tetrahydrofolate dehydrogenase

Summary

Summary: An enzyme of the oxidoreductase class that catalyzes the reaction 7,8-dihyrofolate and NADPH to yield 5,6,7,8-tetrahydrofolate and NADPH+, producing reduced folate for amino acid metabolism, purine ring synthesis, and the formation of deoxythymidine monophosphate. Methotrexate and other folic acid antagonists used as chemotherapeutic drugs act by inhibiting this enzyme. (Dorland, 27th ed) EC 1.5.1.3.

Top Publications

  1. ncbi Intercontinental spread of pyrimethamine-resistant malaria
    Cally Roper
    London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
    Science 305:1124. 2004
  2. pmc Drug coverage in treatment of malaria and the consequences for resistance evolution--evidence from the use of sulphadoxine/pyrimethamine
    Allen L Malisa
    Department of Biological Sciences, Faculty of Science, Sokoine University of Agriculture, SUA, PO Box 3038, Morogoro, Tanzania
    Malar J 9:190. 2010
  3. pmc A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis
    Gira Bhabha
    Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Science 332:234-8. 2011
  4. ncbi A selective sweep driven by pyrimethamine treatment in southeast asian malaria parasites
    Shalini Nair
    Southwest Foundation for Biomedical Research, San Antonio, Texas, USA
    Mol Biol Evol 20:1526-36. 2003
  5. ncbi Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence
    M R Sawaya
    Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093 0506, USA
    Biochemistry 36:586-603. 1997
  6. ncbi Therapeutic efficacy of chloroquine in Plasmodium vivax from areas with different epidemiological patterns in India and their Pvdhfr gene mutation pattern
    Neena Valecha
    Malaria Research Centre ICMR, 22 Sham Nath Marg, Delhi 110 054, India
    Trans R Soc Trop Med Hyg 100:831-7. 2006
  7. pmc Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistance alleles in a population from central Africa
    Andrea M McCollum
    Program in Population Biology, Ecology, and Evolution, Emory University, Atlanta, Georgia, USA
    Antimicrob Agents Chemother 52:4089-97. 2008
  8. pmc Stepwise acquisition of pyrimethamine resistance in the malaria parasite
    Elena R Lozovsky
    Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
    Proc Natl Acad Sci U S A 106:12025-30. 2009
  9. pmc Network of coupled promoting motions in enzyme catalysis
    Pratul K Agarwal
    Department of Chemistry, 152 Davey Laboratory, Pennsylvania State University, University Park, PA 16802, USA
    Proc Natl Acad Sci U S A 99:2794-9. 2002
  10. pmc Association of genetic mutations in Plasmodium vivax dhfr with resistance to sulfadoxine-pyrimethamine: geographical and clinical correlates
    M Imwong
    Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Antimicrob Agents Chemother 45:3122-7. 2001

Detail Information

Publications261 found, 100 shown here

  1. ncbi Intercontinental spread of pyrimethamine-resistant malaria
    Cally Roper
    London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK
    Science 305:1124. 2004
    ..The resistance alleles carried by these migrants are now spreading across Africa at an alarming rate, signaling the end of affordable malaria treatment and presenting sub-Saharan Africa with a public health crisis...
  2. pmc Drug coverage in treatment of malaria and the consequences for resistance evolution--evidence from the use of sulphadoxine/pyrimethamine
    Allen L Malisa
    Department of Biological Sciences, Faculty of Science, Sokoine University of Agriculture, SUA, PO Box 3038, Morogoro, Tanzania
    Malar J 9:190. 2010
    ..These models show that where the basis of resistance is multigenic, the effects of selection can be moderated by high recombination rates, which disrupt the associations between co-selected resistance genes...
  3. pmc A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis
    Gira Bhabha
    Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Science 332:234-8. 2011
    ....
  4. ncbi A selective sweep driven by pyrimethamine treatment in southeast asian malaria parasites
    Shalini Nair
    Southwest Foundation for Biomedical Research, San Antonio, Texas, USA
    Mol Biol Evol 20:1526-36. 2003
    ....
  5. ncbi Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence
    M R Sawaya
    Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093 0506, USA
    Biochemistry 36:586-603. 1997
    ..Loop movement, also unobserved in vertebrate DHFR structures, may preferentially weaken NADP+ vs NADPH binding in ecDHFR, an evolutionary adaptation to reduce product inhibition in the NADP+ rich environment of prokaryotes...
  6. ncbi Therapeutic efficacy of chloroquine in Plasmodium vivax from areas with different epidemiological patterns in India and their Pvdhfr gene mutation pattern
    Neena Valecha
    Malaria Research Centre ICMR, 22 Sham Nath Marg, Delhi 110 054, India
    Trans R Soc Trop Med Hyg 100:831-7. 2006
    ..Although P. vivax has been reported to be inherently resistant to sulfonamide and pyrimethamine, Indian isolates exhibited only double mutations in dhfr in vitro...
  7. pmc Hitchhiking and selective sweeps of Plasmodium falciparum sulfadoxine and pyrimethamine resistance alleles in a population from central Africa
    Andrea M McCollum
    Program in Population Biology, Ecology, and Evolution, Emory University, Atlanta, Georgia, USA
    Antimicrob Agents Chemother 52:4089-97. 2008
    ....
  8. pmc Stepwise acquisition of pyrimethamine resistance in the malaria parasite
    Elena R Lozovsky
    Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
    Proc Natl Acad Sci U S A 106:12025-30. 2009
    ..Our results also suggest an explanation for why I164L is detected in Southeast Asia and South America, but not at significant frequencies in Africa...
  9. pmc Network of coupled promoting motions in enzyme catalysis
    Pratul K Agarwal
    Department of Chemistry, 152 Davey Laboratory, Pennsylvania State University, University Park, PA 16802, USA
    Proc Natl Acad Sci U S A 99:2794-9. 2002
    ..This type of network has broad implications for an expanded role of the protein fold in catalysis as well as ancillaries such as the engineering of altered protein function and the action of drugs distal to the active site...
  10. pmc Association of genetic mutations in Plasmodium vivax dhfr with resistance to sulfadoxine-pyrimethamine: geographical and clinical correlates
    M Imwong
    Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
    Antimicrob Agents Chemother 45:3122-7. 2001
    ..01). The three mutations at the pvdhfr codons for residues 57, 58, and 117 are associated with high levels of S-P resistance in P. vivax. These mutations presumably arose from selection pressure...
  11. pmc Endothelial dihydrofolate reductase: critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase
    Karel Chalupsky
    Section of Cardiology, Department of Medicine, Division of Biological Sciences and Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
    Proc Natl Acad Sci U S A 102:9056-61. 2005
    ..This signaling cascade may represent a universal mechanism underlying eNOS dysfunction under pathophysiological conditions associated with oxidant stress...
  12. pmc Plasmodium falciparum isolates in India exhibit a progressive increase in mutations associated with sulfadoxine-pyrimethamine resistance
    Anwar Ahmed
    Department of Biotechnology, All India Institute of Medical Sciences, New Delhi 110029 Malaria Research Centre, 22 Sham Nath Marg, New Delhi 110054, India
    Antimicrob Agents Chemother 48:879-89. 2004
    ..It was concluded that even though SP is prescribed as a second line of treatment in India, the mutations associated with SP resistance continue to be progressively increasing...
  13. pmc Selection strength and hitchhiking around two anti-malarial resistance genes
    Denae Nash
    Southwest Foundation for Biomedical Research SFBR, San Antonio, TX 78245, USA
    Proc Biol Sci 272:1153-61. 2005
    ..However, the lower levels of LD surrounding resistance alleles in populations under weak selection may simplify identification of functional mutations...
  14. ncbi Selection of antifolate-resistant Plasmodium falciparum by sulfadoxine-pyrimethamine treatment and infectivity to Anopheles mosquitoes
    Fabian Mendez
    Escuela de Salud Publica, Universidad del Valle, Cali, Colombia
    Am J Trop Med Hyg 77:438-43. 2007
    ..23, P < 0.05). Low-level drug resistance mutations have the potential to enhance transmission of P. falciparum and spread resistant parasites...
  15. pmc The role of large-scale motions in catalysis by dihydrofolate reductase
    E Joel Loveridge
    School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, United Kingdom
    J Am Chem Soc 133:20561-70. 2011
    ....
  16. ncbi Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers
    W S Lewis
    Department of Molecular Pharmacology, St Jude Children s Research Hospital, Memphis, Tennessee 38101
    J Biol Chem 270:5057-64. 1995
    ..Tyrosine 22 and arginine 22 relieve short contacts to methotrexate and NADPH by occupying low probability conformations, but this is unnecessary for phenylalanine 22 in the piritrexim complex...
  17. ncbi Plasmodium vivax: prevalence of mutations associated with sulfadoxine-pyrimethamine resistance in Plasmodium vivax clinical isolates from Pakistan
    Sedigheh Zakeri
    Malaria and Vector Research Group, Biotechnology Research Center, Pasteur Institute of Iran, Pasteur Avenue, PO BOX 1316943551, Tehran, Iran
    Exp Parasitol 127:167-72. 2011
    ..6%) and I(13)P(33)F(57)R(58)T(61)N(117)I(173)/A(383)A(553) (12.2%). The presence of mutant haplotypes is worrying and indicates the emergence of drug tolerant/resistant P. vivax isolates in Pakistan in near future...
  18. ncbi Evidence that a 'dynamic knockout' in Escherichia coli dihydrofolate reductase does not affect the chemical step of catalysis
    E Joel Loveridge
    School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK
    Nat Chem 4:292-7. 2012
    ..Although protein motions are clearly important for binding and release of substrates and products, there appears to be no detectable dynamic coupling of protein motions to the hydride transfer step itself...
  19. pmc Correlated motion and the effect of distal mutations in dihydrofolate reductase
    Thomas H Rod
    Department of Molecular Biology, The Scripps Research Institute, TPC6, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 100:6980-5. 2003
    ..On the basis of our new findings, we discuss the role of coupled motions between distant regions in the enzyme, which previously was reported by Radkiewicz and Brooks...
  20. pmc Mycobacterium tuberculosis dihydrofolate reductase is not a target relevant to the antitubercular activity of isoniazid
    Feng Wang
    Department of Biochemistry and Biophysics, Texas A and M University, College Station, Texas 77843 2128, USA
    Antimicrob Agents Chemother 54:3776-82. 2010
    ..The dfrA overexpression experiments, together with the biochemical and sequencing studies, conclusively demonstrate that DHFR is not a target relevant to the antitubercular activity of INH...
  21. ncbi Using pharmacophore models to gain insight into structural binding and virtual screening: an application study with CDK2 and human DHFR
    Samuel Toba
    Accelrys Inc, 10188 Telesis Court, Suite 100, San Diego, California 92121, USA
    J Chem Inf Model 46:728-35. 2006
    ..Additionally, automated refinement of the pharmacophore with these excluded volume features provides a more selective model to reduce false positives and a better enrichment rate in virtual screening...
  22. ncbi Systematic circular permutation of an entire protein reveals essential folding elements
    M Iwakura
    National Institute of Bioscience and Human Technology, 1 1 Higashi, Tsukuba, Ibaraki 305 8566, Japan
    Nat Struct Biol 7:580-5. 2000
    ..However, almost all of the amino acid residues known to be involved in early folding events are located within the folding elements...
  23. pmc Markers of sulfadoxine-pyrimethamine-resistant Plasmodium falciparum in placenta and circulation of pregnant women
    Frank P Mockenhaupt
    Institute of Tropical Medicine and International Health, Spandauer Damm 130, 14050 Berlin, Germany
    Antimicrob Agents Chemother 51:332-4. 2007
    ..Sulfadoxine-pyrimethamine resistance typing in peripheral blood is reasonably representative of P. falciparum infecting pregnant women...
  24. pmc miR-192 Regulates dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit
    Bo Song
    Translational Research Laboratory, Department of Pathology, Stony Brook University Medical Center, Stony Brook, New York 11794 8691, USA
    Clin Cancer Res 14:8080-6. 2008
    ..The purpose of this study is to investigate the molecular mechanism of miR-192 in colon cancer...
  25. ncbi Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript
    Igor Martianov
    Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
    Nature 445:666-70. 2007
    ....
  26. pmc Pyrosequencing, a high-throughput method for detecting single nucleotide polymorphisms in the dihydrofolate reductase and dihydropteroate synthetase genes of Plasmodium falciparum
    Zhiyong Zhou
    Division of Parasitic Diseases, National Center for Zoonotic, Vector Borne and Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Chamblee, Georgia 30341, USA
    J Clin Microbiol 44:3900-10. 2006
    ..Thus, pyrosequencing is a practical alternative method that can be used in a high-throughput format for molecular surveillance of antimalarial-drug resistance...
  27. ncbi Antifolates can have a role in the treatment of Plasmodium vivax
    Vivian N Hawkins
    Department of Genome Sciences, University of Washington, Box 355065, Seattle, WA 98195, USA
    Trends Parasitol 23:213-22. 2007
    ..Other studies have examined the impact of dhps genotype on response to sulfadoxine. These data indicate that, under certain circumstances, SP could be a valuable tool in the fight against P. vivax...
  28. pmc Identification of soluble protein fragments by gene fragmentation and genetic selection
    Michael R Dyson
    Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK
    Nucleic Acids Res 36:e51. 2008
    ..This genetic selection method was shown to generate expression clones useful for both structural studies and antibody generation and does not require a priori knowledge of domain architecture...
  29. ncbi Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding
    C Bystroff
    Department of Chemistry, University of California, San Diego, La Jolla 92093
    Biochemistry 30:2227-39. 1991
    ..We explore the idea that the MTX binary complex in some ways resembles the transition-state complex...
  30. pmc Anti-folate drug resistance in Africa: meta-analysis of reported dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant genotype frequencies in African Plasmodium falciparum parasite populations
    Sankar Sridaran
    Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, 1600 Clifton Road NE, Mail Stop D 67 Atlanta, GA, 30333, USA
    Malar J 9:247. 2010
    ..This meta-analysis attempts to: 1) summarize genotype frequency data that are critical for molecular surveillance of anti-folate resistance and 2) identify the specific challenges facing the development of future molecular databases...
  31. pmc Decline in sulfadoxine-pyrimethamine-resistant alleles after change in drug policy in the Amazon region of Peru
    Zhiyong Zhou
    Division of Parasitic Diseases, National Center for Zoonotic, Vector Borne and Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA
    Antimicrob Agents Chemother 52:739-41. 2008
    ..Microsatellite analysis showed that the dhfr and dhps alleles are of common origin...
  32. ncbi Multiplex PCR-RFLP methods for pfcrt, pfmdr1 and pfdhfr mutations in Plasmodium falciparum
    Maria Isabel Veiga
    Center of Molecular and Structural Biomedicine, Universidade do Algarve, Gambelas, Portugal
    Mol Cell Probes 20:100-4. 2006
    ..In this work, we developed a multiplex PCR-RFLP protocols for the diagnosis of these molecular markers, leading to significant decreases in reagent costs, time, number of manipulations and hence human resources...
  33. ncbi Linkage between nuclear and mitochondrial DNA sequences in avian malaria parasites: multiple cases of cryptic speciation?
    Staffan Bensch
    Department of Animal Ecology, Ecology Building, S 223 62 Lund, Sweden
    Evolution 58:1617-21. 2004
    ..Studies examining parasite virulence and host immune systems must consider this remarkable diversity of avian malaria parasites...
  34. ncbi Roles of specific Plasmodium falciparum mutations in resistance to amodiaquine and sulfadoxine-pyrimethamine in Burkina Faso
    Christian Dokomajilar
    Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, USA
    Am J Trop Med Hyg 75:162-5. 2006
    ..The dhfr 164L and dhps 540E mutations were not seen in any isolates. These results clarify the key roles of a small number of mutations in P. falciparum resistance to SP and AQ in west Africa...
  35. ncbi Negative selection using yeast cytosine deaminase/uracil phosphoribosyl transferase in Plasmodium falciparum for targeted gene deletion by double crossover recombination
    Alexander G Maier
    The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
    Mol Biochem Parasitol 150:118-21. 2006
  36. pmc Pyrimethamine and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax
    Michele D Hastings
    Department of Genome Sciences, University of Washington, Box 357730, Seattle, WA 98195 7730
    Proc Natl Acad Sci U S A 99:13137-41. 2002
    ..If that is the case, this novel class of DHFR inhibitors could provide effective and affordable treatment for chloroquine- and pyrimethamine-resistant vivax and falciparum malaria for many years to come...
  37. pmc Selective sweeps and genetic lineages of Plasmodium falciparum drug -resistant alleles in Ghana
    Md Tauqeer Alam
    Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA
    J Infect Dis 203:220-7. 2011
    ..A comprehensive study of the drug-resistance-associated mutations and their genetic lineages will lead to a better understanding of the evolution of antimalarial drug resistance in this region...
  38. pmc Chloroquine resistance before and after its withdrawal in Kenya
    Leah Mwai
    Kenya Medical Research Institute Wellcome Trust Collaborative Research Programme, Kilifi, Kenya
    Malar J 8:106. 2009
    ..Changes to those that occurred in the dihydrofolate reductase gene (dhfr) that confers resistance to the replacement drug, pyrimethamine/sulphadoxine were also compared...
  39. pmc Novel point mutations in the dihydrofolate reductase gene of Plasmodium vivax: evidence for sequential selection by drug pressure
    Mallika Imwong
    Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, National Science and Technology Development Agency, Bangkok, Thailand
    Antimicrob Agents Chemother 47:1514-21. 2003
    ..Highly mutated genes carry the S-->T rather than the S-->N mutation at residue 117. Mutations at residues 57 and 61 then occur, followed by a fifth mutation at residue 13...
  40. ncbi Relating protein motion to catalysis
    Sharon Hammes-Schiffer
    Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA
    Annu Rev Biochem 75:519-41. 2006
    ..This network is comprised of fast thermal motions that are in equilibrium as the reaction progresses along the reaction coordinate and that lead to slower equilibrium conformational changes conducive to the chemical reaction...
  41. pmc In vitro activity of antifolate and polymorphism in dihydrofolate reductase of Plasmodium falciparum isolates from the Kenyan coast: emergence of parasites with Ile-164-Leu mutation
    Steven M Kiara
    Kenya Medical Research Institute KEMRI Wellcome Trust Collaborative Research Program, P O Box 230, 80108 Kilifi, Kenya
    Antimicrob Agents Chemother 53:3793-8. 2009
    ..We confirmed the presence of this mutation by sequencing. Thus, TMX and MTX are potent against P. falciparum, and quadruple mutants are now emerging in Africa...
  42. ncbi Increasing prevalence of wildtypes in the dihydrofolate reductase gene of Plasmodium falciparum in an area with high levels of sulfadoxine/pyrimethamine resistance after introduction of treated bed nets
    Michael Alifrangis
    Centre for Medical Parasitology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark
    Am J Trop Med Hyg 69:238-43. 2003
    ..The impact of ITNs on the transmission intensity seems not only to affect the overall malaria morbidity, but may even facilitate restoration of susceptibility to antimalarial drugs...
  43. pmc Mammalian nuclei become licensed for DNA replication during late telophase
    Daniela S Dimitrova
    Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
    J Cell Sci 115:51-9. 2002
    ..We conclude that the functional association of Mcm proteins with chromatin (i.e. replication licensing) in CHO cells takes place during telophase, several hours prior to the specification of replication origins at the DHFR locus...
  44. ncbi Sensitivity to antifolates and genetic analysis of Plasmodium vivax isolates from Thailand
    Kanchana Rungsihirunrat
    Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand
    Am J Trop Med Hyg 76:1057-65. 2007
    ..Results suggest that quadruple mutant alleles confer decreased sensitivity to pyrimethamine but retain sensitivity to WR99210...
  45. pmc Protective efficacy of intermittent preventive treatment of malaria in infants (IPTi) using sulfadoxine-pyrimethamine and parasite resistance
    Jamie T Griffin
    MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, Imperial College, London, United Kingdom
    PLoS ONE 5:e12618. 2010
    ..Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance...
  46. pmc Submicroscopic gametocytes and the transmission of antifolate-resistant Plasmodium falciparum in Western Kenya
    Mayke J A M Oesterholt
    Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    PLoS ONE 4:e4364. 2009
    ..In the present study, we determine the association between parasite mutations, submicroscopic P. falciparum gametocytemia and malaria transmission to mosquitoes...
  47. pmc Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment
    W E Harrington
    Seattle Biomedical Research Institute, 307 Westlake Avenue N, Seattle, WA 98109, USA
    Proc Natl Acad Sci U S A 106:9027-32. 2009
    ..Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance...
  48. ncbi Genetic variations of the dihydrofolate reductase gene of Plasmodium vivax in Mandalay Division, Myanmar
    Byoung Kuk Na
    Department of Molecular Parasitology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440 746, Korea
    Parasitol Res 96:321-5. 2005
    ..Our results suggest that antifolate-resistant P. vivax is becoming widespread in Myanmar, as it also is in the neighboring countries in Southeast Asia. It appears that the drug resistance situation may be worsening in the country...
  49. pmc A general chemical method to regulate protein stability in the mammalian central nervous system
    Mari Iwamoto
    Department of Chemical and Systems Biology, Stanford University, CA 94305, USA
    Chem Biol 17:981-8. 2010
    ..The ability of TMP to cross the blood-brain barrier enables the tunable regulation of proteins expressed in the mammalian central nervous system...
  50. pmc Plasmodium falciparum drug resistance in Madagascar: facing the spread of unusual pfdhfr and pfmdr-1 haplotypes and the decrease of dihydroartemisinin susceptibility
    Valérie Andriantsoanirina
    Unité de Recherche sur le Paludisme, Institut Pasteur de Madagascar, Antananarivo, Madagascar
    Antimicrob Agents Chemother 53:4588-97. 2009
    ..In the context of the implementation of the new national policy for the fight against malaria, continued surveillance for the detection of P. falciparum resistance in the future is required...
  51. ncbi Mutation rates in the dihydrofolate reductase gene of Plasmodium falciparum
    S Paget-McNicol
    The University of Queensland and the Malaria and Arbovirus Unit, Queensland Institute of Medical Research, Australia
    Parasitology 122:497-505. 2001
    ....
  52. ncbi Dihydrofolate reductase mutations in Plasmodium vivax from Indonesia and therapeutic response to sulfadoxine plus pyrimethamine
    Michele D Hastings
    Department of Genome Sciences, School of Medicine, University of Washington, Seattle, WA 98195 7730, USA
    J Infect Dis 189:744-50. 2004
    ..Still less is known about associations between specific alleles and the failure of sulfadoxine/pyrimethamine (S/P) to clear the erythrocytic stages of P. vivax in vivo...
  53. pmc Similar trends of pyrimethamine resistance-associated mutations in Plasmodium vivax and P. falciparum
    Mohammad Tauqeer Alam
    Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
    Antimicrob Agents Chemother 51:857-63. 2007
    ..vivax, suggesting that the drug should be used with caution to minimize the development of cross-species resistance in the field...
  54. ncbi IGF-I alleviates diabetes-induced RhoA activation, eNOS uncoupling, and myocardial dysfunction
    Jun Ren
    School of Pharmacy, University of Wyoming, Laramie, WY 82071, USA
    Am J Physiol Regul Integr Comp Physiol 294:R793-802. 2008
    ..These results revealed that IGF-I benefits diabetic hearts via Rho inhibition and antagonism of diabetes-induced decrease in pAkt, eNOS uncoupling, and K+ channel expression...
  55. ncbi 2-tier bacterial and in vitro selection of active and methotrexate-resistant variants of human dihydrofolate reductase
    Elena Fossati
    Departement de Biochimie, Universite de Montreal, Montreal, Quebec, Canada
    J Biomol Screen 13:504-14. 2008
    ..The flexibility and robustness of this method will provide new insights into interactions between ligands and active-site residues of this clinically relevant human enzyme...
  56. pmc Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans
    C Tony Liu
    Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
    Proc Natl Acad Sci U S A 110:10159-64. 2013
    ..The data presented here provide a glimpse into the evolutionary trajectory of functional DHFR through its protein sequence space that lead to the diverged binding and catalytic properties of the E. coli and human enzymes...
  57. ncbi Effect of dimerization on dihydrofolate reductase catalysis
    Jiannan Guo
    School of Chemistry and Cardiff Catalysis Institute, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, United Kingdom
    Biochemistry 52:3881-7. 2013
    ..Our studies demonstrate that EcDHFR is not a good model for understanding the properties of other DHFRs, including TmDHFR...
  58. ncbi Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine: mutations in pvdhfr and pvmdr1
    Jutta Marfurt
    Department of Medical Parasitology and Infection Biology, Swiss Tropical Institute, Basel, Switzerland
    J Infect Dis 198:409-17. 2008
    ..However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce...
  59. ncbi Dihydrofolate reductase inhibitors as antibacterial agents
    Stephen Hawser
    Arpida Ltd, Dammstrasse 36, 4142 Münchenstein, Switzerland
    Biochem Pharmacol 71:941-8. 2006
    ..Iclaprim, a recent example of a novel diaminopyrimidine currently in Phase III clinical trials, is also described together with several examples of anti-DHFR antibacterial compounds in pre-clinical development...
  60. pmc Molecular markers of resistance to sulphadoxine-pyrimethamine during intermittent preventive treatment of pregnant women in Benin
    Gwladys Bertin
    Institut de recherche pour le developpement IRD, Mère et enfant face aux infections tropicales UMR216, Paris Cedex, France
    Malar J 10:196. 2011
    ..falciparum-infected pregnant women before first and second IPTp administration, and at delivery...
  61. pmc Carborane clusters in computational drug design: a comparative docking evaluation using AutoDock, FlexX, Glide, and Surflex
    Rohit Tiwari
    Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA
    J Chem Inf Model 49:1581-9. 2009
    ..Binding energies predicted by all four programs were in accordance with experimental data...
  62. pmc Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions
    Andrew J Adamczyk
    Department of Chemistry Seeley G Mudd 418, University of Southern California, 3620 McClintock Avenue, Los Angeles, CA 90089, USA
    Proc Natl Acad Sci U S A 108:14115-20. 2011
    ..However, this motion is never the reason for catalysis, but rather simply a reflection of the shape of the reaction potential surface...
  63. pmc Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2,4-diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine
    Vivian Cody
    Structural Biology Department, Hauptman Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, NY 14203, USA
    Acta Crystallogr D Biol Crystallogr 64:977-84. 2008
    ..6 A compared with pcDHFR ternary complexes. These data are consistent with the greater inhibitory potency against pcDHFR...
  64. pmc Comparative hydrogen-deuterium exchange for a mesophilic vs thermophilic dihydrofolate reductase at 25 °C: identification of a single active site region with enhanced flexibility in the mesophilic protein
    Olayinka A Oyeyemi
    Department of Chemistry, California Institute for Quantitative Biosciences QB3, University of California, Berkeley, Berkeley, California 94720, USA
    Biochemistry 50:8251-60. 2011
    ..The region with increased flexibility in Ec-DHFR corresponds to one of two regions previously proposed to control the enthalpic barrier for hydride transfer in Bs-DHFR [Oyeyemi et al. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 10074]...
  65. pmc Automated identification of functional dynamic contact networks from X-ray crystallography
    Henry van den Bedem
    Joint Center for Structural Genomics, Stanford Synchrotron Radiation Lightsource, Stanford, California, USA
    Nat Methods 10:896-902. 2013
    ..CONTACT-guided mutagenesis can exploit the structure-dynamics-function relationship in protein engineering and design. ..
  66. ncbi Protection and selection for gene therapy in the hematopoietic system
    Michael D Milsom
    Cancer Research UK Gene Therapy Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK
    J Gene Med 6:133-46. 2004
    ..Here we review potential means of conferring a selective advantage to hematopoietic stem cells and their progeny, and discuss the issues that surround the use of selective advantages in vivo...
  67. pmc Short inverted repeats initiate gene amplification through the formation of a large DNA palindrome in mammalian cells
    Hisashi Tanaka
    Division of Basic Sciences and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 1024, USA
    Proc Natl Acad Sci U S A 99:8772-7. 2002
    ..This finding suggests that short inverted repeats in the mammalian genome can have a critical role in the initiation of gene amplification. This specific mechanism may provide a novel target for cancer therapies...
  68. pmc Five years of large-scale dhfr and dhps mutation surveillance following the phased implementation of artesunate plus sulfadoxine-pyrimethamine in Maputo Province, Southern Mozambique
    Jaishree Raman
    Malaria Research Programme, Medical Research Council, 491 Ridge Road, Durban, 4067, KwaZulu Natal, South Africa
    Am J Trop Med Hyg 82:788-94. 2010
    ..The high "quintuple" mutation prevalence suggests a limited useful therapeutic lifespan of AS-SP for treating uncomplicated malaria, and may curb efficacy of SP-monotherapy for intermittent preventive treatment in Mozambique...
  69. pmc Unraveling the role of protein dynamics in dihydrofolate reductase catalysis
    Louis Y P Luk
    School of Chemistry and Cardiff Catalysis Institute, Cardiff University, Cardiff CF10 3AT, United Kingdom
    Proc Natl Acad Sci U S A 110:16344-9. 2013
    ..The fact that the heavy enzyme is only slightly less active than its light counterpart shows that protein dynamics have a small, but measurable, effect on the chemical reaction rate. ..
  70. pmc Direct detection of structurally resolved dynamics in a multiconformation receptor-ligand complex
    Mary J Carroll
    Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
    J Am Chem Soc 133:6422-8. 2011
    ..The availability of accurate, structurally resolved dynamics in a protein-ligand complex should serve as a valuable benchmark for modeling dynamics in other receptor-ligand complexes and prediction of binding affinities...
  71. ncbi Selectively weakened binding of methotrexate by human dihydrofolate reductase allows rapid ex vivo selection of mammalian cells
    Jordan P Volpato
    Departement de Biochimie, Universite de Montreal, C P 6128, Succursale Centre Ville, Montreal, Quebec H3C 3J7, Canada
    J Mol Recognit 24:188-98. 2011
    ..We have thus demonstrated that bacterial selection of highly antifolate-resistant hDHFR variants can provide selectable markers for rapid ex vivo enrichment of hematopoietic cells...
  72. pmc Compensatory mutations restore fitness during the evolution of dihydrofolate reductase
    Kyle M Brown
    Department of Organismic and Evolutionary Biology, Harvard University, MA, USA
    Mol Biol Evol 27:2682-90. 2010
    ..Our results suggest that high levels of resistance may be selected for without necessarily jeopardizing overall fitness...
  73. ncbi SycE allows secretion of YopE-DHFR hybrids by the Yersinia enterocolitica type III Ysc system
    Mario F Feldman
    Division of Molecular Microbiology, University of Basel, Switzerland
    Mol Microbiol 46:1183-97. 2002
    ..In addition, they show that the secretion apparatus can reject folded proteins if they are not deeply engaged into the injectisome...
  74. ncbi Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria
    James G Kublin
    Malaria Section, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA
    J Infect Dis 185:380-8. 2002
    ..If this model is validated in other populations, it will finally be possible to use molecular markers for surveillance of antifolate-resistant P. falciparum malaria in Africa...
  75. ncbi High prevalence of double Plasmodium falciparum dhfr mutations at codons 108 and 59 in the Sistan-Baluchistan province, Iran
    Sedigheh Zakeri
    J Infect Dis 187:1828-9. 2003
  76. pmc Millisecond timescale fluctuations in dihydrofolate reductase are exquisitely sensitive to the bound ligands
    David D Boehr
    Department of Molecular Biology and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 107:1373-8. 2010
    ....
  77. ncbi Reaction-path energetics and kinetics of the hydride transfer reaction catalyzed by dihydrofolate reductase
    Mireia Garcia-Viloca
    Department of Chemistry and Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota 55455, USA
    Biochemistry 42:13558-75. 2003
    ..The primary KIE is mainly a consequence of the quantization of bound vibrations. In contrast, the secondary KIE, with a value of 1.13, is almost entirely due to dynamical effects on the reaction coordinate, especially tunneling...
  78. ncbi Solvent effects on catalysis by Escherichia coli dihydrofolate reductase
    E Joel Loveridge
    School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff CF10 3AT, UK
    J Am Chem Soc 132:1137-43. 2010
    ....
  79. pmc Ligand binding modulates the mechanical stability of dihydrofolate reductase
    Sri Rama Koti Ainavarapu
    Department of Biological Sciences, Columbia University, New York, NY, USA
    Biophys J 89:3337-44. 2005
    ..Our observations support the view that the rate-limiting step in protein degradation by adenosine triphosphate-dependent proteases is the mechanical unfolding of the target protein...
  80. ncbi Change in mutation patterns of Plasmodium vivax dihydrofolate reductase (Pvdhfr) and dihydropteroate synthase (Pvdhps) in P. vivax isolates from malaria endemic areas of Thailand
    Jiraporn Kuesap
    Pharmacology and Toxicology Unit, Graduate Program in Biomedical Sciences, Thammasat University, Pathumthani, Thailand
    Mem Inst Oswaldo Cruz 106:130-3. 2011
    ..vivax isolates in Thailand carry some combination of mutations in Pvdhfr and Pvdhps. Our findings demonstrate that development of new antifolate drugs effective against sulfadoxine-pyrimethamine-resistant P. vivax is required...
  81. pmc Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics
    P T Ravi Rajagopalan
    Department of Chemistry, Pennsylvania State University, 152 Davey Laboratory, University Park, PA 16802, USA
    Proc Natl Acad Sci U S A 99:13481-6. 2002
    ..Thus the mechanism of methotrexate binding to DHFR involves multiple steps and protein conformational changes...
  82. pmc Influence of substrate binding on the mechanical stability of mouse dihydrofolate reductase
    J P Junker
    Physik Department E22, Technische Universitat Munchen, D 85748 Garching, Germany
    Biophys J 89:L46-8. 2005
    ..These experiments demonstrate that protein mechanics can be used to probe the substrate binding status of an enzyme...
  83. pmc Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis
    Dan McElheny
    Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 102:5032-7. 2005
    ....
  84. pmc Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors
    Aleem Gangjee
    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, USA
    J Med Chem 51:68-76. 2008
    ..The nonclassical analogues were marginal inhibitors of human TS, but four analogues showed potent T. gondii DHFR inhibition along with >100-fold selectivity compared to human DHFR...
  85. ncbi Amino acid mutations in Plasmodium vivax DHFR and DHPS from several geographical regions and susceptibility to antifolate drugs
    Alyson Auliff
    Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, QLD, Australia
    Am J Trop Med Hyg 75:617-21. 2006
    ..Parasites with the S58R/S117N dhfr allelic type showed an MIC level for pyrimethamine and cycloguanil comparable to that previously reported, but were susceptible to WR99210...
  86. ncbi Mitochondrial protein import. Tom40 plays a major role in targeting and translocation of preproteins by forming a specific binding site for the presequence
    D Rapaport
    , , Goethestrasse 33, , Federal Republic of Germany
    J Biol Chem 272:18725-31. 1997
    ..Our study suggests that Tom40 plays an important function in guiding the presequence of a preprotein across the mitochondrial outer membrane. We propose that Tom40 forms a major part of the trans presequence binding site...
  87. pmc Molecular characterisation of trimethoprim resistance in Escherichia coli and Klebsiella pneumoniae during a two year intervention on trimethoprim use
    Alma Brolund
    Department of Microbiology, Tumor and Cell Biology, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden
    PLoS ONE 5:e9233. 2010
    ..We investigated the distribution of dihydrofolate reductase (dfr)-genes and integrons in Escherichia coli and Klebsiella pneumoniae and the effect of the intervention on this distribution...
  88. pmc Rapid increase of Plasmodium falciparum dhfr/dhps resistant haplotypes, after the adoption of sulphadoxine-pyrimethamine as first line treatment in 2002, in southern Mozambique
    Sonia Enosse
    Instituto Nacional de Saude, Ministerio de Saude, Maputo, Mozambique
    Malar J 7:115. 2008
    ....
  89. ncbi Plasmodium vivax dihydrofolate reductase point mutations from the Indian subcontinent
    Suminder Kaur
    International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
    Acta Trop 97:174-80. 2006
    ..Whether these novel mutations are linked to pyrimethamine resistance remains to be established...
  90. pmc Prevalence of mutations associated with antimalarial drugs in Plasmodium falciparum isolates prior to the introduction of sulphadoxine-pyrimethamine as first-line treatment in Iran
    Sedigheh Zakeri
    Malaria and Vector Research Group MVRG, Biotechnology Research Center, Institut Pasteur of Iran, Pasteur Avenue, PO BOX 1316943551, Tehran, Iran
    Malar J 6:148. 2007
    ..This work was carried out to assess the patterns and prevalence of resistance to chloroquine (CQ) and sulphadoxine-pyrimethamine (SP) in Iran...
  91. ncbi Mass spectrometry on segment-specific hydrogen exchange of dihydrofolate reductase
    Tatsuya Yamamoto
    Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Higashi Hiroshima 739 8526
    J Biochem 135:17-24. 2004
    ....
  92. pmc Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells
    Toru Sugiyama
    Cardiovascular and Pulmonary Divisions, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Biol Chem 284:12691-700. 2009
    ....
  93. pmc Deficient BH4 production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes
    Irina A Ionova
    Department of Surgery Transplant Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA
    Am J Physiol Heart Circ Physiol 295:H2178-87. 2008
    ....
  94. ncbi Dispersive initiation of replication in the Chinese hamster rhodopsin locus
    P A Dijkwel
    Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    Exp Cell Res 256:150-7. 2000
    ..Thus, the DHFR and rhodopsin origins belong to a class of complex, polydisperse origins that appears to be unique to higher eukaryotic cells...
  95. pmc The dihydrofolate reductase origin of replication does not contain any nonredundant genetic elements required for origin activity
    L D Mesner
    Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA
    Mol Cell Biol 23:804-14. 2003
    ....
  96. ncbi Geographical distribution of amino acid mutations in Plasmodium vivax DHFR and DHPS from malaria endemic areas of Thailand
    Kanchana Rungsihirunrat
    Faculty of Allied Health Sciences, Thammasat University, Pathumtani, Thailand
    Am J Trop Med Hyg 78:462-7. 2008
    ..Novel mutations that have not been identified previously at codon 512 of pvdhps (K512M, K512E, K512T) were also found...
  97. pmc Molecular characterization of antifolates resistance-associated genes, (dhfr and dhps) in Plasmodium vivax isolates from the Middle East
    Sedigheh Zakeri
    Malaria and Vector Research Group MVRG, Biotechnology Research Center, Institut Pasteur of Iran, Tehran, Iran
    Malar J 8:20. 2009
    ..vivax infections are often exposed to sulphadoxine-pyrimethamine (SP). In the present study, the frequency distribution of mutations associated to SP resistance was investigated in pvdhfr and pvdhps genes from field isolates...
  98. ncbi Effect of pH on hydride transfer by Escherichia coli dihydrofolate reductase
    E Joel Loveridge
    School of Chemistry, Cardiff University, Park Place, Cardiff, UK
    Chembiochem 12:1258-62. 2011
    ....
  99. pmc Molecular determination of point mutation haplotypes in the dihydrofolate reductase and dihydropteroate synthase of Plasmodium falciparum in three districts of northern Tanzania
    Richard J Pearce
    Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, United Kingdom
    Antimicrob Agents Chemother 47:1347-54. 2003
    ..The triple-dhfr/double-dhps genotype is present in all three regions with frequencies ranging between 30 and 63%, indicating that treatment failure rates are likely to be high...
  100. ncbi Tunneling and coupled motion in the Escherichia coli dihydrofolate reductase catalysis
    R Steven Sikorski
    Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
    J Am Chem Soc 126:4778-9. 2004
    ..The data also suggested environmentally coupled tunneling and commitment to catalysis on pre-steady-state isotope effects...
  101. pmc Molecular epidemiology of Plasmodium vivax anti-folate resistance in India
    Surendra K Prajapati
    Genetics and Molecular Biology Laboratory, National Institute of Malaria Research NIMR, Sector 8, Dwarka, New Delhi 110077, India
    Malar J 10:102. 2011
    ..This study presents pattern of point mutations in dhfr/dhps genes among Indian sub-continent...

Research Grants62

  1. DRUG RESISTANCE AND PTERIDINE METABOLISM IN LEISHMANIA
    Stephen M Beverley; Fiscal Year: 2010
    ..10-CHO-THF) in Leishmania metabolism and biology, and to study the enzyme 5,10-methylene tetrahydrofolate dehydrogenase/cyclohydrolase (DHCH1) primarily responsible for its synthesis...
  2. Third Generation Antiopportunistic Agents
    Aleem Gangjee; Fiscal Year: 2003
    ..Screening against tuberculosis (NIAID) and tumor cells in culture (NCI) is also proposed. ..
  3. NOVEL NONINDUCIBLE THYMIDYLATE SYNTHASE INHIBITORS
    Aleem Gangjee; Fiscal Year: 2004
    ....
  4. STRUCTURE BASED ANALOGS AS ANTIOPPORTUNISTIC AGENTS
    Aleem Gangjee; Fiscal Year: 2001
    ..The analogues synthesized will also be submitted for screening against tuberculosis (NIAID) parasitic diseases (WHO) and tumor cells in culture (NCI). ..
  5. Antitumor Antimitotics That Reverse Tumor Resistance
    Aleem Gangjee; Fiscal Year: 2010
    ..The study will also further define the mechanism of action of the novel series and could afford agents for clinical use. ..
  6. Single Agents with Designed Combination Chemotherapy Potential
    Aleem Gangjee; Fiscal Year: 2010
    ..abstract_text> ..
  7. Alpha Folate Receptor Mediated GARFTase Inhibitors as Selective Antitumor Agents
    Aleem Gangjee; Fiscal Year: 2010
    ....
  8. Novel Single, Dual and Multitargeted Inhibitors of RTKs
    Aleem Gangjee; Fiscal Year: 2007
    ..abstract_text> ..
  9. Novel, P. jirovecii Specific Antipneumocystis Agents
    Aleem Gangjee; Fiscal Year: 2009
    ..These agents could be used alone or in combination to treat PCP thus providing novel agents against a new target. ..
  10. Structural Studies of AIDS-Responsive Drugs
    Vivian Cody; Fiscal Year: 2010
    ..These results will help guide the design of species selective inhibitors. Mutagenesis studies will be carried out to test these possibilitiesin the structure-based correlations to help design novel pjDHFRinhibitors. ..
  11. NOVEL APPROACHES TO ANTIFOLATE CHEMOTHERAPY
    Andre Rosowsky; Fiscal Year: 2003
    ..The focus will be on enhancing polyglutamation of the lead compound dmAMT by modification of the B-ring and/or pABA moiety. ..
  12. LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS
    Andre Rosowsky; Fiscal Year: 2004
    ..Analogs of PT653 with a COOH, NH2, or OH group on the tricyclic moiety, and prodrugs thereof, will be made with the goal of improving aqueous solubility without sacrificing potency or selectivity. ..
  13. SIMULATION OF PROTON AND HYDRIDE TRANSFER IN ENZYMES
    Sharon Hammes Schiffer; Fiscal Year: 2010
    ....
  14. FolK, a Mycobacterium tuberculosis Drug Target
    WILLIAM SULING; Fiscal Year: 2004
    ..It will also provide purified HPPK for future drug discovery studies based upon structure-activity relationships, molecular modeling and crystallographic structure-based drug design. ..
  15. Enhancement of methotrexate uptake in childhood ALL
    John McGuire; Fiscal Year: 2009
    ..If successful, this research could provide a way to increase the effectiveness of methotrexate, a key drug used in treating childhood acute lymphoblastic leukemia, and thus increase the cure rate in this disease. ..
  16. Inhibitor of FtsZ Polymerization in M. tuberculosis
    Robert Reynolds; Fiscal Year: 2004
    ..Data from the biological screening and the EM structural studies will feed back into compound design in an interactive, iterative drug design cycle that critically focuses on antibacterial potency and selectivity. ..
  17. New DHFR Deletion Polymorphism - A Risk Factor for SB?
    William Johnson; Fiscal Year: 2003
    ..Forms of foliate that are already reduced could be preferable as foliate supplements during pregnancy for prevention of SB. ..
  18. EFFECTS OF CHROMATIN ARCHITECTURE ON ORIGIN ACTIVITY
    PIETER DIJKWEL; Fiscal Year: 2003
    ..abstract_text> ..
  19. FOLYLPOLYGLUTAMATE SYNTHETASE IN CANCER CHEMOTHERAPY
    John McGuire; Fiscal Year: 2003
    ..This may explain why high-level resistance to pulse MTX can occur in the absence of a large decrease in total FPGS activity or a rise in glutamyl hydrolase activity. ..
  20. Crystallization of the Galactosyltransferase from Mtb
    Robert Reynolds; Fiscal Year: 2002
    ..This effort, however, is innovative in the choice of target and the impact that structural biology can have on our funded program. ..
  21. GLYCOSYLTRANSFERASES AS DRUG TARGETS IN MYCOBACTERIA
    Robert Reynolds; Fiscal Year: 2002
    ..These compounds will be screened in vitro using a broth dilution assay and cell-free assay transferase. Selected active compounds will be screened in vitro and in vivo in a macrophage assay and a murine TB model, respectively. ..
  22. DIHYDRONEOPTERIN ALDOLASE, A TUBERCULOSIS DRUG TARGET
    WILLIAM SULING; Fiscal Year: 2002
    ..It will also provide purified DHNA for future drug discovery studies based upon structure-activity relationships, molecular modeling and crystallographic structure-based drug design. ..
  23. REGULATION OF P53 STABILITY BY SER315 PHOSPHORYLATION
    Mats Ljungman; Fiscal Year: 2002
    ..We will express wild-type or mutant CDC14 in MCF7 cells and study what effect it will have on basal and induced levels of p53. ..
  24. Water-Soluble and Metabolically Stable Calpain Inhibitors as Cardioprotectants
    ISAAC DONKOR; Fiscal Year: 2008
    ..Furthermore, the proposed studies will provide mechanistic insight into the mode of action of calpain inhibitors as cardioprotectants. ..
  25. GENETIC DISSECTION OF TOXOPLASMA GONDII
    David Roos; Fiscal Year: 2008
    ..In addition to their value for the analysis of folate metabolism and drug resistance, these tools should be broadly applicable to other studies on the biology and biochemistry of Toxoplasma. ..
  26. Chemoprevention Potential of Calpain Inhibitors
    ISAAC DONKOR; Fiscal Year: 2007
    ..The proposal is significant and innovative because it seeks to investigate calpain as a pharmacological target for the discovery of a new class of chemoprevention agents. [unreadable] [unreadable] [unreadable]..
  27. Large-scale chromatin structure and dynamics
    Andrew Belmont; Fiscal Year: 2007
    ..Knowledge gained from this research should provide valuable insight into regulation of basic molecular processes and may serve to guide design of future gene therapy vectors and stable transgene expression. ..
  28. The gating mechanism of the viral ion channel M2
    JASON SCHNELL; Fiscal Year: 2007
    ..These studies will assist in the discovery of true channel blockers for anti-viral therapy, and lead the way toward investigation of other viral channels. ..
  29. High Resolution Genomic Analysis of Amplicon Structure
    Donna Albertson; Fiscal Year: 2007
    ..abstract_text> ..
  30. Role of Acetaldehyde in Alcoholic Cardiomyopathy
    Jun Ren; Fiscal Year: 2008
    ..Our long-term goal is to establish the toxic mechanism of acetaldehyde in the development of alcoholic cardiomyopathy so that prevention and treatment can be optimized [unreadable] [unreadable]..
  31. INTERMEDIATES IN PROTEIN FOLDING
    Carl Frieden; Fiscal Year: 2008
    ..Both these projects employ novel real-time and equilibrium NMR methodology in addition to standard. ..
  32. Characterization of prion protein conformational changes
    VALERIE D DAGGETT; Fiscal Year: 2010
    ....
  33. New Hydropathy-Based computer Tools for Drug Discovery
    GLEN KELLOGG; Fiscal Year: 2009
    ..Specific collaborative arrangements are in place to apply these tools to a range of current drug discovery problems. ..
  34. Mechanism of Action of Folate Antagonist
    Joseph Bertino; Fiscal Year: 2008
    ..The use of MEF cells null for p53, p19 ARF and both will be utilized to test in a more well defined system the function of these proteins on DHFR levels. ..
  35. Genomic and Functional Analysis of Oral Cancer Development
    Donna Albertson; Fiscal Year: 2009
    ..The most fundamental way to make progress toward improving diagnosis and treatment of oral cancer is to elucidate the specific genes and the interactions among genes that become abnormal as cancer develops. ..
  36. Folic Acid Enhances Repair Mechanism in the Adult CNS
    Bermans J Iskandar; Fiscal Year: 2010
    ....
  37. Imaging Enzyme Structure and Dynamics: Specific Function and Functional Diversity
    Hua Deng; Fiscal Year: 2010
    ..The fruits of this work can lead to more thoroughly understanding disease and then to the discovery of new drugs and methods as well as laboratory diagnostic methods. ..
  38. Reactivation Methylation-Silenced Genes by Polyphenols
    Chung Yang; Fiscal Year: 2007
    ..5. To determine whether EGCG, alone or in combination with other agents, can prevent hypermethylation of genes and tumor development in the intestinal tumorigenesis model in the Min mice. ..
  39. Modulation of Aflatoxin B1-induced hepatocarcinogenesis by RB loss
    Erik Knudsen; Fiscal Year: 2007
    ..These studies will identify critical facets of RB function in vivo and delineate specific consequences of RB loss that are germane to tumor formation following genotoxic insult. [unreadable] [unreadable] [unreadable]..
  40. ESOPHAGEAL ADENOCARCINOGENESIS AND ITS PREVENTION
    Chung Yang; Fiscal Year: 2007
    ..These studies are expected to fully elucidate the roles of oxidative stress and aberrant AA metabolism in the formation of EAC and help develop effective agents for its prevention. ..
  41. 2004 Gordon Research Conference on Biopolymers
    Valerie Daggett; Fiscal Year: 2004
    ..The program encompasses some of the most exciting research in the field of nucleic acid and protein biophysics and promises to generate lively discussions both in and outside of the sessions. ..
  42. Role of 10-formyldihydrofolate in purine biosynthesis
    Tsunenobu Tamura; Fiscal Year: 2004
    ..If this pathway is proven, derivatives of 10-HCO-H2folate could be used to inhibit de novo purine biosynthesis for developing new anticancer drugs. ..
  43. Protein Nitration in Retinal Light Damage
    Masaru Miyagi; Fiscal Year: 2004
    ..Results will reveal protein targets of nitration and proteins up and down regulated by light exposure. The results will lead to a better understanding of the mechanisms associated with retinal light damage. ..
  44. VIBRATIONAL AND DYNAMICAL STUDIES OF ENZYMES
    Robert Callender; Fiscal Year: 2002
    ....
  45. INHIBITION OF BREAST TUMORIGENICITY BY C MYC PO RNA
    SCOTT BLUME; Fiscal Year: 2002
    ..3. Assess the degree to which artificial manipulation of the PO 5'-untranslated sequence alters the inherent tumorigenic, invasive, and metastatic potential of human breast carcinoma xenografts in immunocompromised mice. ..
  46. PROBING THE S' SUBSITES OF CALPAIN
    ISAAC DONKOR; Fiscal Year: 2002
    ..Selected potent and cell permeable inhibitors will be tested in the rat isolated heart ischemia model for cardioprotective effect. ..
  47. Narrow-Spectrum Drug Targets for Bacillus anthracis
    WILLIAM BARROW; Fiscal Year: 2004
    ....
  48. MECHANISTIC STUDIES ON TEA AND CARCINOGENESIS
    Chung Yang; Fiscal Year: 2005
    ..The applicant and colleagues will address key issues concerning the bioavailability and bioactivities of O-methyl, glucuronide, and sulfate derivatives and two ring-fission metabolites of tea catechins. ..
  49. Fostriecin and Related Protein Phosphatase Inhibitors
    Dale Boger; Fiscal Year: 2005
    ....
  50. Intrabody Therapy in Drosophila for Huntington's Disease
    WILLIAM WOLFGANG; Fiscal Year: 2006
    ..If successful this will provide validation of intrabodies as disease therapeutics and impetus to proceed to preclinical testing in vertebrate models of HD. ..
  51. Folate Deficiency, Metabolism & Sporadic Retinoblastoma
    Manuela Orjuela; Fiscal Year: 2006
    ..If our results are as anticipated, this project may lead to the development of new preventive strategies for those populations with an elevated incidence of sporadic retinoblastoma. ..
  52. Molecular Epidemiology of Human P. carinii Pneumonia
    Laurence Huang; Fiscal Year: 2006
    ..abstract_text> ..
  53. Screen for Mycobacterium Tuberculosis (RMI)
    E White; Fiscal Year: 2005
    ..tuberculosis. 3) To study the effect of these novel inhibitors on the pantothenate pathway in M. smegmatis. 4) To co-crystallize these compounds with pantothenate synthetase to study their mode of binding ..
  54. INHIBITION OF CARCINOGENESIS BY TEA AND TEA CONSTITUENTS
    Chung Yang; Fiscal Year: 2005
    ..Jointly, we intend to make major contributions to the use of tea for the I chemoprevention of cancer. ..
  55. Targeting Calpain for Novel Anticancer Agents
    ISAAC DONKOR; Fiscal Year: 2005
    ..Additionally, the compounds are useful biomedical tools for investigating the intracellular roles of Calpain due to their metabolic stability. The compounds are also potential anticancer agents. ..
  56. Single Molecule Studies of Enzyme Catalysis
    Gordon Hammes; Fiscal Year: 2005
    ..These experiments are directed at understanding better how enzymes catalyze physiological reactions. A better understanding of enzyme mechanisms is essential for understanding the physiology of disease and the development of new drugs. ..
  57. AMPLIFICATION--MODEL FOR GENETIC INSTABILITY IN CANCER
    JOYCE HAMLIN; Fiscal Year: 2005
    ..abstract_text> ..
  58. IGF-1, Oxidative Stress and Cardiovascular Aging
    Jun Ren; Fiscal Year: 2002
    ..Our long-term goal is to establish the causal link among IGF-1 deficiency, enhanced oxidative damage and ventricular dysfunction in the progression of cardiovascular aging so that hormonal or antioxidant therapy can be optimized...