ALAS1 (5'-aminolevulinate synthase 1; HGNC:396, NCBI Gene ID 211) is a human locus mapped to chromosome band 3p21.2 that encodes mitochondrial matrix PLP-dependent 5-aminolevulinate synthase 1 (640 aa; EC 2.3.1.37). ALAS1 acts in rate-limiting first step of non-erythroid heme biosynthesis (glycine + succinyl-CoA to ALA), together with PPARGC1A (PGC-1alpha Coactivator Gene), FOXO1 Transcription Factor Gene, and Small Interfering RNA (siRNA). Encodes the rate-limiting hepatic mitochondrial enzyme of heme biosynthesis; target of givosiran siRNA in acute hepatic porphyria.
Rate-limiting first step of non-erythroid heme biosynthesis (glycine + succinyl-CoA to ALA)
Clinical / Therapeutic Role
Neurotoxic ALA/PBG overproduction in Acute Hepatic Porphyria; target of FDA-approved givosiran (Givlaari) siRNA
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 11-exon housekeeping gene on chromosome 3p21.2 containing fasting-inducible PGC-1alpha (PPARGC1A)/FOXO1 response elements and xenobiotic-inducible CAR/PXR elements in its promoter, plus N-terminal cysteine-proline (CP) heme-regulatory motifs that block mitochondrial import when free heme is abundant.
Cellular & Tissue Expression Profile: Ubiquitously expressed across all non-erythroid tissues and highest in hepatic hepatocytes (where abundant cytochrome P450 enzymes require continuous heme synthesis), in contrast to erythroid-specific ALAS2 on the X chromosome.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Uses pyridoxal 5-prime-phosphate (PLP, vitamin B6) as a cofactor inside the mitochondrial matrix to condense glycine and succinyl-CoA into 5-aminolevulinic acid (ALA) and CO2; free intracellular heme exerts tight negative feedback on ALAS1 transcription, mRNA stability, and mitochondrial translocation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: In autosomal dominant Acute Hepatic Porphyrias (such as Acute Intermittent Porphyria caused by HMBS haploinsufficiency), triggers that deplete hepatic regulatory heme or induce PGC-1alpha (fasting, cytochrome P450-inducing drugs, progesterone) cause massive derepression of hepatic ALAS1, flooding the circulation with neurotoxic porphyrin precursors ALA and porphobilinogen (PBG) that provoke severe neurovisceral pain crises and motor neuropathy.
Therapeutic & Clinical Pharmacology: Directly silenced in hepatocytes by givosiran (Givlaari, FDA-approved in 2019), a GalNAc-conjugated siRNA that cleaves hepatic ALAS1 mRNA, normalizes urinary ALA and PBG levels, and reduces annualized porphyria attack rates by >74%.