5-aminolevulinate synthase (ALAS) (ALAS)

5-aminolevulinate synthase (ALAS) is the rate-limiting enzyme in the heme biosynthetic pathway, catalyzing the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA) (UniProt P13196). It exists in two distinct isoforms: ALAS1, which is expressed ubiquitously and regulated by heme levels via feedback inhibition, and ALAS2, which is specific to erythroid cells and regulated by iron availability (UniProt P22392). Dysregulation of ALAS1 leads to the accumulation of neurotoxic precursors like ALA and porphobilinogen, which are central to the pathogenesis of acute hepatic porphyrias (StatPearls NBK537311). Conversely, mutations in ALAS2 are associated with X-linked sideroblastic anemia and erythropoietic protoporphyria (PubMed 21910714). Therapeutically, ALAS1 is targeted by RNA interference (siRNA) therapies like givosiran to reduce the overproduction of toxic intermediates in patients with porphyria (FDA Givosiran Label). Additionally, ALAS activity is sensitive to pyridoxal phosphate (vitamin B6) levels, making it a target for pharmacological modulation in certain anemias (PubMed 11444254).

Other names

Delta-aminolevulinate synthase5-aminolevulinic acid synthaseALAS1ALAS2ALA synthase

RNA interference (siRNA) mediated degradation of ALAS1 mRNA; Feedback inhibition of ALAS1 enzyme activity and synthesis; Pyridoxal phosphate (PLP) cofactor modulation.