Pyruvate dehydrogenase kinase is a kinase that inactivates phosphopyruvate dehydrogenase by using ATP. Therefore, PDK is involved in the regulation of pyruvate dehydrogenase complex with pyruvate dehydrogenase as the first component. Both PDK and pyruvate dehydrogenase complexes are located in the mitochondrial matrix of eukaryotes. The role of this complex is to convert pyruvate (a product of glycolysis in the cytoplasm) to acetyl-CoA, and then oxidize to generate energy in the mitochondria in the citric acid cycle. By down-regulating the activity of this complex, PDK will reduce the oxidation of pyruvate in the mitochondria and increase the conversion of pyruvate to lactic acid in the cytoplasm. The opposite effect of PDK, that is, phosphorylation and activation of pyruvate dehydrogenase by phosphoprotein phosphatase catalytic.
Production
The hydroxyethylthiamine diphosphate produced by the decarboxylation of pyruvate reacts with lipoic acid to form acetyldihydrolipoic acid, the acetyl group is transferred, the dihydrolipoic acid is oxidized, and the hydrogen is finally passed to the enzyme. In this reaction cycle, except for acetyl and NAD, they are tightly bound to enzymes. The enzyme complex can be extracted from animal tissues and bacteria, but more research has been done on purification from E. coli. The complex is a polygon with a diameter of about 30 nanometers, and it seems that each of the three enzymes contains 24 molecules. Physiologically, it is extremely important as a stage of forming acetyl from pyruvate when the oxygen-consuming sugar is decomposed. A substance very similar to this enzyme complex is the complex of α-ketoglutarate dehydrogenase.
Pyruvate dehydrogenase complex (PDHC)
Pyruvate dehydrogenase complex (PDHC) is a multi-enzyme complex located in the mitochondrial matrix. PDHC is a group of rate-limiting enzymes that catalyze the irreversible oxidative decarboxylation of pyruvate into acetyl-CoA, linking the aerobic oxidation of sugar with the tricarboxylic acid cycle and oxidative phosphorylation, and its role in the energy metabolism of the mitochondrial respiratory chain Important.
PDHC mutations
The research on the PDHA1 gene is in-depth. To date, 82 mutations have been found, most of which are nonsense or missense mutations, with 43 mutations. Except for exon 2, mutations have been found, including exons 3, 7, 8, and 11 Most common. While nonsense or missense mutations are more common in exons 3, 7, and 8, deletion and insertion mutations are mainly found in exons 10 and 11. The vast majority of male patients carry nonsense or missense mutations, whereas women carry deletion or insertion mutations. Naito et al. Reported that the PDHA1 gene mutations in patients who responded to lipoic acid include the following loci: H44R, R88S, G89S, R263G, V389fs, V71A, and C101F, of which H44R, V71A, R88S, and G89S are located on exon 3, suggesting PDHA1 Patients with exon 3 mutations responded better to lipoic acid treatment. The R263G mutation in exon 8 of PDHA1 gene was the most common mutation in 11 patients.
Clinical manifestation
PDHC deficiency is one of the most common causes of mitochondrial energy metabolism disorders. It is also the most common cause of childhood lactic acidosis and early-onset degenerative neurodegenerative disease. Almost all acetyl-CoA in the brain is derived from pyruvate, so the lack of PDHC often causes a variety of neurological damage. According to the standards proposed by Robinson et al., The clinical manifestations of patients can be divided into three levels, level Ⅰ: patients have severe lactic acidemia early after birth, PDHC activity is extremely low, and male children develop more symptoms than embryonic stages, leading to abortion, Stillbirth, congenital striatum hypoplasia, and hypoxic-ischemic encephalopathy often die of lactic acidosis early in the newborn. Grade Ⅱ: Lactic acidemia is milder than grade Ⅰ, normal at birth, retarded mental movement and physical development, more children die than infants, and a few survive to their teens. Grade Ⅲ: Patients have mild lactic acidemia, and the residual survival of PDHC is more than 20%. The most common manifestations of neuropathological examinations in patients with E3BP deficiency are Leigh syndrome, thinned or missing corpus callosum, and basal ganglia symmetrical necrotic lesions; meanwhile, patients with E3BP deficiency have relatively high residual survival of PDHC enzyme.
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