Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various reports have described that amino acid substitutions can alter substrate, positional, inhibitory, and target gene specificities of proteins. By using the method of Chou and Fasman, the present work predicts that critical amino acids for converting these substrate specificities of trypsin, L-lactate dehydrogenase, aspartate aminotransferase, beta-lactamase, and cytochrome P-450 are found to exist within regions predicted as beta-turns. The ratios of hydroxylation and oxygenation positions of substrates by cytochrome P-450 and lipoxygenase, respectively, are varied by changes of the protein structures, probably around turn conformations. Inhibitory specificities of bovine pancreatic trypsin inhibitor and alpha 1-antitrypsin and target gene specificity of glucocorticoid receptor are converted by changing turn structures. Occurrence of beta-turn probabilities can be predicted around the amino acid alteration positions of an evolutionally antecedent protein of a nylon degradation enzyme. These findings will have relevance to work on protein engineering and enzyme evolution.
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PMID:Critical amino acids responsible for converting specificities of proteins and for enhancing enzyme evolution are located around beta-turn potentials: data-based prediction. 813 29

Interstitial collagenases, members of the matrix metalloproteinase family, are key initiators of collagen destruction during various disorders such as rheumatoid arthritis. Recently interstitial collagenases were found to efficiently degrade an additional non-collagenous substrate, the serum alpha-1-antitrypsin (AAT also called alpha-1-proteinase inhibitor or serpin). Serpins are major endogenous inhibitors of serine proteinases, particularly neutrophil elastase. Of relevance to neutrophil-mediated collagen degradation, the tetracycline family of antibiotics are now known to inhibit inhibit mammalian collagenases by a mechanism unrelated to their antimicrobial activity. This study identifies an additional mechanism by which tetracyclines may retard tissue breakdown during inflammatory diseases. Doxycycline, added to the reaction mixture as in concentrations as low as 10 microM, which correspond to levels of the drug readily achieved in vivo, produced detectable inhibition of serpinase activity of neutrophil collagenase, although levels of 50-100 microM or greater were required to reduce AAT degradation more than 75%. The concentration of doxycycline to inhibit 50% (IC50 of serpinase activity) of AAT degradation by neutrophil collagenase was found to approximate 20 microM, a value similar to the IC50 for doxycycline required to inhibit collagen degradation by neutrophil collagenase. Doxycycline was also found to inhibit at cell level neutrophil-mediated degradation of AAT. The protection of bodies' AAT-shield from serpinolytic activity of collagenase would result in inhibition of serine proteinases such as neutrophil elastase. Tetracyclines may thus protect matrix constituents from a wider spectrum of neutral proteases than previously recognized, not just from the matrix metalloproteinases collagenase and gelatinase.
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PMID:Doxycycline protects serum alpha-1-antitrypsin from human neutrophil collagenase. 845 33

It has been supposed that there are differences with regard to clinical course and outcome due to the underlying etiological factor in acute pancreatitis. Therefore, the objective of this study was to analyze the severity of the disease, serum enzymes, indicators of necrosis, systemic complications, and mortality in acute pancreatitis with regard to the etiology. One hundred ninety patients with acute pancreatitis (127 male, 63 female) were studied prospectively and subdivided into three etiological groups: (i) alcohol, (ii) gallstones, and (iii) other causes and idiopathic acute pancreatitis. Severity scores (Ranson and Bank) and findings by contrast-enhanced computed tomography were similar in all three groups. Analysis of serum enzymes [lipase, aspartate aminotransferase (ASAT)] and indicators of necrosis (C-reactive protein, alpha 1-antitrypsin, alpha 2-macroglobulin, and lactate dehydrogenase) showed only for ASAT within 24 h significantly higher levels in biliary acute pancreatitis in comparison with the other groups. There were no differences in the rate of infected pancreatic necrosis and mortality in alcohol-related acute pancreatitis (31 and 5.3%), biliary acute pancreatitis (38 and 10%) and acute pancreatitis due to other etiological factors (43 and 5.5%). In conclusion, this study clearly showed that once the pathogenetic mechanisms have initiated the disease, the course and outcome of acute pancreatitis are not influenced by the underlying etiological factor.
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PMID:Influence of etiology on the course and outcome of acute pancreatitis. 889 93

SPAAT has previously been shown to be a competitive inhibitor of the model serine protease, chymotrypsin. We now present evidence that SPAAT is likewise a competitive inhibitor of human neutrophil elastase and cathepsin G with Ki's of 15-20 and 40 microM, respectively. The mechanism of this inhibition was investigated by comparing the relative effectiveness of the 23-residue N-terminal fragment of SPAAT (N-SPAAT) to inhibit chymotrypsin and human neutrophil elastase. N-SPAAT, which does not contain the primary chymotrypsin cleavage site, was approximately 10-fold less effective as an inhibitor of chymotrypsin than SPAAT (Ki of 65 microM versus 7.5 microM). In contrast, this fragment, which contains the primary human neutrophil elastase cleavage site, was found to competitively inhibit human neutrophil elastase with a Ki of 24 microM which was comparable to that of SPAAT (Ki = 15-20 microM). Thus it appears that SPAAT is a reversible inhibitor of these enzymes rather than an irreversible, stoichiometric one like its parent protein, AAT. Such fragmentation of AAT, however, might provide a mechanism whereby a cascade of decreasingly potent, but increasingly specific SPAAT-related inhibitory peptides could be generated. These results further substantiate the view that SPAAT may play a role in vivo in the protection of extracellular proteins from inappropriate attack by proteases which are elevated during various pathophysiological conditions.
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PMID:Inhibition of human serine proteases by SPAAT, the C-terminal 44-residue peptide from alpha1-antitrypsin. 921 22

SPAAT (short piece of alpha 1-antitrypsin [AAT]), the 44-residue C-terminal peptide of AAT, was originally isolated from human placenta [Niemann et al. (1992): Matrix 12:233-241]. It was shown to be a competitive inhibitor of serine proteases [Niemann et al. (in press): Biochem Biophys Acta]. The binding of SPAAT to one or more proteins of the extracellular matrix (ECM) was initially suggested on the basis of its recovery from tissue residues following a series of extractions designed to remove easily solubilized proteins [Niemann et al. (1992): Matrix 12:233-241]. Our binding studies with the model ECMs, Matrigel and Amgel, suggested that SPAAT might be bound by a specific collagen type as well as one or more non-collagenous ECM proteins. Individual ECM components were screened for their ability to bind SPAAT. When the four commonly occurring fiber-forming collagens (types I, II, III, and V) were evaluated, type III was found to be preferred. In addition, although SPAAT bound to preformed type III collagen fibers in a concentration dependent fashion, it did not bind to type III collagen molecules undergoing fibril formation. This is consistent with a physiological mode of interaction between SPAAT and type III collagen in vivo. Of the non-collagenous ECM macromolecules (laminin-1, fibronectin, entactin, and heparan sulfate) tested, laminin-1 was preferred. The binding of radiolabelled SPAAT to type III collagen and laminin-1 was competitively inhibited by unlabelled SPAAT as well as an unrelated protein, human serum albumin (HSA), to establish binding specificity. The kinetics of the release of the bound radiolabelled SPAAT were also examined to substantiate the non-covalent and reversible nature of this association. These results support the view that susceptible proteins of the ECM may actually be coated with SPAAT in vivo, possibly affording protection against inappropriate protease digestion.
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PMID:Binding of SPAAT, the 44-residue C-terminal peptide of alpha 1-antitrypsin, to proteins of the extracellular matrix. 925 91

The purpose of this study was to elucidate the interaction of cationic liposomes and plasmid cDNA by examining their ultrastructure, zeta potential, stability in aqueous media and protection from DNaseI digestion; their potential for hemolysis and platelet aggregation was evaluated as it may serve as an in vitro toxicity screen. Liposomes consisting of N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA) or 3 beta-[N-(N',N'-dimethylaminoethane)-carbamoyl]-cholesterol (DC-Chol) and dioleylphosphatidylethanolamine (DOPE) were complexed with plasmid constructs of ovine prostaglandin G/H synthase (pCMV4-PGH) or human alpha 1-antitrypsin (pCMV4-AAT) at lipid:plasmid (L/P) ratios of 3:1-8:1 (w/w). The electron micrographs showed bead-like attachment of liposomes to cDNA and coating of plasmid strands. The zeta potential showed isoelectric points at L/P ratios of 3.5-4 (DOTMA/DOPE) and 5.5-6.5, corresponding to a pKa of 6.45 (DC-Chol/DOPE). Liposome cDNA complexes were stable in water, saline and 5% dextrose for 48 h, but precipitated instantaneously in PBS. An increase in the L/P ratio corresponded with increased protection from DNaseI digestion. DOTMA/DOPE liposomes alone were highly hemolytic and DC-Chol/DOPE liposomes moderately hemolytic; hemolysis was abolished by cDNA complexation, with the exception of very high (> or = 7:1) L/P ratios. Both liposomes alone and cDNA complexes caused transient serum turbidity, while none caused platelet aggregation. It was concluded that current cationic lipid cDNA formulations are metastable and appear to have very little if any toxicity with respect to hemolytic potential and untoward interaction with other blood components.
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PMID:Physicochemical properties and in vitro toxicity of cationic liposome cDNA complexes. 937 44

At routine determination of serum activities of transaminases (aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) increased levels are frequently found. An algorithm may be used in the analysis of elevated transaminase levels: after elimination of the most frequent causes of hepatitis (alcoholic hepatitis, chronic hepatitis B and C) and some rare conditions (autoimmune hepatitis, alpha 1-antitrypsin deficiency, haemochromatosis and Wilson's disease), the diagnosis will often be nonalcoholic steatohepatitis. Although nonalcoholic steatohepatitis is considered a stable disease, recent literature shows a progression to cirrhosis in 8-17%. So far, no effective therapeutic strategies are available for nonalcoholic steatohepatitis.
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PMID:[Management of asymptomatic elevated serum aminotransferase levels, particularly in nonalcoholic steatohepatitis]. 1032 Dec 58

Recombinant human alpha 1-antitrypsin (rAAT) was expressed and secreted from transgenic rice cell suspension cultures in its biologically active form. This was accomplished by transforming rice callus tissues with an expression vector, p3D-AAT, containing the cDNA for mature human AAT protein. Regulated expression and secretion of rAAT from this vector was achieved using the promoter, signal peptide, and terminator from a rice alpha-amylase gene Amy3D. The Amy3D gene of rice is tightly controlled by simple sugars such as sucrose. It was possible, therefore, to induce the expression of the rAAT by removing sucrose from the cultured media or by allowing the rice suspension cells to deplete sucrose catabolically. Although transgenic rice cell produced a heterogeneous population of the rAAT molecules, they had the same N-terminal amino acids as those found in serum-derived (native) AAT from humans. This result indicates that the rice signal peptidase recognizes and cleaves the novel sequence between the Amy3D signal peptide and the first amino acid of the mature human AAT. The highest molecular weight band seen on Western blots (AAT top band) was found to have the correct C-terminal amino acid sequence and normal elastase binding activity. Staining with biotin-concanavalin A and avidin horseradish peroxidase confirmed the glycosylation of the rAAT, albeit to a lesser extent than that observed with native AAT. The rAAT, purified by immunoaffinity chromatography, had the same association rate constant for porcine pancreatic elastase as the native AAT. Thermostability studies revealed that the rAAT and native AAT decayed at the same rate, suggesting that the rAAT is correctly folded. The productivity of rice suspension cells expressing rAAT was 4.6-5.7 mg/g dry cell. Taken together, these results support the use of rice cell culture as a promising new expression system for production of biologically active recombinant proteins.
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PMID:Production of functional human alpha 1-antitrypsin by plant cell culture. 1057 Jul 99

Alpha-1 antitrypsin (AAT; HUGO symbol, SERPINA1) is one of the major serine protease inhibitors (serpins) in human plasma. Deficiency of AAT is a recognised risk factor for chronic obstructive pulmonary disease (COPD), attributed to uninhibited neutrophil elastase released into the lung tissue during inflammatory states. In this study we used sequencing to screen the exonic regions, 5' and 3' flanking sequence of the AAT gene in order to generate a high density map of single nucleotide polymorphisms (SNPs). 16 SNPs were identified throughout AAT. Haplotypes based on SNPs with a minor allele frequency of > or =5% were estimated using genotypic information from 225 healthy control individuals and 41 AAT deficient Pi-ZZ individuals. AAT shows a large amount of variation in the control population, with 17 haplotypes accounting for 88% of the observed variation. The haplotype distribution of the common deficiency Pi-Z variant of AAT was significantly different when compared to the normal variants. In addition to the haplotype information, we present evidence for a functional effect of a SNP in intron 1.
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PMID:Haplotypes of the alpha-1 antitrypsin gene in healthy controls and Z deficiency patients. 1553 29

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.
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PMID:Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. 1856 11


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