5-aminolevulinate synthase 1 (ALAS1) (ALAS1)

5-Aminolevulinate synthase 1 (ALAS1), also known as the non-specific or housekeeping isoform, is a mitochondrial enzyme that catalyzes the rate-limiting first step in heme biosynthesis by condensing glycine and succinyl-CoA to form 5-aminolevulinic acid (ALA) in a pyridoxal 5'-phosphate (PLP)-dependent manner. Expressed ubiquitously across tissues, it maintains cellular heme homeostasis, distinct from the erythroid-specific ALAS2 isoform found in red blood cell precursors. ALAS1 activity and mitochondrial import are tightly regulated by heme through feedback inhibition via heme regulatory motifs, preventing toxic porphyrin buildup. Structurally, it forms a homodimer with three domains per monomer, binding PLP at the active site interface involving conserved residues like Lys248. Dysregulation or mutations in related ALAS isoforms contribute to disorders like X-linked sideroblastic anemia, though ALAS1 itself links to acute porphyria. No approved drugs directly target ALAS1, but its central role positions it as a potential therapeutic node in heme-related pathologies.

Other names

5-aminolevulinic acid synthase 1ALAS-HALASHDelta-ALA synthaseHEM1