Roche T E, Hiromasa Y
Department of Biochemistry, Kansas State University, Chalmers Hall, Manhattan, KS 66506, USA.
Cell Mol Life Sci. 2007 Apr;64(7-8):830-49. doi: 10.1007/s00018-007-6380-z.
The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2 60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2, which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.
丙酮酸脱氢酶复合体（PDC）处于活性形式的比例会因特定的丙酮酸脱氢酶激酶同工酶（PDK1、PDK2、PDK3和PDK4）的活性而降低。通过与二氢硫辛酰胺乙酰转移酶（E2 60聚体）的内部硫辛酰胺结构域（L2）结合，PDK能迅速接近其与E2结合的PD底物。广泛分布的PDK2的E2增强活性受ADP从其C端催化结构域解离的限制，而丙酮酸与N端调节（R）结构域结合会进一步减缓这种解离。通过PDC反应的逆向过程，NADH和乙酰辅酶A将L2的硫辛酰胺基团还原乙酰化，该基团与R结构域结合，并通过加速ADP解离来刺激PDK2活性。在丙酮酸或硫辛酰胺结合位点结合的合成PDK抑制剂对PDC的激活减少了心脏缺血期间的损伤，并降低了胰岛素抵抗动物的血糖。PDC激活还会触发癌细胞的凋亡，这些癌细胞会选择性地将葡萄糖转化为乳酸。
