. Similar to mitochondria, peroxisomes can metabolize fatty acids to generate ATP, in a process known as β-oxidation. While mitochondria are in charge of metabolizing the majority of fatty acids, including those with long, medium and short acyl chains, peroxisomes metabolize a wider range of substrates2. These less studied organelles metabolize very-long and long-chain fatty acids (VL/LCFA), as well as dicarboxylic fatty acids, 2-methyl-branched-chain fatty acids, and CoA esters of eicosanoids and bile acid intermediates4. Peroxisomes have even been described to metabolize medium-chain fatty acids, illustrating their versatility and overlapping function with mitochondria5. Peroxisomal β-oxidation is essential for the shortening of fatty acids that are poor substrates for mitochondria. It has been suggested that the peroxisomal β-oxidation has a preference for monounsaturated fatty acids when compared to their respective saturated forms6,7. Peroxisomal β-oxidation also has the ability to oxidize polyunsaturated fatty acids (PUFAs)8,9. Peroxisomes contain two systems of enzymes to perform the β-oxidization of fatty acids. The first set of enzymes, which are induced by PPAR-α activation, is in charge of metabolizing straight-chain acyl-CoAs to produce acetyl-CoA. The PPAR-α non-inducible system can metabolize 2-methyl-branched-chain acyl-CoAs into propionyl-CoA10. This should not be confused with fatty-acid α-oxidation, which oxidizes 3-methyl-branched acyl-CoA species11. In both cases, the peroxisomal β-oxidation consists of four reactions: 1) oxidation of the acylCoA into a 2-enoyl-CoA by introduction of a double bond between C2 and C3, 2) hydration to form a 3-hydroxyacyl-CoA, 3) a dehydrogenation to form 3-oxoacyl-CoA and 4) a thiolytic cleavage that produces a shortened acyl-CoA and acetyl-CoA or propionyl-CoA depending on the starting substrate12. Prior to the metabolization of the fatty acids, these need to be activated into their CoA form. Detailed kinetic models are highly useful computational tools used to decipher the functioning of biological processes. Kinetic models permit researchers to predict metabolite concentrations as well as fluxes over time of a given pathway. Since they are based on detailed enzyme kinetic parameters, model simulations can be used to predict the impact of specific mutations,
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