期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 64, 期 7-8, 页码 830-849出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-007-6380-z
关键词
pyruvate dehydrogenase; pyruvate dehydrogenase kinase; lipoyl domain; glucose; energy metabolism; starvation; diabetes; heart ischemia
资金
- NIDDK NIH HHS [DK18320] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK018320, R55DK018320] Funding Source: NIH RePORTER
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.
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