Overview of Structure and Function of PDH
The pyruvate dehydrogenase complex (PDH) is at the centre of aerobic carbohydrate metabolism. It is localized in the matrix space of mitochondria where it catalyzes the irreversible oxidative decarboxylation of pyruvate entering the organelle to produce acetyl-CoA, NADH and CO2. Thus it links and regulates the flow of energy in cells by determining when pyruvate should be used for oxidative phosphorylation versus "neutralized" to lactic acid to allow continued glycolysis. At the same time the control of acetyl Co-A directly influences fatty acid oxidation and production of ketone bodies.
PDH is a large complex (MW around 9 MDa) consisting of multiple copies of three enzymes: pyruvate dehydrogenase (E1), dihydrolipoamide transacetylase (E2) and dihydrolipoamide dehydrogenase (E3). The E1 enzyme is a tetramer comprised of two α and two β subunits and is present in 30 copies. In the mammalian enzyme, 60 copies of E2 forms the core with the other subunits organized regularly around its periphery. Intermediates of one enzyme are passed physically to become substrate for the next in a reaction sequence that is a prototype substrate channeling mechanism. In addition, one structural subunit has been identified, the E3 binding protein. This protein supports the interactions between the E2 and E3 subunits.
The activity of PDH is regulated by reversible phosphorylation of three serine residues on the E1α subunit. The phosphorylation of these sites is catalyzed by PDH kinases (PDK). There are four known isoforms of PDKs that are distributed differently in tissues. Their expressions are regulated differently by factors such as starvation, hypoxia and utilization of glucose and fatty acids in various tissues. In addition, transcription regulators such as PGC-1α, retinoic acid and the glucocorticoid receptor are involved.
Dephosporylation to restore the activity of PDH is catalyzed by PDH phosphatases (PDP). There are two known isoforms of PDPs, which are expressed differently in various tissues; PDP1 is present in high levels in skeletal muscle and PDP2 in liver and adipocytes.
PDH deficiencies, diabetes, starvation, sepsis, and possibly Alzheimer's have been linked to altered PDH functioning.
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