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| Titel: |
Effect of dihydropyrimidine derivatives on kinetic parameters of E.carotovora L-asparaginase |
| Auteur: |
Warangkar S.C. Khobragade C.N. Dawane B.S. Bhosale R.B. |
| Verschenen in: |
International journal of biotechnology applications |
| Paginering: | Jaargang 1 (2009) nr. 1 pagina's 05-13 |
| Jaar: |
2009 |
| Inhoud: |
Purified L-asparaginase in combination with other anticancer drugs like pyrimidinederivatives is administered usually in the body to treat ALL. In the present study, L-asparaginase waspurified from Erwinia carotovora up to 247.6 fold and its catalytic properties were studied in thepresence of eight different dihydropyrimidine (DHP) derivatives, out of eight derivatives only two viz4- (2'-hydroxy phenyl) -6- methyl -2- thioxo)-1 -N - benzilydene - 1, 4 - dihydropyrimidine - 5 -carboxylic acid ethyl ester (P1) and 4 -(2'-hydroxy-5'-chlorophenyl)-5-acetyl-6-methyl-2 pyrimidinone(P2) were found to be activators of L-asparaginase. Their catalytic effect was assayed at optimum pH8.6 and at temperature 35°C in the absence and presence of derivatives P1 and P2 (20-40 μM) at 0.02-0.1 mM concentration of asparagine. It was found that derivatives below the concentration 5 μg/mlhave no effect on the activity. Derivative P1 is found to be a strong activator of the asparaginaseactivity that was reflected by an increase in the Vmax (1.75 fold by P1 and 2.80 fold by P2 respectively)and decrease in the Km (0.91 fold by P1 and 0.81 fold by P2 respectively). The activation ofasparaginase is explained by suppressing the cooperativity for the substrate, producing hyperbolickinetics with Km of 0.080 mM and by 3 fold increase in the Vmax of the enzyme. The activation byderivative P1 and P2 were additive, at optimal or suboptimal concentrations of both activators (up to 30μg/ ml). The DHP derivatives were further analyzed for quantitative SAR study (QSAR) by usingPASS, online software to determine their Pa value. Toxicity and drug relevant properties wereanalyzed by PALLAS software in terms of their molecular weight and log p values. The resultsshowed both the derivatives P1 and P2 are positive modulators of asparaginase activity and maysupport the development of novel combination therapy for the treatment of Leukemia and solid bloodtumors. |
| Uitgever: |
Bioinfo Publications (provided by DOAJ) |
| Bronbestand: |
Elektronische Wetenschappelijke Tijdschriften |
Details van artikel 2 van 5 gevonden artikelen
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