5-aminolevulinate synthase 2 (ALAS2)

5-aminolevulinate synthase 2 (ALAS2) is a mitochondrial, erythroid-specific enzyme that catalyzes the first and rate-limiting step of heme biosynthesis, converting glycine and succinyl-CoA to 5-aminolevulinate (ALA) in developing red blood cells using pyridoxal phosphate (vitamin B6) as a cofactor[1][5][7]. ALAS2 is tightly regulated, possessing a unique C-terminal extension that modulates enzyme activity through an autoinhibitory mechanism[3][7]. Mutations in the ALAS2 gene cause X-linked sideroblastic anemia (loss-of-function, impaired heme synthesis, iron accumulation in erythroblasts) or X-linked protoporphyria (gain-of-function, excess porphyrin synthesis, leading to phototoxicity)[4][6][7]. ALAS2 activity or expression can be modified by genetic mutations in coding or regulatory regions, or by cofactor (PLP/pyridoxine) availability. Current pharmacological interest revolves around developing ALAS2 inhibitors for substrate reduction therapy in porphyria disorders with toxic heme intermediate accumulation[7].

Other names

5-aminolevulinate synthase, erythroid-specific, mitochondrialALAS-EALASEASBDelta-ALA synthase 2Delta-aminolevulinate synthase 2Sideroblastic/hypochromic anemia geneErythroid-specific delta-aminolevulinate synthaseSIDBA1XLDPPXLEPPXLSAaminolevulinate, delta-, synthase 2delta-ALA synthetaseANH1

Pyridoxine supplementation: increases PLP (active vitamin B6) levels, enhances residual ALAS2 enzymatic activity in vitamin B6–responsive forms of sideroblastic anemia[4] (Candidate inhibitors) may bind regulatory C-terminal extension, block conformational changes, inhibit excess ALAS2 activity for porphyria therapy[7]