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Background
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BCAA's are essential AA that must be obtained through external food. BCAA's serve as building blocks in complex proteins, and also a sources for the biosynthesis of sterol, keto-bodies, and glucose. The BCAA are metabolized by an enzyme complex Branched chain a-ketoacid dehydrogenase. Branched-chain α -ketoacid dehydrogenase kinase (BCKD1 kinase) is a mitochondrial multi-enzyme complex conformed by three components: a decarboxylase (E1) composed of two alpha and two beta subunits, a dihydrolipoyl transacylase (E2, DBT gene) and a dihydrolipoamide dehydrogenase (E3, DLD gene). The complex also contains two regulatory enzymes, a kinase and a phophotase. Impaired function of BCKD kinase has been linked to maple syrup urine disease (MSUD). The first step in BCAA catabolism is the conversion of BCAA into branched-chain α -ketoacids (BCKA's) by branched-chain amino transferase. The BCAAs are then decarboxylated by the BCKD-complex in the liver and eventually degraded into acetyl-coenzyme A (acetyl CoA). Several MSUD-causing mutations have been identified in genes encoding catalytic subunits of the BCKD complex, including missense and nonsense substitutions and small insertions/deletions, only four large deletions have been reported as causative of MSUD, all of them located in the DBT gene. The BCKD complex is genetically linked with the pyruvate dehydrogenase complex (PDH) because they share extensive homology in their subunit composition and regulation. Like PDH, BCKD holoenzyme contains 24 copies of catalytic subunits E2/E3 and an equal number of regulatory subunits E1α and E1β. At low BCAA levels, E1α is hyperphosphorylated by BCKD kinase, leading to lower BCKD activity and reduced loss of BCAA. At a high BCAA level, E1α is dephosphorylated by BCKD phosphatase, leading to induced BCKD activity and the removal of excess BCAA. BCKD phosphorylation by BCKD and dephosphorylation is critical to BCAA homeostasis .
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