DNA and RNA Synthesis:  Antifolates

Kompis, I.; Islam, Khalid; Then, Rudolf L.

doi:10.1021/cr0301144

Cited by 216 publications

(162 citation statements)

References 250 publications

(468 reference statements)

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“…DHFR is part of a bifunctional enzyme required for the synthesis of tetrahydrofolate, an essential precursor of purines and several amino acids (10,11). Although pyrimethamine and other antifolates are currently the first-line treatment for malaria in many parts of Africa (12)(13)(14), high-level resistance has been reported elsewhere (4,13,15).…”

mentioning

confidence: 99%

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

Lozovsky

Chookajorn

Brown

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

266

328

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The spread of high-level pyrimethamine resistance in Africa threatens to curtail the therapeutic lifetime of antifolate antimalarials. We studied the possible evolutionary pathways in the evolution of pyrimethamine resistance using an approach in which all possible mutational intermediates were created by site-directed mutagenesis and assayed for their level of drug resistance. The coding sequence for dihydrofolate reductase (DHFR) from the malaria parasite Plasmodium falciparum was mutagenized, and tests were carried out in Escherichia coli under conditions in which the endogenous bacterial enzyme was selectively inhibited. We studied 4 key amino acid replacements implicated in pyrimethamine resistance: N51I, C59R, S108N, and I164L. Using empirical estimates of the mutational spectrum in P. falciparum and probabilities of fixation based on the relative levels of resistance, we found that the predicted favored pathways of drug resistance are consistent with those reported in previous kinetic studies, as well as DHFR polymorphisms observed in natural populations. We found that 3 pathways account for nearly 90% of the simulated realizations of the evolution of pyrimethamine resistance. The most frequent pathway (S108N and then C59R, N51I, and I164L) accounts for more than half of the simulated realizations. Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa.adaptive landscape ͉ drug resistance ͉ evolution

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mentioning

confidence: 99%

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

Lozovsky

Chookajorn

Brown

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

266

328

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“…Like most eukaryotes, humans depend upon ThyA, so there has been special interest in the enzyme of ThyX-dependent pathogens such as Helicobacter pylori, Campylobacter jejuni, Borrelia burgdorferi, and Treponema pallidum (see reference 22 for a review). ThyX in these organisms is an attractive drug target (4,6,15,23). Eubacterial species in the corynebacterium group are unusual because they have retained the genes for both the ThyA/ DHFR and the ThyX pathways (22,23).…”

mentioning

confidence: 99%

Functional Analysis of the Mycobacterium tuberculosis FAD-Dependent Thymidylate Synthase, ThyX, Reveals New Amino Acid Residues Contributing to an Extended ThyX Motif

et al. 2008

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A novel FAD-dependent thymidylate synthase, ThyX, is present in a variety of eubacteria and archaea, including the mycobacteria. A short motif found in all thyX genes, RHRX 7-8 S, has been identified. The three-dimensional structure of the Mycobacterium tuberculosis ThyX enzyme has been solved. Building upon this information, we used directed mutagenesis to produce 67 mutants of the M. tuberculosis thyX gene. Each enzyme was assayed to determine its ability to complement the defect in thymidine biosynthesis in a ⌬thyA strain of Escherichia coli. Enzymes from selected strains were then tested in vitro for their ability to catalyze the oxidation of NADPH and the release of a proton from position 5 of the pyrimidine ring of dUMP. The results defined an extended motif of amino acids essential to enzyme activity in M. tuberculosis (Y44X 24 H69X 25 R95H RX 7 S105XRYX 90 R199 [with the underlined histidine acting as the catalytic residue and the underlined serine as the nucleophile]) and provided insight into the ThyX reaction mechanism. ThyX is found in a variety of bacterial pathogens but is absent in humans, which depend upon an unrelated thymidylate synthase, ThyA. Therefore, ThyX is a potential target for development of antibacterial drugs.

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“…DHFR bakteri, protozoa ve mantarlarca oluşan çeşitli enfeksiyonların ve kansere karşı geliştirilen ilaçların önemli bir hedefidir (Şekil 2) [4,26].…”

Section: Dihidrofolat Redüktaz (Dhfr)unclassified

Folat Eksikliği ve Probiyotikler

Yuksekdag¹

2014

Nevşehir Bilim Ve Teknoloji Dergisi

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ÖzetFolat, insanların canlılık faaliyetlerini sürdürmesi için çok önemlidir. Organizmanın tek karbon reaksiyonlarına katılarak, hayati faaliyetleri katalizlediğinden folat eksikliği organizma için ciddi risk taşımaktadır. İnsanlarda folat eksikliği ile ilişkili olarak birçok hastalık baş gösterebilir. İnsanlar folatı sentezleyemediğinden, dışarıdan folat bakımından zengin gıdalarla ve folik asit takviyesi ile folat ihtiyaçlarını gidermektedirler. Bu nedenle diyette sık tüketilen gıdaların folat bakımından zengin olması önem kazanmaktadır.Bu amaçla gıdalardaki folat miktarını arttırıcı etkenler belirlenip gıdalarda folat miktarının arttırılması sağlanabilir. Yoğurt gibi fermente gıdalardaki folatın etkenleri olan probiyotik laktik asit bakterilerinin bu amaca hizmet edebileceği düşünülmektedir.Yüksek folat üreten probiyotik suşlarla üretilen fermente gıdaların tüketimi ile insanlardaki folat eksikliğinin görülme sıklığı azaltılabilecektir.Anahtar Kelimeler: Folat, folat eksikliği, probiyotik, laktik asit bakterileri Folate Deficiency and Probiotics AbstractFolate is very important for people to continue the activities of vitality. The main reason for this participate the one carbon reactions of the organism. When these reactions are to catalysis the vital activity, folate deficiency is a serious risk to the organism. Even occur in many diseases associated with folate deficiency in people. Hence people cannot synthesize folate, folate-rich foods and folic acid supplements with the outside must be obtained. Therefore its importance gaining from folate-rich foods frequently consumed in the diet. For this purpose, increasing factors the amount of folate in foods can be identified, increasing the amount of folate in foods can be provided. Folate agent such as probiotic lactic acid bacteria in fermented foods (especially yogurt) are thought to serve this purpose. Fermented foods which are produced by probiotic high folate producing strains will reduce the prevalence of folate deficiency in people.

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DNA and RNA Synthesis: Antifolates

Cited by 216 publications

References 250 publications

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

Stepwise acquisition of pyrimethamine resistance in the malaria parasite

Functional Analysis of the Mycobacterium tuberculosis FAD-Dependent Thymidylate Synthase, ThyX, Reveals New Amino Acid Residues Contributing to an Extended ThyX Motif

Folat Eksikliği ve Probiyotikler

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