Delta-aminolevulinic acid synthase 1 (ALAS1)

Delta-aminolevulinic acid synthase 1 (ALAS1) is a nuclear-encoded mitochondrial enzyme that serves as the first and rate-limiting step in the heme biosynthetic pathway in the liver and other non-erythroid tissues [4, 8]. It catalyzes the condensation of glycine and succinyl-CoA into delta-aminolevulinic acid (ALA) using pyridoxal 5-phosphate as a cofactor [12]. In patients with acute hepatic porphyrias (AHP), genetic mutations in downstream enzymes lead to a compensatory and pathological upregulation of ALAS1, resulting in the accumulation of neurotoxic intermediates such as ALA and porphobilinogen (PBG) [1, 15]. These toxic precursors are responsible for the severe, life-threatening neurovisceral attacks and chronic symptoms characteristic of the disease [5, 6]. Givosiran is an FDA-approved small interfering RNA (siRNA) therapeutic that specifically targets hepatic ALAS1 mRNA for degradation, thereby reducing the production of these neurotoxic precursors and preventing porphyria attacks [3, 9]. Beyond its role in porphyria, ALAS1 is increasingly recognized for its involvement in metabolic homeostasis and its potential as a target in certain cancers where heme demand is elevated to support rapid proliferation [11, 18].

Other names

5-aminolevulinate synthase 15-aminolevulinate synthase, non-specific, mitochondrialALAS-HALASHDelta-aminolevulinate synthase 1Migration-inducing protein 4MIG4

RNA interference (siRNA) targeting ALAS1 mRNA for degradation to reduce enzyme expression; Feedback inhibition of enzyme activity and transcription by heme analogs.