Disease relevance of SERPINA1

• Reduced circulating levels of alpha 1-antitrypsin (alpha 1 AT) are associated with certain alpha 1 AT genotypes and increased susceptibility to emphysema [1].
• Characterization of a 54 kDa, alpha 1-antitrypsin-like protein isolated from ascitic fluid of an endometrial cancer patient [2].
• As mastitis is associated with leakage of small molecular weight plasma proteins, such as alpha 1-antitrypsin, into milk, this antitrypsin can be used as an indicator of mastitis [3].
• Fibrinogen was a reliable indicator for detecting the presence of bacterial infection in all heifers. alpha 1-Proteinase inhibitor activity was of low diagnostic value in this study [4].
• This toxicity could be prevented by including the protease inhibitor alpha 1-antitrypsin to the cultures exposed to smoke particles [5].

High impact information on SERPINA1

• The levels and transcription rates of four mRNAs (albumin, alpha-1-antitrypsin, apolipoprotein A1, and major urinary protein [MUP]) fell sharply [6].
• Alpha 1-acid glycoprotein and alpha 1-antitrypsin inhibit TNF-induced but not anti-Fas-induced apoptosis of hepatocytes in mice [7].
• Kinetic analyses showed that anhydrotrypsin had little or no ability to compete with trypsin for binding to alpha 1-proteinase inhibitor (alpha 1PI), plasminogen activator inhibitor 1 (PAI-1), antithrombin (AT), or AT-heparin complex when present at up to a 100-fold molar excess over trypsin [8].
• We show here that the archetypal serpin, alpha 1-antitrypsin, can also be induced to adopt the latent conformation by heating at high temperatures in 0.7 M citrate for 12 h [9].
• Pre-existing inhibition of intracellular processing of alpha 1-antitrypsin by ionomycin was fully reversible upon removal of the ionophore with fatty acid-free bovine serum albumin [10].

Biological context of SERPINA1

• Comparison of the translated amino acid sequence of the bovine alpha 1-antitrypsin with those of the human, baboon, sheep, rat and mouse demonstrates the preservation of most of the critical structural determinants [11].
• A cDNA clone coding for the entire bovine alpha 1-antitrypsin molecule has been isolated from a lambda gt11 bovine liver cDNA library using a human alpha 1-antitrypsin cDNA as a probe [11].
• Binding sites of LF-A1 are present in the promoter regions of several genes expressed in the liver (alpha 1-antitrypsin, apolipoproteins A1, B1, A4 and pyruvate kinase) [12].
• The most significant difference between ATIII and alpha 1-antitrypsin lies in the 45 residue N-terminal extension in ATIII which contribute to the definition of the heparin binding site [13].
• RESULTS: The median (interquartile range, IQR) concentration of fecal alpha-1 antitrypsin was 2.3 mg/g (range, 1.2-3.3 mg/g) during breast-feeding and 0 (0.0-1.9 mg/g) after weaning to a tolerated hypoallergenic formula, z = -4.23, P < 0.0001 [14].

Anatomical context of SERPINA1

• In a reticulocyte and in a wheat germ cell-free system a propeptide concentration of 600 micro M inhibited albumin synthesis by 50%, whereas total protein synthesis was inhibited by 19% only, and the synthesis of alpha 1-antitrypsin was not inhibited [15].
• At normal plasma concentrations, the alpha 1-AT preparation prevented PLY injury to bovine pulmonary artery endothelial cells, rat alveolar epithelial cells, and human erythrocytes [16].
• The urinary recovery ratios of orally administered lactulose and mannitol, fecal alpha-1 antitrypsin and urinary methylhistamine, and eosinophil protein X concentrations were assessed during breast-feeding and after weaning [14].
• The anticryptosporidial potential of the protease inhibitors alpha-1-antitrypsin (AAT), antipain, aprotinin, leupeptin, methoxysuccinyl-ala-ala-pro-valine chloromethylketone (MAAPVCK), soybean trypsin inhibitor (SBTI), and phenylmethylsulfonyl fluoride (PMSF) was evaluated in a bovine fallopian tube epithelial (BFTE) cell culture system [17].
• Interference of cartilage surface with interaction of granulocyte elastase with alpha 1-proteinase inhibitor. An in vitro model of enzyme inhibition in the joint space [18].

Associations of SERPINA1 with chemical compounds

• Exposure to dithiothreitol reduced albumin export while affecting alpha 1-antitrypsin export minimally [10].
• Ionomycin blocked processing of alpha 1-antitrypsin at the conversion from the high mannose to the complex glycosylated form without affecting ATP or GTP contents [10].
• Serine esterase inhibitors such as phenylmethanesulphonyl fluoride, di-isopropyl fluorophosphate and alpha 1-proteinase inhibitor, and TAME, a synthetic substrate for serine esterase, prevent the increase in serine esterase activity, PLA2 activity and AA release caused by t-Bu-OOH [19].
• Synergistic anticryptosporidial potential of the combination alpha-1-antitrypsin and paromomycin [20].
• The enzyme was inhibited by certain protease inhibitors such as diisopropyl fluorophosphate, N-alpha-p-tosyl-L-lysine chloromethyl ketone, phenylmethylsulfonyl fluoride, L-1-tosylamide-2-phenylethylchloromethyl ketone, alpha-1-antitrypsin, and soybean trypsin inhibitor [21].

Other interactions of SERPINA1

• Sequential changes in plasma fibrinogen, serum haptoglobin, acid-soluble glyco-proteins and alpha 1-proteinase inhibitor activity were analysed and compared with both the clinical and bacteriological findings and the final outcome of the disease after calving [4].
• In addition, alpha 2-macroglobulin, but not alpha 1-antitrypsin, inhibits the action of the proteinases [22].
• The rate constant of association (kon) between the proteinase and alpha 1 antitrypsin is decreased from 2.8 10(5) M-1 sec-1 to 1.24 10(5) M-1 sec-1 in presence of 1 mg/ml of insoluble elastin and 0.83 10(5) M sec-1 in presence of the same concentration of alpha-elastin [23].
• Cloning of fibrinogen, prothrombin, and alpha 1-antitrypsin [24].

Analytical, diagnostic and therapeutic context of SERPINA1

• Kinetic dissection of alpha 1-antitrypsin inhibition mechanism [25].
• A key step was affinity chromatography employing an antiserum which had been depleted of alpha-1-AT antibodies [26].
• Molecular weight studies by sedimentation equilibrium ultracentrifugation in aqueous buffer and in 6 M guanidine as well as sodium dodecyl sulfate polyacrylamide gel electrophoresis suggest that alpha-1-AT is a single polypeptide chain having a molecular weight of 49,500 [26].
• Complexes of alpha 1-proteinase inhibitor with proteases were examined by SDS-PAGE in 7.5% polyacrylamide gel and in a gel gradient [27].
• This method provides > 90% viability of differentiated, primary human hepatocytes 8 mo after cryopreservation as measured by trypan blue exclusion, preserves hepatocyte morphology, liver-specific gene expression (alpha 1 antitrypsin), and replication [28].

References