ALAS2

ALAS2 is the erythroid 5-aminolevulinate synthase, a mitochondrial pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of glycine and succinyl-CoA to form 5-aminolevulinate, CoA and CO2. This first step of heme biosynthesis supplies the heme component of hemoglobin during erythropoiesis. Human ALAS2 forms a homodimer with active sites built from both subunits; PLP forms an internal aldimine with Lys391. An N-terminal targeting sequence directs mitochondrial import, and the mature enzyme acts on the matrix side of the inner membrane. The major exon-4-skipped isoform retains catalytic activity and mitochondrial targeting. ALAS2 differs from the broadly expressed ALAS1 isozyme in its erythroid specialization and iron-responsive translation. Its activity is also controlled by a C-terminal autoinhibitory extension, and hypoxia stabilizes the protein in erythroid cell experiments. Physical association with the ATP-specific succinyl-CoA synthetase beta subunit SUCLA2 is established, while the extent of substrate channeling by this interaction remains unresolved. Loss-of-function variants cause X-linked sideroblastic anemia; C-terminal gain-of-function variants cause X-linked protoporphyria.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.