Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P17174 (aspartate aminotransferase)
 14,872 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The homodimeric, pyridoxal 5'-phosphate (PLP)-dependent enzyme glutamine transaminase K/cysteine conjugate beta-lyase (GTK/beta-lyase) has been implicated in the bioactivation of chemopreventive compounds. This paper describes the first homology model of rat renal GTK/beta-lyase and its active site residues, deduced from molecular dynamics (MD) simulations of the binding mode of 13 structurally diverse cysteine S-conjugates and amino acids after Amber-parametrization of PLP. Comparison with Thermus thermophilus aspartate aminotransferase (tAAT) and Trypanosoma cruzi tyrosine aminotransferase (tTAT), used as templates for modeling GTK/beta-lyase, showed that the PLP-binding site of GTK/beta-lyase is highly conserved. Binding of the ligand alpha-carboxylate-group occurred via the conserved residues Arg(432) and Asn(219), and Asn(50) and Gly(70). Two pockets accommodated the various ligand side chains. A small pocket, located directly above PLP, was of a highly hydrophobic and aromatic character. A larger pocket, formed partly by the substrate access channel, was more hydrophilic and notably involved the salt bridge partners Glu(54) and Arg(99*) (* denotes the other subunit). Ligand-binding residues included Leu(51), Phe(71), Tyr(135), Phe(373) and Phe(312*), and pi-stacking interactions were often observed. Tyr(135) and Asn(50) were prominent in hydrogen bonding with the sulfur-atom of cysteine S-conjugates. The observed binding mode of the ligands corresponded well with their experimentally determined inhibitory potency toward GTK/beta-lyase. The current homology model thus provides a starting point for further validation of the role of active site residues in ligand-binding by means of mutagenesis studies. Ultimately, insight in the binding of ligands to GTK/beta-lyase may result in the rational design of new ligands and selective inhibitors.
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PMID:Modeling and molecular dynamics of glutamine transaminase K/cysteine conjugate beta-lyase. 1279 91

The aryl hydrocarbon receptor (AHR) binds planar aromatic compounds and up-regulates the transcription of a battery of xenobiotic-metabolizing enzymes. To identify proteins involved in the biosynthesis of endogenous AHR ligands, we screened extracts of various mouse tissues for AHR signaling activity. We found heart extract to activate AHR and identified the active component to be the enzyme aspartate aminotransferase (EC 2.6.1.1). We demonstrate that this transaminase can activate AHR signaling by converting l-tryptophan to indole-3-pyruvate. In turn, indole-3-pyruvate spontaneously reacts in aqueous solution to form a large number of compounds that act as agonists of AHR. Tyrosine and the serotonin-precursor 5-hydroxytryptophan also activate AHR signaling in combination with aspartate aminotransferase, suggesting that 4-hydroxyphenylpyruvate and 5-hydroxyindolepyruvate also act as proagonists of AHR. This study demonstrates that the known tryptophan metabolic-intermediate indole-3-pyruvate is a proagonist of AHR that reacts in aqueous solution to form a variety of AHR agonists.
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PMID:Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor. 1292 Jan 90

4-Aminophenol (4-AP) and D-serine are established rodent nephrotoxins that selectively damage renal proximal tubules. In an attempt to understand the mechanism of action of these toxicants in greater detail, a high throughput proteomics approach was used to profile protein changes in the plasma of animals treated with these compounds. Male Fischer 344 and Alderley Park rats were treated with increasing doses of 4-AP or D-serine and plasma samples were collected over time. Control groups received either saline or the non-toxic enantiomer, L-serine. Using high throughput two-dimensional gel analysis, a number of plasma proteins showing dose- and time-dependent regulation were identified. One toxicity-associated plasma protein was identified as the cellular enzyme fumarylacetoacetate hydrolase (FAH), which is known to be required for tyrosine metabolism. The FAH gene is mutated in the human genetic disorder type I tyrosinaemia, which is associated with liver and kidney abnormalities and neurological disorders. FAH was elevated in the plasma of animals treated with 4-AP and D-serine at early time points and returned to baseline levels after 3 weeks. The protein was not elevated in the plasma of control animals or those treated with L-serine. The presence of FAH in plasma is intriguing as it is normally a cellular enzyme with no known function in plasma. It is possible that 4-AP and D-serine may work through a previously unknown mechanism in the kidney via regulation of tyrosine metabolism or FAH activity. Therefore, FAH may function in a fashion analogous to the aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes that are used to measure liver injury. The link between kidney toxicants and inherited tyrosinaemia also raises the possibility that FAH may be a marker of kidney toxicity in humans. These observations highlight the value of proteomics in identifying new biomarkers and providing new unprecedented insights into complex biological mechanisms.
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PMID:A potential biomarker of kidney damage identified by proteomics: preliminary findings. 1294 77

A subfamily I aminotransferase gene homologue containing an open reading frame encoding 381 amino acid residues (Mr=42,271) has been identified in the process of the genome project of an extremely thermophilic bacterium, Thermus thermophilus HB8. Alignment of the predicted amino acid sequence using FASTA shows that this protein is a member of aminotransferase subfamily Igamma. The protein shows around 40% identity with both T. thermophilus aspartate aminotransferase [EC 2.6.1.1] and mammalian glutamine:phenylpyruvate aminotransferase [EC 2.6.1.64]. The recombinant protein expressed in Escherichia coli is a homodimer with a subunit molecular weight of 42,000, has one pyridoxal 5'-phosphate per subunit, and is highly active toward glutamine, methionine, aromatic amino acids, and corresponding keto acids, but has no preference for alanine and dicarboxylic amino acids. These substrate specificities are similar to those described for mammalian glutamine: phenylpyruvate aminotransferase. This is the first enzyme reported so far that has the glutamine aminotransferase activity in non-eukaryotic cells. As the presence of aromatic amino acid:2-oxoglutarate aminotransferase [EC 2.6.1.57] has not been reported in T. thermophilus, this enzyme is expected to catalyze the last transamination step of phenylalanine and tyrosine biosynthesis. It may also be involved in the methionine regeneration pathway associated with polyamine biosynthesis. The enzyme shows a strikingly high pKa value (9.3) of the coenzyme Schiff base in comparison with other subfamily I aminotransferases. The origin of this unique pKa value and the substrate specificity is discussed based on the previous crystallographic data of T. thermophilus and E. coli aspartate aminotransferases.
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PMID:Glutamine:phenylpyruvate aminotransferase from an extremely thermophilic bacterium, Thermus thermophilus HB8. 1476 73

X-linked hyper-immunoglobulin M (IgM) syndrome (XHIGM) is a rare genetic primary immunodeficiency disease caused by mutations of the CD40 ligand (CD40L) gene with normal or elevated levels of IgM and markedly decreased serum IgG, IgA, and IgE. Liver disease may occur as a clinical manifestation in XHIGM. This complication appears to increase with age. We report an 18-year-old male patient who had recurrent episodes of acalculous cholecystitis (AC) and sclerosing cholangitis (SC). The diagnosis of XHIGM was confirmed by the finding of CD40L expression < 1% of normal and a tyrosine 169 asparaginase (t526a) mutation in exon 5 (the tumor necrosis factor domain) of the CD40L gene. The patient had direct hyperbilirubinemia (direct bilirubin 5.5 mg/dL, total bilirubin 8.7 mg/dL), cholestasis (alkaline phosphatase 1133 U/L, gamma-glutamyl transferase 1019 U/L) and elevated transaminases (aspartate aminotransferase 70 U/L, alanine aminotransferase 101 U/L). Findings on abdominal ultrasound and abdominal computed tomography were compatible with AC. After the fourth episode of cholecystitis, cholecystectomy and liver biopsy were performed. Operative cholangiography revealed poor opacification of the hepatic duct and proximal common bile duct; the upstream intrahepatic bile ducts were not visualized. The biopsy specimen showed marked fibrosis of the portal areas. Enterococcus species was cultured from the bile. Children or adolescents with recurrent AC and SC should be evaluated for an underlying immunodeficiency syndrome such as XHIGM.
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PMID:Recurrent acalculous cholecystitis and sclerosing cholangitis in a patient with X-linked hyper-immunoglobulin M syndrome. 1603 32

We have increased the contents of several amino acids in the seeds of Arabidopsis thaliana by introduction of aspartate aminotransferase (AAT), an enzyme of the aspartate biosynthetic pathway. mRNA was prepared from one-week-old seedlings of Glycine max cv. enrei and the cDNA encoding AAT5 was isolated and linked to the CaMV35S promoter in the plant vector pBI121. The AAT5 gene encodes a protein of 462 amino acid residues that shows 51% amino acid sequence similarity to A. thaliana chloroplast Asp3. The soybean AAT5 also contains a chloroplast transit peptide and is able to functionally complement a Saccharomyces cerevisiae mutant lacking the Asp5 gene. A. thaliana was transformed with the AAT5 gene from Agrobacterium tumefaciens by the vacuum infiltration method. The AAT5 gene was detected in the transcript and genomic DNA from the transgenic T2 plants. The T3 progeny showed a 3:1 segregation ratio indicating the presence of a single integration. Expression of G. max AAT5 in A. thaliana transformants caused 3-, 4-, 23-, and 50-fold increases in the contents of free glycine, alanine, asparagine, and glutamine, respectively, in the T3 seeds. A decrease in the contents of valine, tyrosine, isoleucine, leucine, and phenylalanine by several folds was also observed. Thus, it is of interest that a key gene expression resulted in marked changes of metabolites in plant seeds.
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PMID:Variation of the amino acid content of Arabidopsis seeds by expressing soybean aspartate aminotransferase gene. 1623 95

The protective effect of a 30 kDa glycoprotein (GF-AS) isolated from the stem bark of Acanthopanax senticosus against acute and chronic alcohol-induced hepatotoxicity were studied. N-terminal amino acid sequence of GF-AS showed NH(2)-Val-Ala-Tyr-Pro-Trp-Ala-Gly-Phe-Ala-Leu-Ser-Leu-Glx-Pro-Pro-Ala-Gly-Tyr-. GF-AS significantly increases the activities of alcohol-metabolizing enzymes, including alcohol dehydrogenase, microsomal ethanol metabolizing system, and acetaldehyde dehydrogenase in rats acutely treated with alcohol, resulting in decreased plasma alcohol levels. GF-AS also increases the activities of antioxidant enzymes and glutathione level. Markers of liver injury induced by alcohol: elevated serum levels of aspartate aminotransferase, alanine aminotransferase, triglyceride and cholesterol, are reduced by GF-AS in both acutely and chronically treated rats. The activities of lipogenic enzymes including malic enzyme, glucose-6-phosphate dehydrogenase, and 6-phosphoglucuronic acid dehydrogenase in chronic alcohol-treated rats are significantly decreased by GF-AS. Furthemore, GF-AS improves histological change in fatty liver and hepatic lesions induced by alcohol. Collectively, GF-AS may alleviate alcohol-induced hepatotoxicity through increasing ethanol and lipid metabolism, as well as antioxidant defense systems in livers injured by acute- and chronic-alcohol treatment.
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PMID:Glycoprotein isolated from Acanthopanax senticosus protects against hepatotoxicity induced by acute and chronic alcohol treatment. 1646 37

This study investigated the in vivo effects of the Bothrops jararaca venom (BjV) on general metabolic profile and, specifically, on muscle protein metabolism in rats. The crude venom (0.4 mg/kg body weight, IV) was infused in awake rats, and plasma activity of enzymes and metabolites levels were determined after 1, 2, 3, and 4 hours. BjV increased urea, lactate, and activities of creatine kinase, lactate dehydrogenase, and aspartate aminotransferase after 4 hours. The content of liver glycogen was reduced by BjV. Protein metabolism was evaluated by means of microdialysis technique and in isolated muscles. BjV induced increase in the muscle interstitial-arterial tyrosine concentration difference, indicating a high protein catabolism. The myotoxicity induced by this venom is associated with reduction of protein synthesis and increase in rates of overall proteolysis, which was accompanied by activation of lysosomal and ubiquitin-proteasome systems without changes in protein levels of cathepsins and ubiquitin-protein conjugates.
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PMID:In vivo effects of Bothrops jararaca venom on metabolic profile and on muscle protein metabolism in rats. 1898 21

3-Acetamido-3,6-dideoxy-alpha-d-glucose or Quip3NAc is an unusual deoxyamino sugar found in the O-antigens of some Gram-negative bacteria and in the S-layers of Gram-positive bacteria. It is synthesized in these organisms as a dTDP-linked sugar via the action of five enzymes. The focus of this investigation is on QdtB from Thermoanaerobacterium thermosaccharolyticum E207-71, a PLP-dependent aminotransferase that catalyzes the penultimate step in the production of dTDP-Quip3NAc. For this analysis, the enzyme was crystallized in the presence of its product, dTDP-Quip3N, and the structure was solved and refined to 2.15 A resolution. QdtB is a dimer, and its overall fold places it into the well-characterized aspartate aminotransferase superfamily. Electron density corresponding to the bound product reveals the presence of a Schiff base between C-4' of the PLP cofactor and the amino nitrogen of the sugar. Those amino acid side chains involved in binding the dTDP-sugar into the active site include Tyr 183, His 309, and Tyr 310 from subunit 1 and Lys 219 from subunit 2. Notably there is a decided lack of interactions between the pyranosyl C-4' hydroxyl of the dTDP-sugar and the protein. In keeping with this observation, we show that QdtB can also turn over dTDP-3-acetamido-3,6-dideoxy-alpha-d-galactose. This investigation represents the first structural analysis of a sugar-modifying aminotransferase with a bound product in its active site that functions at the C-3' rather than the C-4' position of the hexose.
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PMID:Structural analysis of QdtB, an aminotransferase required for the biosynthesis of dTDP-3-acetamido-3,6-dideoxy-alpha-D-glucose. 1917 82

Hepatic fibrosis is a major complication of various chronic liver diseases. Activated hepatic stellate cells (HSCs) play a critical role in the development of liver fibrosis and the axis of platelet-derived growth factor (PDGF)/PDGF receptor (PDGFR), a member of receptor tyrosine kinases (RTKs), is closely associated with the activation of HSC. Insulin-like growth factor (IGF)-1 receptor (IGF-1R), which also belongs to RTKs, interacts with the PDGF/PDGFR axis, thereby cooperatively promoting hepatic fibrosis. We herein examined the effects of (-)-epigallocatechin gallate (EGCG), which inhibits the activation of several types of RTKs, on the development of rat liver fibrosis induced by carbon tetrachloride (CCl4). Drinking water with 0.1% EGCG significantly decreased the serum levels of both aspartate aminotransferase and alanine aminotransferase raised by CCl4, thus indicating an improvement of liver injury. In CCl4-injected rats, EGCG markedly attenuated hepatic fibrosis and decreased the amount of hydroxyproline in the experimental liver. The expression of PDGFRbeta and IGF-1R mRNAs in the liver was significantly lowered by the treatment with EGCG. EGCG also decreased the expression of PDGFRbeta and alpha-smooth muscle actin proteins, thus indicating the inhibition of HSC activation. These findings suggest that EGCG can exert, at least in part, an anti-fibrotic effect on the liver by targeting PDGFRbeta and IGF-1R. EGCG might therefore be useful in both the prevention and treatment of hepatic fibrosis.
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PMID:(-)-Epigallocatechin gallate prevents carbon tetrachloride-induced rat hepatic fibrosis by inhibiting the expression of the PDGFRbeta and IGF-1R. 1964 78


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