SERPINA1 (serpin family A member 1; HGNC:8941, NCBI Gene ID 5265) is a human locus mapped to chromosome band 14q32.13 that encodes secreted acute-phase glycoprotein Alpha-1 Antitrypsin / AAT (394 mature aa; 52 kDa). SERPINA1 acts in suicide-substrate inhibition of neutrophil elastase, proteinase 3 & cathepsin G, together with Small Interfering RNA (siRNA), CRISPR-Cas9 & Base Editing, and Antisense & RNA-Editing Oligonucleotides. Encodes alpha-1 antitrypsin, the major plasma serine protease inhibitor protecting pulmonary alveoli from neutrophil elastase.
Suicide-substrate inhibition of neutrophil elastase, proteinase 3 & cathepsin G
Clinical / Therapeutic Role
PiZZ (p.Glu342Lys) causes Alpha-1 Antitrypsin Deficiency (emphysema & liver cirrhosis); target of fazirsiran siRNA & RNA/DNA base editing
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 7-exon gene (exons IA, IB, IC, and coding exons II–V) within the serpin gene cluster on chromosome 14q32.13, driven by distinct hepatocyte- and monocyte-specific promoters and encoding a metastable 394-residue core folded into three beta-sheets (A–C), nine alpha-helices, and an exposed reactive center loop (RCL) presenting Met358-Ser359 as a bait substrate.
Cellular & Tissue Expression Profile: Synthesized predominantly by hepatic hepatocytes and secreted into plasma at 1.0–2.0 g/L (making it the most abundant circulating protease inhibitor, rising 3- to 4-fold during acute-phase IL-6 stimulation), with local synthesis in alveolar macrophages and bronchial epithelial cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Diffuses into the pulmonary interstitium and alveolar lining fluid where neutrophil elastase cleaves the Met358-Ser359 bond of the reactive center loop, triggering a dramatic spring-loaded mousetrap conformational snap that translocates the covalently trapped elastase 70 angstroms to the opposite pole of AAT and inserts the cleaved RCL as strand 4 of beta-sheet A.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: In classic codominant Alpha-1 Antitrypsin Deficiency (AATD), the Z allele (rs28929474, c.1096G>A, p.Glu342Lys at the hinge of the RCL) disrupts the Glu342-Lys290 salt bridge, causing ~85% of nascent Z-AAT chains to loop-sheet polymerize inside the hepatocyte rough endoplasmic reticulum (driving toxic gain-of-function neonatal cholestasis, fibrosis, and cirrhosis) while leaving plasma and lungs severely deficient in AAT (driving loss-of-function panacinar basal emphysema, accelerated by cigarette smoke oxidizing Met358).
Therapeutic & Clinical Pharmacology: Pulmonary deficiency is treated by intravenous plasma-purified AAT augmentation, hepatic toxic Z-polymer accumulation is targeted by the GalNAc-siRNA fazirsiran (ARO-AAT), and dual-action correction of the single c.1096G>A point mutation to wild-type M-AAT is in human clinical trials using ADAR-mediated oligonucleotide RNA editing (WVE-006) and LNP-delivered CRISPR adenine base editing (BEAM-302).