Disease relevance of SERPINA3

• SERPINA3 polymorphism is not associated with primary intracerebral hemorrhage in a Polish population [1].
• Alpha1-antichymotrypsin gene (SERPINA3) A/T polymorphism as a risk factor for aneurysmal subarachnoid hemorrhage [2].
• A logistic regression model showed that the presence of genotype with T allele (AT+TT; odds ratio [OR], 2.01; 95% CI, 1.19 to 3.38; P=0.009) or AA genotype (OR, 0.49; 95% CI, 0.30 to 0.84; P=0.009) of the SERPINA3 influences the risk for aneurysmal SAH independently from smoking, excessive alcohol consumption, and hypertension [2].
• Recent reports suggested that alpha-1-antichymotrypsin (A1AC) deficiency may also be a possible cause of chronic liver disease [3].
• Role of alpha-1-antichymotrypsin deficiency in promoting cirrhosis in two siblings with heterozygous alpha-1-antitrypsin deficiency phenotype SZ [3].

Psychiatry related information on SERPINA3

• Alpha-1-antichymotrypsin (ACT or SERPINA3) polymorphism may affect age-at-onset and disease duration of Alzheimer's disease [4].
• We tested this possibility by genotyping a large series of clinically and neuropathologically confirmed cases of AD and a series of cases with dementia with Lewy bodies (DLB) with a matched control group for the AACT locus and apoE [5].
• The present study discusses the protective roles and defense mechanisms of LY, LF, alpha 1-ACT, and alpha 1-AT in developing human salivary glands [6].
• Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia [7].

High impact information on SERPINA3

• APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism [8].
• Antisera against purified alpha 1-antichymotrypsin stained Alzheimer amyloid deposits, both in situ and after detergent extraction from brain [9].
• DNA sequence analysis showed that these clones code for alpha 1-antichymotrypsin [9].
• The protease inhibitor alpha 1-antichymotrypsin and the lipid transport protein apolipoprotein E (apoE) are intimately associated with the 42-amino-acid beta-peptide (A beta) in the filamentous amyloid deposits of Alzheimer's disease [10].
• We hypothesize that the activity of these neutrophil serine proteases is regulated by the expression of naturally occurring inhibitors (serpina1 and serpina3) produced locally within the bone marrow [11].

Chemical compound and disease context of SERPINA3

• Both siblings were heterozygous for A1AT and A1AC deficiency suggesting that combined deficiency of these two major serine protease inhibitors may enhance the risk of developing liver disease [3].
• The Alanine/Threonine Polymorphism of the Alpha-1-Antichymotrypsin (SERPINA3) Gene and Ruptured Intracranial Aneurysms in the Japanese Population [12].
• A leucine-to-proline substitution causes a defective alpha 1-antichymotrypsin allele associated with familial obstructive lung disease [13].
• In a pulse-chase experiment, 1- deoxynojirimycin greatly reduced the rate of secretion of alpha 1-antitrypsin and alpha 1-antichymotrypsin by human hepatoma HepG2 cells, but had marginal effects on secretion of the glycoproteins C3 and transferrin, or of albumin [14].
• The protease inhibitor alpha-1-antichymotrypsin, which binds to chymotrypsin-like enzymes in a sodium dodecyl sulfate-resistant manner, has been shown recently to be both a normal constituent of brain and an integral component of the neuritic plaques that form in Down's syndrome and Alzheimer's disease [15].

Biological context of SERPINA3

• RESULTS: The distribution of SERPINA3 genotypes was similar among PICH patients (AA 27.4%; AT 46.3%; TT 26.3%) and controls (AA 23.7%; AT 50.5%; TT 25.8%; P=NS) [1].
• A/T polymorphism of the SERPINA3 gene was investigated using polymerase chain reaction restriction fragment length polymorphism method [1].
• Physical mapping of four serpin genes: alpha 1-antitrypsin, alpha 1-antichymotrypsin, corticosteroid-binding globulin, and protein C inhibitor, within a 280-kb region on chromosome I4q32.1 [16].
• Genetic linkage analysis suggests tight linkage between PI and AACT [16].
• A previously reported point mutation in exon III (Pro(229) to Ala substitution) of the A1AC gene was not detected by polymerase chain reaction amplification and a single strand conformation polymorphism analysis [3].

Anatomical context of SERPINA3

• Antichymotrypsin (SERPINA3) is a widely expressed member of the serpin superfamily, required for the regulation of leukocyte proteases released during an inflammatory response and with a permissive role in the development of amyloid encephalopathy [17].
• Immunohistochemistry revealed an apparent accumulation of both A1AT and A1AC in hepatocytes [3].
• Both alpha 1-PI and alpha 1-ACT inhibited defensin cytotoxicity toward the human lung carcinoma cell line A549, whereas the elastase inhibitor antileukoprotease did not [18].
• Alpha 1-antichymotrypsin (alpha 1-ACT) is a serine proteinase inhibitor (serpin) with cathepsin G, mast cell chymase and chymotrypsin as target enzymes [19].
• Synthesis of alpha 1-antichymotrypsin and alpha 1-antitrypsin by human trophoblast [20].

Associations of SERPINA3 with chemical compounds

• BACKGROUND AND PURPOSE: The member 3 of clade A of serine proteinase inhibitors (SERPINA3), known previously as the alpha1-antichymotrypsin, is an acute phase protein, the levels of which increase in acute and chronic inflammation [2].
• We also found that a variety of inflammatory mediators, cytokines, and steroid hormones are able to stimulate synthesis of alpha 1-AT and alpha 1-ACHY by MCF-7 cells [21].
• Defensin interactions with either alpha 1-PI or alpha 1-ACT were not affected by iodoacetamide or high salt concentration [18].
• METHODS AND RESULTS: Serial paraffin sections of nine consecutive cases of PTC were tested with anti-A1AT and anti-A1ACT antibodies [22].
• We hypothesize that specific interactions of A beta with the inflammatory serpin, alpha 1-antichymotrypsin, abolish the serpin proteinase inhibitor activity and stimulate formation of the neurotoxic fibrillar form of A beta [23].

Physical interactions of SERPINA3

• Prostate-specific antigen (PSA) is a tissue-specific serine protease which forms complexes with protease inhibitors such as alpha 1-antichymotrypsin and alpha 2-macroglobulin [24].
• We have now identified in rat brain a Mr 25,000 alpha-1-antichymotrypsin-binding protein classified as a chymotrypsin-like protease by its inhibitor profile and substrate specificity [15].
• The protein is secreted rather than stored in the cell, has a similar size to plasma alpha 1 ACh (68 kDa) and can complex with human cathepsin G [25].

Regulatory relationships of SERPINA3

• SERPINA3 can be related to aneurysmal subarachnoid hemorrhage (SAH) by influencing inflammation or by regulating cathepsin G activity [2].
• Increased levels of alpha-1-antichymotrypsin in brains of patients with Alzheimer's disease correlate with activated astrocytes and are affected by APOE 4 genotype [26].
• The chymotryptic activity of PSA was further confirmed by the ability of alpha-1-antichymotrypsin and chymostatin to block PSA cleavage of radiolabeled IGFBP-3.(ABSTRACT TRUNCATED AT 250 WORDS)[27]
• Alpha-1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease [28].
• Low concentrations of this antiproteinase and of human plasma alpha 1-antichymotrypsin inhibited TNF-induced PAF synthesis in neutrophils, macrophages, and vascular endothelial cells [29].

Other interactions of SERPINA3

• Binding of peptide 105Y is also blocked by peptides with sequence corresponding to carboxy-terminal fragments of the serpins AT III and alpha 1-ACT, but not by peptides having the sequence of the extreme amino terminus of alpha 1-AT [30].
• Apolipoprotein E and alpha-1 antichymotrypsin polymorphism genotyping in Alzheimer's disease and in dementia with Lewy bodies. Distinctions between diseases [5].
• PSA isolated under reducing conditions was enzymatically inactive and could not bind to the protease inhibitors alpha 1-ACH and alpha 2-M [31].
• Conversion of alpha 1-antichymotrypsin into a human neutrophil elastase inhibitor: demonstration of variants with different association rate constants, stoichiometries of inhibition, and complex stabilities [32].
• The present results demonstrate that part of the cathepsin G, despite the presence of increased concentrations of alpha 1-ACT, was in an uncomplexed, free and functionally active form [33].

Analytical, diagnostic and therapeutic context of SERPINA3

• PATIENTS: Two adult siblings with an A1AT Pi SZ phenotype and reduced levels of A1AC consistent with heterozygosity who developed cirrhosis and underwent liver transplantation [3].
• Demonstration of alpha-1-antitrypsin and alpha-1-antichymotrypsin in fibrous histiocytomas using the immunoperoxidase technique [34].
• In situ hybridization data demonstrate that both alpha 1-PI and alpha 1-ACT map to the same region, q31-q32.3, on chromosome 14 [35].
• Immunoblotting following sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed that alpha 1-antichymotrypsin in plasma and lung secretions are of similar molecular size and no enzyme-alpha 1-antichymotrypsin complexes could be detected in sputum or bronchoalveolar lavage fluids [36].
• However, in contrast to the alpha 1-antichymotrypsin purified from plasma, the lavage protein gave a broad elution profile following anion-exchange chromatography [36].

References