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

Holotyrosine phenol-lyase (EC 4.1.99.2), a pyridoxal-5'-phosphate (PLP)- requiring enzyme, was shown to rapidly dissociate when injected into BDF1 mice. The holoenzyme dissociated when incubated in plasma but not 0.01 M potassium phosphate (pH 7.4) buffer at 37 degrees C. A nonspecific alkaline phosphatase from calf intestine was found to inactivate the holoenzyme at pH 7.4 and 37 degrees C. This inactivation was inhibited in the presence of 0.5 M potassium phosphate buffer. Two other PLP-requiring enzymes, aspartate aminotransferase (EC 2.6.1.1), and alanine aminotransferase (EC 2.6.1.2) were inactivated by alkaline phosphatase in a similar manner. Incubation of holotyrosine phenol-lyase in the presence of bovine serum albumin also resulted in a reduction of holoenzyme activity but partially protected the enzyme from inactivation by alkaline phosphatase. A nuclear fraction having PLP-hydrolyzing activity also inactivated holotyrosine phenol-lyase. A regulatory function for alkaline phosphatase in the metabolism of PLP-requiring enzymes is suggested by these data.
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PMID:Albumin and alkaline phosphatase as factors involved in the regulation of tyrosine phenol-lyase activity. 65 5

Tyr225 in the active site of Escherichia coli aspartate aminotransferase (AspAT) was replaced by phenylalanine or arginine by site-directed mutagenesis. X-ray crystallographic analysis of Y225F AspAT showed that the benzene ring of Phe225 was situated at the same position as the phenol ring of Tyr225 in wild-type AspAT. The mutations resulted in a great decrease in the rate of the transamination reaction, suggesting that Tyr225 is important for efficient catalysis. The kinetic analysis of half-transamination reactions of Y225F AspAT with four substrates (aspartate, glutamate, oxalacetate, and 2-oxoglutarate) and some analogues (2-methylaspartate, succinate, and glutarate) revealed a considerable increase in the affinities for all these compounds. In contrast, affinity for the amino acid substrates was decreased by mutation to arginine, but affinities for the keto acid substrates and the two dicarboxylates (succinate and glutarate) were increased. The electrostatic interaction between O(3') of the coenzyme [pyridoxal 5'-phosphate (PLP)] and the residue at position 225 affected the pKa value of the Schiff base, which is formed between the epsilon-amino group of Lys258 and the aldehyde group of PLP; based on the spectrophotometric titration the pKa values were determined to be 6.8 for wild-type AspAT, 8.5 for Y225F AspAT, and 6.1 for Y225R AspAT in the absence of substrate. The absorption spectra of the three AspATs were almost identical in the acidic pH region, but the spectrum of Y225F AspAT differed from that of wild-type or Y225R AspAT in the alkaline pH region.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tyr225 in aspartate aminotransferase: contribution of the hydrogen bond between Tyr225 and coenzyme to the catalytic reaction. 186 10

Tyrosine phenol-lyase from Erwinia herbicola was purified from a cell-free extract in a single step on Cibacron Blue F3GA-agarose. The protein was purified as the apoenzyme and was unstable after affinity chromatography. Alanine aminotransferase and aspartate aminotransferase from porcine heart also bound to Cibacron Blue F3GA-agarose. These enzymes were partially purified as holoenzymes from a crude porcine heart extract by elution with NADH and KCl. Alanine aminotransferase was purified 19 fold by this procedure.
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PMID:Affinity chromatography of some pyridoxal phosphate-requiring enzymes on Cibacron Blue F3GA-agarose. 725 63

Tyrosine phenol-lyase (TPL), which catalyzes the beta-elimination reaction of L-tyrosine, and aspartate aminotransferase (AspAT), which catalyzes the reversible transfer of an amino group from dicarboxylic amino acids to oxo acids, both belong to the alpha-family of vitamin B6-dependent enzymes. To switch the substrate specificity of TPL from L-tyrosine to dicarboxylic amino acids, two amino acid residues of AspAT, thought to be important for the recognition of dicarboxylic substrates, were grafted into the active site of TPL. Homology modeling and molecular dynamics identified Val-283 in TPL to match Arg-292 in AspAT, which binds the distal carboxylate group of substrates and is conserved among all known AspATs. Arg-100 in TPL was found to correspond to Thr-109 in AspAT, which interacts with the phosphate group of the coenzyme. The double mutation R100T/V283R of TPL increased the beta-elimination activity toward dicarboxylic amino acids at least 10(4)-fold. Dicarboxylic amino acids (L-aspartate, L-glutamate, and L-2-aminoadipate) were degraded to pyruvate, ammonia, and the respective monocarboxylic acids, e.g. formate in the case of L-aspartate. The activity toward L-aspartate (kcat = 0.21 s-1) was two times higher than that toward L-tyrosine. beta-Elimination and transamination as a minor side reaction (kcat = 0.001 s-1) were the only reactions observed. Thus, TPL R100T/V283R accepts dicarboxylic amino acids as substrates without significant change in its reaction specificity. Dicarboxylic amino acid beta-lyase is an enzyme not found in nature.
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PMID:Conversion of tyrosine phenol-lyase to dicarboxylic amino acid beta-lyase, an enzyme not found in nature. 988 May 2

Central neuropeptides play important roles in many instances of physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Stressors and sympathetic nerve activation are reported to exacerbate experimental liver injury. Some stressors are known to stimulate corticotropin-releasing factor (CRF) synthesis in the central nervous system and induce activation of sympathetic nerves in animal models. The effect of intracisternal CRF on carbon tetrachloride (CCl4)-induced acute liver injury was examined in rats. Intracisternal injection of CRF dose dependently enhanced elevation of the serum alanine aminotransferase (ALT) level induced by CCl4. Elevations of serum aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels by CCl4 were also enhanced by intracisternal CRF injection. Intracisternal injection of CRF also aggravated CCl4-induced hepatic histological changes. Intracisternal CRF injection alone did not modify the serum ALT level. Intravenous administration of CRF did not influence CCl4-induced acute liver injury. The aggravating effect of central CRF on CCl4-induced acute liver injury was abolished by denervation of hepatic plexus with phenol and by denervation of noradrenergic fibers with 6-hydroxydopamine treatment but not by hepatic branch vagotomy or atropine treatment. These results suggest that CRF acts in the brain to exacerbate acute liver injury through the sympathetic-noradrenergic pathways.
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PMID:Effect of central corticotropin-releasing factor on carbon tetrachloride-induced acute liver injury in rats. 1007 38

Proliferol is an investigational new drug containing lidocaine hydrochloride 0.25%, dextrose 12.5%, glycerin 12.5%, and phenol 1.0% in aqueous solution. Despite extensive human experience with similar drugs administered by intraligamentous injection for chronic musculoskeletal disorders, little is known concerning preclinical toxicity. The purpose of this study was to assess the acute toxicity of intramuscular Proliferol in 96 (48 male, 48 female) Charles River strain rats, which were randomly assigned to low- (1x), medium- (5x), or high- (10x) dose Proliferol (derived from a human dose of 20 ml on a volume per bodyweight basis), or high-dose saline placebo. Observations included clinical observations, biochemistry, hematology, urinalysis, and full histopathology after 24 h or 14 days. There were no signs of ill health or reaction to treatment, and gait and body temperature were within normal limits. Biochemistry findings at 24 h included elevated aspartate aminotransferase, alanine aminotransferase, and haptoglobin; at 14 days all values were within normal ranges. Urinalysis findings at 24 h included increased urobilinogen and blood in all dose groups compared with placebo. Urine concentrations of phenol and lidocaine were greatest at 2 h and absent at 24 h. Histopathology findings included localized acute inflammatory soft tissue changes at the injection sites at 24 h and skeletal muscle regeneration at 14 days, which were consistent with the anticipated mechanism of action of Proliferol. There was no evidence of systemic toxicity from intramuscular injection of Proliferol in rats at up to 10x the human dose.
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PMID:Acute toxicity evaluation of proliferol: a dose-escalating, placebo-controlled study in rats. 1796 32

The aim of this study was to investigate the possible beneficial effects of amburoside A, AMB [4-(O-beta- D-glycopyranosyl)benzyl protocatechoate], against carbon tetrachloride (CCl (4)) toxicity in rats. AMB is a phenol glucoside from the Brazilian medicinal plant Amburana cearensis, popularly used for the treatment of respiratory tract affections. Acute AMB (25 and 50 mg/kg, I. P. or P. O.) treatments of CCl (4)-intoxicated rats significantly inhibited the increase in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, as compared to the group treated with CCl (4) only. Histological studies showed less centrolobular necrosis and inflammatory cell infiltrates in the liver of animals treated with AMB plus CCl (4), when compared to the group treated with CCl (4) alone. In hepatic tissues, AMB at both doses inhibited CCl (4)-induced thiobarbituric acid-reactive substances (TBARS) formation, indicating a blockade of CCl (4)-induced lipid peroxidation. AMB also reversed the decrement in glutathione contents of hepatic tissues in CCl (4)-intoxicated rats. Furthermore, it restored catalase activity to normal values, which was significantly increased after CCl (4) treatment. Our results indicate that CCl (4)-induced oxidative damage in hepatic tissues is reversed by AMB treatment. The protective effect of AMB is probably due to the phenolic nature of this glucoside.
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PMID:Protective effects of amburoside A, a phenol glucoside from Amburana cearensis, against CCl4-induced hepatotoxicity in rats. 1840 96

Cirsium arisanense Kitamura (Compositae) has been used for hundreds of years in Taiwan as a folk medicine for hepatoprotection. However, no scientific research has demonstrated this effect. In the present study, we extracted the phenol-containing aqueous components of C. arisanense roots (CaR) and leaves/stem (CaL), and then assessed their hepatoprotective activities in both human hepatocellular carcinoma Hep 3B cells and C57BL/6 mice strain. High performance liquid chromatography (HPLC) analysis revealed that the components of CaR and CaL differed from those of the positive control silymarin. CaR exhibited a higher phenolic content and antioxidant capacity than CaL. Hep 3B cells treated with silymarin (0-200 microg/ml) demonstrated a concentration-dependent decrease in viability; however, both CaR and CaL did not exhibit any apparent cytotoxicity. Silymarin at 100 microg/ml, as well as CaR and CaL, not only protect Hep 3B cells from tacrine-induced hepatotoxicity but also decrease the expression of hepatitis B surface antigen (HBsAg). Moreover, an animal experiment demonstrated that CaR, CaL, and silymarin have hepatoprotective effects in C57BL/6 mice injected with tacrine, and they significantly decrease the levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST). These effects of CaR and silymarin, but not of CaL, may occur via an increase in the hepatic glutathione level and the elimination of the nitric oxide production. In conclusion, the phenol-containing aqueous components from C. arisanense have potential in hepatoprotection.
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PMID:Hepatoprotective effect of Cirsium arisanense Kitamura in tacrine-treated hepatoma Hep 3B cells and C57BL mice. 1845 66

This study sought to characterize the distribution of phenols and antioxidant activities in hot short pepper (Capsicum frutescens var. abbreviatum) and their inhibition of cyclophosphamide-induced oxidative stress in rat's brain. The total phenol content and antioxidant activities of pepper flesh (pericarp) and seeds were determined in vitro and in vivo. The results of the study revealed that intraperitoneal administration of cyclophosphamide (75mg/kg of body weight) caused a significant increase (P<0.05) in the malondialdehyde (MDA) content of the brain; however, there was a significant decrease (P<0.05) in the brain MDA content, in those of rats fed diet containing pepper; the flesh showed a higher inhibitory effect. In addition, dietary inclusion of the pepper (seed and flesh) also caused a dose-dependent inhibition of serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate transaminase (SGPT), alkaline phosphatase and total bilirubin; likewise, dietary inclusion of the flesh inhibited MDA production than the seeds. The higher inhibition of oxidative stress in brain and serum enzymes and metabolites by the flesh could be attributed to its significantly higher (P<0.05) total phenol content, reducing power and free-radical scavenging ability. Therefore, dietary hot short pepper (Capsicum frutescens L. var. abbreviatum) could prevent cyclophosphamide-induced oxidative stress in brain; although the flesh is a better protectant, the possible contributory role of the seeds cannot be neglected. However, this protective effect of the pepper could be attributed to their antioxidant properties.
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PMID:Cyclophosphamide-induced oxidative stress in brain: protective effect of hot short pepper (Capsicum frutescens L. var. abbreviatum). 1944 89

Prolotherapy is one of the many treatments available for chronic musculoskeletal disorders. A commonly used drug contains dextrose 12.5%, glycerin 12.5%, phenol 1.0%, and lidocaine hydrochloride 0.25% in aqueous solution (recently termed Proliferol). For chronic low back pain, this is injected into lumbosacral ligaments to stimulate connective tissue repair. Despite generally positive clinical results, the toxicity of this drug is not well characterized and was assessed in 48 (24 male, 24 female) Yucatan miniature swine randomly assigned to low (1x), medium (5x), or high (10x) dose or saline placebo. Outcomes included clinical observations, clinical chemistry, hematology, coagulation, urinalysis, toxicokinetics, and full gross and microscopic histopathology after 24 hours or 14 days. Findings attributable to Proliferol after 24 hours included dose-response elevations in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase, which returned to normal after 14 days. There were no remarkable findings in hematology, coagulation, or urinalysis. Urine concentrations of lidocaine and phenol both peaked after 8 hours. Histopathology findings after 24 hours included hemorrhage, inflammation, necrosis, and vascular changes in the ligaments and adjacent soft tissues at the sites of injection. After 14 days, there was evidence of repair under way, with fibrosis and skeletal muscle regeneration at the injection sites.
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PMID:Acute toxicity evaluation of proliferol: a dose-escalating, placebo-controlled study in swine. 1954 60


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