Institute of Biomedical Sciences,
Academia Sinica
Nankang, Taipei 11529, Taiwan R.O.C.
Tel: 886-2-2652-3036

886-2-27899030

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Update: Jan. 22. 2008
---by Ching-Yu Chou

Structure and Function of Branched-Chain α-Ketoacid Dehydrogenase Complex


  •     The mammalian branched-chain α-ketoacid dehydrogenase complex (BCKDC) is a member of the highly conserved a-ketoacid dehydrogenase complexes comprising pyruvate dehydrogenase complex (PDC), a-ketoglutarate dehydrogenase complex (KGDC) and the BCKDC with similar structure and function. The BCKDC catalyzes the oxidative decarboxylation of branched-chain a-ketoacids derived from leucine, isoleucine and valine to give rise to branched-chain acyl-CoAs. The reaction products are indirectly channeled into the Krebs cycle or linked to lipid and cholesterol biosynthesis. In patients with inherited maple syrup urine disease (MSUD), the activity of the BCKDC is deficient, which results in the accumulation of branched-chain a-ketoacids. This metabolic block has severe clinical consequences including often-fatal ketoacidosis, neurological derangement and mental retardation in survivors.

        The human BCKDC is a 4-million dalton catalytic machine. There are three catalytic components in human BCKDC: a heterotetrameric (a2b2) branched-chain a-ketoacid decarboxylase (E1), a homo-24 meric dihydrolipoyl transacylase (E2), and a homodimeric dihydrolipoamide dehydrogenase (E3). The BCKDC is organized around the cubic E2 core, to which 12 copies of E1, and unspecified copies of E3, the BCKD kinase and the BCKD phosphatase are attached through ionic interactions.

        The E2 subunit contains three separate domains, the lipoyl-bearing domain (hbLBD), the subunit-binding domain (hbSBD) and the core domain that are utilized to carry out E2 functions in substrate channeling and recognition. We have employed multidimensional heteronuclear NMR techniques to study the structure, dynamics, and function of E2 subunit.

  • Sequence and secondary structure elements of hbLBD and hbSBD construct. Sequence for hbLBD is underlined in blue and sequence for hbSBDc is underlined in red. Linker between two domains is marked in gray.



hbLBD

hbSBD

Publications


  1. Chang, C.F., Chou, H.T., Lin, Y.J., Lee, S.J., Chuang, J.L., Chuang,, D.T. and Huang, T.-h.*
    Structure of the Subunit Binding Domain and Dynamics of the “Di-domain” Region from the Core of Human Branched-Chain α-Ketoacid Dehydrogenase Complex J. Biol. Chem. 281 (38), 28345-53. (2006)

  2. Kouza, M., Chang, C.-F., Hayryan, S., Yu, T.H., Li, M.S., Huang, T.-h.* and Hu, C.K*.
    Folding of the protein domain hbSBD. Biophys. J. 89, 3353-3361. (2005)

  3. Naik, M. and Huang, T.-h.*
    Conformational Stability and Thermodynamic Characterization of the Lipoic Acid Bearing Domain of Human Mitochondrial Branched Chain a-Ketoacid Dehydrogenase. Protein Sci. 13, 2483-2492. (2004)

  4. Naik, M., Chang, Y.C. and Huang, T.-h.*
    Folding kinetics of the lipoic acid-bearing domain of human mitochondrial branched chain a-ketoacid dehydrogenase complex. FEBS Lett. 530, 133-138. (2002)

  5. Chang, C.F., Chou, H.T., Chuang, J., Chuang, D. and Huang, T.-h.*
    Solution Structure and Dynamics of the Lipoyl Acid-Bearing Domain of the E2 component of Human Mitochondria Branched-Chain Alpha-Ketoacid Dehydrogenase. J. Biol. Chem. 277, 15865-15873. (2002)