Interaction between succinyl CoA synthetase and the heme-biosynthetic enzyme ALAS-E is disrupted in sideroblastic anemia
AUTOR(ES)
Furuyama, Kazumichi
FONTE
American Society for Clinical Investigation
RESUMO
The first and the rate-limiting enzyme of heme biosynthesis is δ-aminolevulinate synthase (ALAS), which is localized in mitochondria. There are 2 tissue-specific isoforms of ALAS, erythroid-specific (ALAS-E) and nonspecific ALAS (ALAS-N). To identify possible mitochondrial factors that modulate ALAS-E function, we screened a human bone marrow cDNA library, using the mitochondrial form of human ALAS-E as a bait protein in the yeast 2-hybrid system. Our screening led to the isolation of the β subunit of human ATP-specific succinyl CoA synthetase (SCS-βA). Using transient expression and coimmunoprecipitation, we verified that mitochodrially expressed SCS-βA associates specifically with ALAS-E and not with ALAS-N. Furthermore, the ALAS-E mutants R411C and M426V associated with SCS-βA, but the D190V mutant did not. Because the D190V mutant was identified in a patient with pyridoxine-refractory X-linked sideroblastic anemia, our findings suggest that appropriate association of SCS-βA and ALAS-E promotes efficient use of succinyl CoA by ALAS-E or helps translocate ALAS-E into mitochondria.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=377455Documentos Relacionados
- Changes in Succinyl CoA Synthetase Activity in Etiolated Bean Leaves Caused by Illumination 12
- Influence of Certain Cations on Activity of Succinyl CoA Synthetase From Tobacco 12
- A Turkish Patient With Succinyl-CoA:3-Oxoacid CoA Transferase Deficiency Mimicking Diabetic Ketoacidosis
- Adaptation of muscle to exercise: Increase in levels of palmityl CoA synthetase, carnitine palmityltransferase, and palmityl CoA dehydrogenase, and in the capacity to oxidize fatty acids
- Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.