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Alas2  -  aminolevulinic acid synthase 2, erythroid

Mus musculus

Synonyms: 5-aminolevulinate synthase, 5-aminolevulinate synthase, erythroid-specific, mitochondrial, 5-aminolevulinic acid synthase 2, ALAS, ALAS-E, ...
 
 
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Disease relevance of Alas2

 

High impact information on Alas2

 

Chemical compound and disease context of Alas2

 

Biological context of Alas2

  • Sb1.8 was sublocalized to band F of the mouse X chromosome, distal to Alas2 and proximal to DXPas1, which confirms a region of conservation between band Xp11.21-p11.22 in human and band XF in mouse [10].
  • Mice with the Alas2-null phenotype showed massive cytoplasmic, but not mitochondrial, iron accumulation in their primitive erythroblasts [7].
  • Apex2 consists of six exons and is flanked on the 3' end by Alas2 on X chromosome 63 [11].
  • These findings thus indicate that heme formation, which is determined by the level of ALAS-E, plays an essential role on gene expression of many proteins necessary for erythroid development [12].
  • This could lead to up-regulation of globin gene transcription, thereby releasing iron that in turn controls production of ferritins, and further up-regulating aminolevulinate synthase 2 (Alas2) [13].
 

Anatomical context of Alas2

 

Associations of Alas2 with chemical compounds

  • In MEL cells in which an antisense ALAS-E RNA was expressed (AS clone), sense ALAS-E mRNA levels in both untreated and dimethylsulfoxide (DMSO)-treated cells were decreased compared with their respective controls [12].
  • While recent reports have clearly demonstrated that GATA-1 is involved in the induction of erythroid cell-specific forms of 5-aminolevulinate synthase (ALAS-2) and porphobilinogen (PBG) deaminase and that cellular iron status plays a regulatory role for ALAS-2, little is known about regulation of the remainder of the pathway [16].
  • 5-Aminolevulinate synthase (ALAS), a pyridoxal 5'-phosphate-dependent enzyme, catalyzes the first, and regulatory, step of the heme biosynthetic pathway in nonplant eukaryotes and some bacteria [17].
  • Both ALAS-E and ALAS-N mRNAs were detected in a clone of dimethyl sulfoxide (Me2SO)-sensitive MEL cells, termed DS-19, without cross-hybridization [2].
  • 5-Aminolevulinate synthase is a dimeric protein having an ordered kinetic mechanism with glycine binding before succinyl-CoA and with aminolevulinate release after CoA and carbon dioxide [17].
 

Regulatory relationships of Alas2

  • These findings suggest that ALAS-E and ALAS-N mRNAs are under separate controls and that the expression of ALAS-E mRNA is a critical event in erythroid differentiation [18].
 

Other interactions of Alas2

 

Analytical, diagnostic and therapeutic context of Alas2

  • Although the roles of defined amino acids in the active site and catalytic mechanism have been recently explored using site-directed mutagenesis, much less is known about the role of the 5-aminolevulinate synthase polypeptide chain arrangement in folding, structure, and ultimately, function [23].
  • To examine the roles heme plays during hematopoiesis and to create animal models of XLSA, we disrupted the mouse ALAS-E gene [24].

References

  1. Heme deficiency in erythroid lineage causes differentiation arrest and cytoplasmic iron overload. Nakajima, O., Takahashi, S., Harigae, H., Furuyama, K., Hayashi, N., Sassa, S., Yamamoto, M. EMBO J. (1999) [Pubmed]
  2. Erythroleukemia differentiation. Distinctive responses of the erythroid-specific and the nonspecific delta-aminolevulinate synthase mRNA. Fujita, H., Yamamoto, M., Yamagami, T., Hayashi, N., Sassa, S. J. Biol. Chem. (1991) [Pubmed]
  3. Expression of mammalian 5-aminolevulinate synthase in Escherichia coli. Overproduction, purification, and characterization. Ferreira, G.C., Dailey, H.A. J. Biol. Chem. (1993) [Pubmed]
  4. Zinc mesoporphyrin represses induced hepatic 5-aminolevulinic acid synthase and reduces heme oxygenase activity in a mouse model of acute hepatic porphyria. Schuurmans, M.M., Hoffmann, F., Lindberg, R.L., Meyer, U.A. Hepatology (2001) [Pubmed]
  5. Pre-steady-state reaction of 5-aminolevulinate synthase. Evidence for a rate-determining product release. Hunter, G.A., Ferreira, G.C. J. Biol. Chem. (1999) [Pubmed]
  6. 5-Aminolevulinate synthase is at 3p21 and thus not the primary defect in X-linked sideroblastic anemia. Sutherland, G.R., Baker, E., Callen, D.F., Hyland, V.J., May, B.K., Bawden, M.J., Healy, H.M., Borthwick, I.A. Am. J. Hum. Genet. (1988) [Pubmed]
  7. Aberrant iron accumulation and oxidized status of erythroid-specific delta-aminolevulinate synthase (ALAS2)-deficient definitive erythroblasts. Harigae, H., Nakajima, O., Suwabe, N., Yokoyama, H., Furuyama, K., Sasaki, T., Kaku, M., Yamamoto, M., Sassa, S. Blood (2003) [Pubmed]
  8. Active site of 5-aminolevulinate synthase resides at the subunit interface. Evidence from in vivo heterodimer formation. Tan, D., Ferreira, G.C. Biochemistry (1996) [Pubmed]
  9. Pyridoxine refractory X-linked sideroblastic anemia caused by a point mutation in the erythroid 5-aminolevulinate synthase gene. Furuyama, K., Fujita, H., Nagai, T., Yomogida, K., Munakata, H., Kondo, M., Kimura, A., Kuramoto, A., Hayashi, N., Yamamoto, M. Blood (1997) [Pubmed]
  10. The mouse Sb1.8 gene located at the distal end of the X chromosome is subject to X inactivation. Sultana, R., Adler, D.A., Edelhoff, S., Carrel, L., Lee, K.H., Chapman, V.C., Willard, H.F., Disteche, C.M. Hum. Mol. Genet. (1995) [Pubmed]
  11. Characterization of the genomic structure and expression of the mouse Apex2 gene. Ide, Y., Tsuchimoto, D., Tominaga, Y., Iwamoto, Y., Nakabeppu, Y. Genomics (2003) [Pubmed]
  12. The role of the erythroid-specific delta-aminolevulinate synthase gene expression in erythroid heme synthesis. Meguro, K., Igarashi, K., Yamamoto, M., Fujita, H., Sassa, S. Blood (1995) [Pubmed]
  13. Light pulse-induced heme and iron-associated transcripts in mouse brain: a microarray analysis. Ben-Shlomo, R., Akhtar, R.A., Collins, B.H., Judah, D.J., Davies, R., Kyriacou, C.P. Chronobiol. Int. (2005) [Pubmed]
  14. Deficient heme and globin synthesis in embryonic stem cells lacking the erythroid-specific delta-aminolevulinate synthase gene. Harigae, H., Suwabe, N., Weinstock, P.H., Nagai, M., Fujita, H., Yamamoto, M., Sassa, S. Blood (1998) [Pubmed]
  15. Regulation of 5-aminolevulinate synthase in mouse erythroleukemic cells is different from that in liver. Elferink, C.J., Sassa, S., May, B.K. J. Biol. Chem. (1988) [Pubmed]
  16. Biphasic ordered induction of heme synthesis in differentiating murine erythroleukemia cells: role of erythroid 5-aminolevulinate synthase. Lake-Bullock, H., Dailey, H.A. Mol. Cell. Biol. (1993) [Pubmed]
  17. Transient state kinetic investigation of 5-aminolevulinate synthase reaction mechanism. Zhang, J., Ferreira, G.C. J. Biol. Chem. (2002) [Pubmed]
  18. Differential induction responses of delta-aminolevulinate synthase mRNAs during erythroid differentiation: use of nonradioactive in situ hybridization. Mitani, K., Fujita, H., Hayashi, N., Yamamoto, M., Sassa, S. Am. J. Hematol. (1992) [Pubmed]
  19. Transcriptional regulation of the murine erythroid-specific 5-aminolevulinate synthase gene. Kramer, M.F., Gunaratne, P., Ferreira, G.C. Gene (2000) [Pubmed]
  20. Fine genetic mapping of the Hyp mutation on mouse chromosome X. Du, L., Desbarats, M., Cornibert, S., Malo, D., Ecarot, B. Genomics (1996) [Pubmed]
  21. Effect of Griseofulvin on 5-aminolevulinate synthase and on ferrochelatase in mouse liver neoplastic nodules. Denk, H., Kalt, R., Abdelfattach-Gad, M., Meyer, U.A. Cancer Res. (1981) [Pubmed]
  22. Protein tyrosine phosphatase-dependent activation of beta-globin and delta-aminolevulinic acid synthase genes in the camptothecin-induced IW32 erythroleukemia cell differentiation. Wang, M.C., Liu, J.H., Wang, F.F. Mol. Pharmacol. (1997) [Pubmed]
  23. Circular permutation of 5-aminolevulinate synthase. Mapping the polypeptide chain to its function. Cheltsov, A.V., Barber, M.J., Ferreira, G.C. J. Biol. Chem. (2001) [Pubmed]
  24. Animal models for X-linked sideroblastic anemia. Yamamoto, M., Nakajima, O. Int. J. Hematol. (2000) [Pubmed]
 
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