Pyruvate dehydrogenase complex

From energy generation to novel drug target

Energy generation in prokaryotic and eukaryotic organisms is a highly efficient, multistep and tightly regulated process. Normally, glucose is metabolized initially via the glycolytic pathway, generating pyruvate and small amounts of ATP. To harness the full energy content of glucose, pyruvate undergoes further oxidation in the Krebs cycle, generating large amounts of ATP required for cellular functions. The key enzyme complex bridging these two processes is known as the pyruvate dehydrogenase complex, or PDC, and is the subject of a minireview published in the Journal of Biological Chemistry recently.
 
In this review, Mulchand S. Patel and colleagues have compiled the latest developments in PDC research, compared PDC structural and regulatory mechanisms in bacteria and in humans, and considered their implications on human health. Patel, a distinguished professor and associate dean at the State University of New York at Buffalo, and Frank Jordan, a professor at Rutgers University, Newark, have collaborated for several years to understand the evolutionary changes leading to the functioning of these multienzyme complexes, have used novel methods to identify different steps in the catalytic reactions, and have elucidated high-resolution structures of several PDC component proteins.
 
PDC is composed of three distinct catalytic enzymes, namely pyruvate dehydrogenase, dihydrolipoamide acetyltransferase and dihydrolipoamide dehydrogenase, which work in tandem to convert pyruvate in to acetyl-CoA, CO2 and NADH (H+). Acetyl-CoA is then used as a substrate in the Krebs cycle to generate ATP or used for biosynthetic processes, such as lipid formation. The unique interactions among these components in the complex ensure efficiency as well as regulation of the aforementioned metabolic process. The downside of the human complex is that even a minor change in the complex can have a profound impact on health conditions ranging from neurodegenerative disorders to obesity, type-2 diabetes, and some types of cancer.
 
In contrast with E. coli PDC, mammalian PDCs have an additional structural component (a binding protein) and specific kinases and phosphatases for stringent regulation. The activity of human PDC is tightly regulated by tissue-specific kinases and phosphatases, which respond to different nutritional and disease states. For example, some cancer cells have activated levels of the kinase1, resulting in inhibition of PDC, which is not favorable for normal cells but is suitable for cancer-cell survival and growth. By studying structural and compositional aspects of the human PDC and its regulation, one can exploit mechanistic differences for therapeutic advantages to combat cancer and other human diseases.

Alok UpadhyayAlok Upadhyay (alok7930@gmail.com) is a postdoctoral associate at Fox Chase Cancer Center. His major research area is Notch signaling regulation during cell fate decisions and neural crest stem cell development. Follow him on Twitter at www.twitter.com/alok7667.