Pyruvate dehydrogenase kinase is a kinase that inactivates phosphopyruvate dehydrogenase by using ATP. Another name for pyruvate dehydrogenase is the pyruvate dehydrogenase system, which is a multi-enzyme complex that catalyzes the pyruvate decarboxylation reaction. Dihydrolipoate dehydrogenase and six co-factors, under the synergistic effect of them, convert pyruvate to acetyl and carbon dioxide.
Mechanism
Pyruvate dehydrogenase is inactivated after being phosphorylated by PDK. Generally, the active site of pyruvate dehydrogenase is in a stable and ordered conformation supported by a hydrogen bond network. However, due to the increase in size and the negative charge associated with the phosphorylated residue, phosphorylation of PDK at position 1 caused a spatial conflict with another nearby serine residue. This disrupts the hydrogen bond network and disrupts the conformation of the two phosphorylated rings. These loops prevent the reductive acetylation step, thereby stopping the overall activity of the enzyme. The mechanism of conformational changes and phosphorylation inactivation at sites 2 and 3 is unclear.
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.
Treatment and prognosis
There is no satisfactory method for the treatment of mitochondrial diseases. For patients with PDHC deficiency, a ketogenic diet, lipoic acid, dichloroacetic acid, L-carnitine, and coenzyme Q10 have some effect. Brown et al. Believe that ketogenic diet is the best treatment for patients with PDHC deficiency in men with mild lactic acidosis and normal development. If patients have a response to lipoic acid, TPP therapy can be supplemented with ketogenic diet therapy, which may produce better treatment results. Dichloroacetic acid is considered to be the drug with the greatest potential to reduce lactic acid levels and can stimulate the aerobic oxidation rate limiting step of sugar. However, some scholars believe that although dichloroacetic acid can reduce the lactic acid released by mutant cells through the activation of normal cell enzymes, it has little significance for improving pyruvate oxidation in mutant cells. Among patients with PDHA1 subunit gene deficiency, patients who respond to lipoic acid have a better prognosis. Studies have shown that the concentration of lipoic acid in patients is positively related to the improvement of their neurological symptoms, while patients who do not respond to lipoic acid have a poor prognosis. Gene therapy for patients with a clear genetic diagnosis will be a promising method.
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