Myra E. Conway
The cytosolic and mitochondrial branched-chain aminotransferase
Conway, Myra E.; Hutson, Susan
Victor R. Preedy
Vinood B. Patel
• 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.
• Structurally the BCAT proteins are homodimers, where the active site between each isoform is largely conserved.
• 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.
• 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.
• Leucine is a nutrient signal and involved in mTOR signalling, which controls the synthesis of cellular protein levels.
• 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.
• 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.
• Oxidation, S-nitrosation and S-glutathionylation are important redox regulators of BCAT activity and are reversibly controlled through the glutaredoxin/glutathione system.
• 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.
|Publication Date||Oct 15, 2015|
|Peer Reviewed||Peer Reviewed|
|Series Title||Nutrition and Health|
|Book Title||Branched Chain Amino Acids in Clinical Nutrition|
|Institution Citation||Conway, M. E., & Hutson, S. (2015). The cytosolic and mitochondrial branched-chain aminotransferase. In R. Rajendram, V. R. Preedy, & V. B. Patel (Eds.), Branched Chain Amino Acids in Clinical Nutrition, 25-40. Springer. https://doi.org/10.1007/978-1-4939-1923-9_3|
|Keywords||BCATm, BCATc, brain-glutamate metabolism, metabolite shuttling, BCKDC, redox-regulation, S-nitrosylation and X-ray crystallography|