The cytosolic and mitochondrial branched-chain aminotransferase

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Conway, M. E. ; Hutson, S. (2015)

Key Points\ud • The branched chain aminotransferases (BCAT) are PLP dependent proteins which catalyze the transfer of an amino group from the donor amino acid to α-ketoglutarate, forming glutamate and the respective keto acids. \ud • Structurally the BCAT proteins are homodimers, where the active site between each isoform is largely conserved. \ud • The cytosolic and mitochondrial isoforms show cell and tissue specific expression where the aminotransferase proteins play an integrated role in shuttling metabolites between cells and tissues.\ud • These anaplerotic shuttles interface with core metabolic pathways and protein complexes such as the branched-chain α-keto acid dehydrogenase complex and glutamate dehydrogenase, respectively, indicating a role in the regeneration of key metabolites such as the primary neurotransmitter glutamate. \ud • Leucine is a nutrient signal and involved in mTOR signalling, which controls the synthesis of cellular protein levels.\ud • Moreover, the BCAT proteins have a unique redox active CXXC motif regulated through changes in the redox environment, likely to play a key role in this signalling mechanism. \ud • Site-directed mutagenesis studies have identified that the N-terminal cysteine acts as the ‘redox sensor’ and the C-terminal cysteine as its resolving partner, which permits reversible regulation.\ud • Oxidation, S-nitrosation and S-glutathionylation are important redox regulators of BCAT activity and are reversibly controlled through the glutaredoxin/glutathione system.\ud • Biochemical and X-ray crystallography studies of the redox-active mutant proteins describe the importance of the N-terminal cysteine in the orientation of the substrate and its interaction with key residues of the interdomain loop.
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