کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5915933 | 1163342 | 2009 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Catalytic and ligand-binding characteristics of Plasmodium falciparum serine hydroxymethyltransferase
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کلمات کلیدی
THFMTHF5,10-Methylenetetrahydrofolate - 5،10-متیلن تترا هیدرو فولاتdhfr - DhfrEnzyme - آنزیم یا کاتالیزگرInhibitor - بازدارندهtetrahydrofolate - تتراهیدروفولاتdihydrofolate reductase - دی هیدروفلات ردوکتازdUMP - زبالهthymidylate synthase - سمیاتید تیمیدیلاتKinetics - سینتیک (جنبش شناسی) Malaria - مالاریاRNA binding - پیوند RNA
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شناسی مولکولی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The plant-like, bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) from malaria parasites has been a good target for drug development. Dihydrofolate reductase (DHFR) is inhibited by clinically established antimalarials, pyrimethamine and cycloguanil. Thymidylate synthase (TS) is the target of potent experimental antimalarials such as 5-fluoroorotate and 1843U89. Another enzyme in folate recycling, serine hydroxymethyltransferase (SHMT), produces 5,10-methylenetetrahydrofolate which, in many cells, is required for the de novo, biosynthesis of thymidine and methionine. Thus, the biochemical characterization of malarial SHMT was of interest. The principle, active Plasmodium falciparum SHMT (PfSHMT) was expressed in E. coli and purified using an N-terminal histidine tag. Unlike the plant enzyme, but like the host enzyme, PfSHMT requires the cofactor pyridoxal 5â²-phosphate for enzymatic activity. The substrate specificities for serine, tetrahydrofolate, and pyridoxal 5â²-phosphate were comparable to those for SHMT from other organisms. Antifolates developed for DHFR and TS inhibited SHMT in the mid-micromolar range, offering insights into the binding preferences of SHMT but clearly leaving room for improved new inhibitors. As previously seen with P. falciparum DHFR-TS, PfSHMT bound its cognate mRNA but not control RNA for actin. RNA binding was not reversed with enzyme substrates. Unlike DHFR-TS, the SHMT RNA-protein interaction was not tight enough to inhibit translation. Another gene PF14_0534, previously proposed to code for an alternate mitochondrial SHMT, was also expressed in E. coli but found to be inactive. This protein, nor DHFR-TS, enhanced the catalytic activity of PfSHMT. The present results set the stage for developing specific, potent inhibitors of SHMT from P. falciparum.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Molecular and Biochemical Parasitology - Volume 168, Issue 1, November 2009, Pages 74-83
Journal: Molecular and Biochemical Parasitology - Volume 168, Issue 1, November 2009, Pages 74-83
نویسندگان
Cullen K.T. Pang, Joshua H. Hunter, Ramesh Gujjar, Ramulu Podutoori, Julie Bowman, Devaraja G. Mudeppa, Pradipsinh K. Rathod,