A New Serine Protease in Mitochondria of Erythroblasts and Pyridoxine Responsive Anemia
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Apo-ALA synthetase obtained from patients with pyridoxine responsive anemia showed marked increment of the susceptibility to the new serine protease in mitochondria of erythroblasts, Almost all features characteristic to this anemia could be ascribed to this result.<BR>Patients with primary sideroblastic anemia including those with pyridoxine responsive anemia usually show hypochromic, microcytic anemia, increased serum iron with high saturation of total iron binding capacity, and the presence of a large number of ring sideroblasts with erythroid hyperplasia in the bone marrow. Ferrokinetic studies show somewhat increased plasma iron disappearance and reduced red cell utilization. Almost all symptoms characteristic to primary sideroblastic anemia could be ascribed to the decrease of δ-arninolevulinic acid synthetase (ALAs) activity in erythroblasts. ALM activity in erythroblasts of two patients with pyridoxine responsive anemia before therapy was also decreased. Administration of a large amount of pyridoxal phosphate to the patients caused the increment of the enzyme activity to nearly normal level, and parallel improvement of anemia was observed. The enzyme activity in erythroblasts of both patients before treatment was measured both with and without addition of pyridoxal phosphate to the incubation mixture. The result showed that the amount of both apo-and holo-ALAs was extremely decreased in erythroblasts of this disease before therapy. Apparent affinity to pyridoxal phosphate of apo-ALAs in erythroblasts of both patients was almost the same as that of normal controls. These results indicate that in contrast to other pyridoxine dependency syndromes which are considered to be caused by the decreased affinity of certain apo-pyridoxal enzymes to their cofactor, pyridoxal phosphate, pyridoxine responsive anemia is not caused by the reduced affinity of apo-ALAs to pyridoxal phosphate. On the other hand, ALAs obtained from erythroblasts of this disease showed marked inactivation during the procedure for the conversion to apoform by dialysis against 0.2 M Tris-HCl (pH7.0) containing 0.1 mM hydroxylamine. These results seems to indicate easy inactivation of apo-ALAs in erythroblasts of this disease.<BR>Recently we found a new protease in mitochondria of bone marrow cells including erythroblasts and granulocytes. Its molecular weight is 31, 800, and optimum pH 8.5. The protease inactivated specifically apoforms of certain pyridoxal enzymes, and is considered to be engaged in the regulation of ALAs levels in erythroblasts through degradation of apo-ALAs. The protease activity in erythroblasts of the patients was within normal levels, however, apo-ALAs from erythroblasts of the patients showed marked increment of the susceptibility to the protease as compared with that from normal controls. Therefore, the following mechanisms are considered as the pathogenesis of this disease. Patients with pyridoxine responsive anemia show severe hypochromic anemia because of impared heme synthesis due to decreased ALAs activity caused by the increased degradation of apo-ALAs by the protease in mitochondria of erythroblasts. Administration of a large amount of pyridoxal phosphate causes increased holo-to apo-ALAs ratio in erythroblasts, which diminishes degradation of the enzyme, by the protease, causing the elevation of ALAs levels, and improving the disturbance of heme synthesis in erythroblasts. Therefore, anemia could be improved by the administration of a large amount of pyridoxal phosphate.<BR>This is the first instance of the disease which is considered to be caused by the hypercatabolism of an enzyme due to its increased susceptibility to an intracellular protease.
- Japan Society of Clinical Chemistryの論文
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関連論文
- A New Serine Protease in Mitochondria of Erythroblasts and Pyridoxine Responsive Anemia
- δ-Aminolevu-inic Acid Synthetase in Erythrob-asts of Patients with Primary Sideroblastic Anemia