Glycolysis as a target for the design of new anti-trypanosome drugs.

Glycolysis is perceived as a promising target for new drugs against parasitic trypanosomatid protozoa because this pathway plays an essential role in their ATP supply. Trypanosomatid glycolysis is unique in that it is compartmentalized, and many of its enzymes display unique structural and kinetic features. Structure- and catalytic mechanism-based approaches are applied to design compounds that inhibit the glycolytic enzymes of the parasites without affecting the corresponding proteins of the human host. For some trypanosomatid enzymes, potent and selective inhibitors have already been developed that affect only the growth of cultured trypanosomatids, and not mammalian cells.

[1]  C. Clayton,et al.  Elongation and clustering of glycosomes in Trypanosoma brucei overexpressing the glycosomal Pex11p , 1998, The EMBO journal.

[2]  M. Bolognesi,et al.  The allosteric regulation of pyruvate kinase , 1996, FEBS letters.

[3]  Paul W Smith,et al.  Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. , 1998, Structure.

[4]  J. Périé,et al.  Inhibition of yeast hexokinase: a kinetic and phosphorus nuclear magnetic resonance study , 1999 .

[5]  C. Walsh,et al.  The behavior and significance of slow-binding enzyme inhibitors. , 2006, Advances in enzymology and related areas of molecular biology.

[6]  J. Périé,et al.  Class I aldolases: substrate specificity, mechanism, inhibitors and structural aspects. , 1995, Progress in biophysics and molecular biology.

[7]  A. Lucas The UNDP/world bank/WHO special programme for research and training in tropical diseases. , 1978, Papua and New Guinea medical journal.

[8]  K. Tipton,et al.  Purification and regulatory properties of phosphofructokinase from Trypanosoma (Trypanozoon) brucei brucei. , 1985, The Biochemical journal.

[9]  Barbara M. Bakker,et al.  What Controls Glycolysis in Bloodstream Form Trypanosoma brucei?* , 1999, The Journal of Biological Chemistry.

[10]  P. Herdewijn,et al.  Synthesis and structure-activity relationships of analogs of 2'-deoxy-2'-(3-methoxybenzamido)adenosine, a selective inhibitor of trypanosomal glycosomal glyceraldehyde-3-phosphate dehydrogenase. , 1995, Journal of medicinal chemistry.

[11]  J. Schloss Significance of slow-binding enzyme inhibition and its relationship to reaction-intermediate analogs , 1988 .

[12]  '. FREDM.D.VELLIEUXa,et al.  Structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma brucei determined from Laue data. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[13]  F. Opperdoes,et al.  Cloning and characterization of the NAD-linked glycerol-3-phosphate dehydrogenases of Trypanosoma brucei brucei and Leishmania mexicana mexicana and expression of the trypanosome enzyme in Escherichia coli. , 1996, Molecular and biochemical parasitology.

[14]  K. Nagai,et al.  An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei. , 1997, Molecular and biochemical parasitology.

[15]  A. Sjoerdsma Suicide enzyme inhibitors as potential drugs , 1981, Clinical pharmacology and therapeutics.

[16]  Wim G. J. Hol,et al.  In search of new lead compounds for trypanosomiasis drug design: A protein structure-based linked-fragment approach , 1992, J. Comput. Aided Mol. Des..

[17]  F. Opperdoes,et al.  The glycosomal ATP-dependent phosphofructokinase of Trypanosoma brucei must have evolved from an ancestral pyrophosphate-dependent enzyme. , 1997, European journal of biochemistry.

[18]  M. Barrett,et al.  Kinetoplastid glucose transporters. , 1997, The Biochemical journal.

[19]  J. H. Quastel Advances in Enzymology , 1950, Nature.

[20]  G. H. Reed,et al.  Structure of rabbit muscle pyruvate kinase complexed with Mn2+, K+, and pyruvate. , 1994, Biochemistry.

[21]  A pyruvate-proton symport and an H+-ATPase regulate the intracellular pH of Trypanosoma brucei at different stages of its life cycle. , 2000 .

[22]  Andreas Seyfang,et al.  Specificity of glucose transport in Trypanosoma brucei , 1991 .

[23]  F. Bringaud,et al.  Metabolic aspects of glycosomes in trypanosomatidae - new data and views. , 2000, Parasitology today.

[24]  Bradley E. Bernstein,et al.  Synergistic effects of substrate-induced conformational changes in phosphoglycerate kinase activation , 1997, Nature.

[25]  F. Opperdoes,et al.  Glycerol kinase of Trypanosoma brucei. Cloning, molecular characterization and mutagenesis. , 2000, European journal of biochemistry.

[26]  D. Mecke,et al.  Inhibition of glyceraldehyde-3-phosphate dehydrogenase by pentalenolactone in Trypanosoma brucei. , 1986, Molecular and biochemical parasitology.

[27]  H. Tabak,et al.  Proteins involved in peroxisome biogenesis and functioning. , 1996, Biochimica et biophysica acta.

[28]  W. Hol,et al.  Structures of type 2 peroxisomal targeting signals in two trypanosomatid aldolases. , 2000, Journal of molecular biology.

[29]  J. Costa,et al.  Therapy of human African trypanosomiasis: current situation. , 1999, Memorias do Instituto Oswaldo Cruz.

[30]  J. Sygusch,et al.  Inhibition of rabbit muscle aldolase by phosphorylated aromatic compounds. , 1997, The Biochemical journal.

[31]  F. Young Biochemistry , 1955, The Indian Medical Gazette.

[32]  F. Opperdoes,et al.  Subcellular distribution and characterization of glucosephosphate isomerase in Leishmania mexicana mexicana. , 1994, Molecular and biochemical parasitology.

[33]  M. Saraste,et al.  FEBS Lett , 2000 .

[34]  A. Tielens,et al.  Differences in energy metabolism between trypanosomatidae. , 1998, Parasitology today.

[35]  F. Opperdoes,et al.  Regulation of glycolysis in Trypanosoma brucei: hexokinase and phosphofructokinase activity. , 1982, Acta tropica.

[36]  Barbara M. Bakker,et al.  Roles of triosephosphate isomerase and aerobic metabolism in Trypanosoma brucei. , 2001, The Biochemical journal.

[37]  F. Opperdoes,et al.  Cloning and analysis of the PTS-1 receptor in Trypanosoma brucei. , 1999, Molecular and biochemical parasitology.

[38]  C L Verlinde,et al.  Structure of the complex between trypanosomal triosephosphate isomerase and N‐hydroxy‐4‐phosphono‐butanamide: Binding at the active site despite an “open” flexible loop conformation , 1992, Protein science : a publication of the Protein Society.

[39]  Barbara M. Bakker,et al.  Compartmentation protects trypanosomes from the dangerous design of glycolysis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A. Cornish-Bowden,et al.  Prospects for Antiparasitic Drugs , 1998, The Journal of Biological Chemistry.

[41]  J. Cazzulo Aerobic fermentation of glucose by trypanosomatids , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[42]  F. Opperdoes Compartmentation of carbohydrate metabolism in trypanosomes. , 1987, Annual review of microbiology.

[43]  Y. J. Sun,et al.  The crystal structure of a multifunctional protein: phosphoglucose isomerase/autocrine motility factor/neuroleukin. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  H. Fromm,et al.  The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate. , 1998, Structure.

[45]  F. Millenaar,et al.  A Gene Encoding the Plant‐Like Alternative Oxidase is Present in Phytomonas but Absent in Leishmania spp. , 1998, The Journal of eukaryotic microbiology.

[46]  D. Barford,et al.  The structure of cat muscle pyruvate kinase. , 1986, The EMBO journal.

[47]  M. Gelb,et al.  Selective tight binding inhibitors of trypanosomal glyceraldehyde-3-phosphate dehydrogenase via structure-based drug design. , 1998, Journal of medicinal chemistry.

[48]  M. J. Jedrzejas,et al.  Structure and mechanism of action of a novel phosphoglycerate mutase from Bacillus stearothermophilus , 2000, The EMBO journal.

[49]  J. Cazzulo,et al.  Aerobic glucose fermentation by Trypanosoma cruzi axenic culture amastigote-like forms during growth and differentiation to epimastigotes. , 1987, Molecular and biochemical parasitology.

[50]  P. Michels,et al.  Evolution of glycolysis. , 1993, Progress in biophysics and molecular biology.

[51]  F. Opperdoes,et al.  Inhibition of the glycolytic enzymes in the trypanosome: an approach in the development of new leads in the therapy of parasitic diseases. , 1993, Pharmacology & therapeutics.

[52]  S. Helfert,et al.  Compartmentation of phosphoglycerate kinase in Trypanosoma brucei plays a critical role in parasite energy metabolism. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[53]  G. C. Hill,et al.  Cloning, sequencing, and functional activity of the Trypanosoma brucei brucei alternative oxidase. , 1996, Molecular and biochemical parasitology.

[54]  J Van Roy,et al.  Trypanosoma brucei contains a 2,3-bisphosphoglycerate independent phosphoglycerate mutase. , 2000, European journal of biochemistry.

[55]  J. Périé,et al.  Selective inhibition of Trypanosoma brucei GAPDH by 1,3-bisphospho-D-glyceric acid (1,3-diPG) analogues. , 2001, Bioorganic & medicinal chemistry.

[56]  F. Opperdoes,et al.  Pyruvate kinase of Leishmania mexicana mexicana. Cloning and analysis of the gene, overexpression in Escherichia coli and characterization of the enzyme. , 1994, Molecular and biochemical parasitology.

[57]  F. Opperdoes,et al.  Structure-based design of submicromolar, biologically active inhibitors of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  F. Opperdoes,et al.  Inhibition of glyceraldehyde-3-phosphate dehydrogenase by phosphorylated epoxides and alpha-enones. , 1994, Biochemistry.

[59]  Y. Shirakihara,et al.  Crystal structure of the complex of phosphofructokinase from Escherichia coli with its reaction products. , 1988, Journal of molecular biology.

[60]  F. Opperdoes,et al.  New approach to screening drugs for activity against African trypanosomes , 1977, Nature.

[61]  S J Remington,et al.  Structure of the regulatory complex of Escherichia coli IIIGlc with glycerol kinase , 1993, Science.

[62]  M. Bolognesi,et al.  Binding of non-catalytic ATP to human hexokinase I highlights the structural components for enzyme-membrane association control. , 1999, Structure.

[63]  G. H. Coombs,et al.  Leishmania mexicana: energy metabolism of amastigotes and promastigotes. , 1982, Experimental parasitology.

[64]  P. Michels,et al.  Trypanosoma cruzi glycosomal glyceraldehyde‐3‐phosphate dehydrogenase: structure, catalytic mechanism and targeted inhibitor design , 1998, FEBS letters.

[65]  S. Phillips,et al.  The structure of pyruvate kinase from Leishmania mexicana reveals details of the allosteric transition and unusual effector specificity. , 1999, Journal of Molecular Biology.

[66]  C. van der Meer,et al.  Trypanosoma brucei: trypanocidal effect of salicylhydroxamic acid plus glycerol in infected rats. , 1979, Experimental parasitology.

[67]  F. Opperdoes,et al.  Glycolytic enzymes of Trypanosoma brucei. Simultaneous purification, intraglycosomal concentrations and physical properties. , 1986, European journal of biochemistry.

[68]  J. Périé,et al.  A Fourier transform infrared spectroscopic study of yeast hexokinase: conformational changes under interaction with substrates and inhibitors. , 1998, Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.

[69]  C. Sensen,et al.  Enolase from Trypanosoma brucei, from the amitochondriate protist Mastigamoeba balamuthi, and from the chloroplast and cytosol of Euglena gracilis: pieces in the evolutionary puzzle of the eukaryotic glycolytic pathway. , 2000, Molecular biology and evolution.

[70]  Athel Cornish-Bowden,et al.  Technological and Medical Implications of Metabolic Control Analysis , 2000 .

[71]  F. Opperdoes,et al.  Glucosephosphate isomerase from Trypanosoma brucei. Cloning and characterization of the gene and analysis of the enzyme. , 1989, European journal of biochemistry.

[72]  M. Gelb,et al.  Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: elucidation of a novel binding mode for a 2-amino-N(6)-substituted adenosine. , 2000, Journal of medicinal chemistry.

[73]  P. Pedersen,et al.  Glucose catabolism in African trypanosomes. Evidence that the terminal step is catalyzed by a pyruvate transporter capable of facilitating uptake of toxic analogs. , 1993, The Journal of biological chemistry.

[74]  Z Dauter,et al.  Crystal structure of human muscle aldolase complexed with fructose 1,6‐bisphosphate: Mechanistic implications , 2008, Protein science : a publication of the Protein Society.

[75]  M. Soriano-garcia,et al.  Differences in the intersubunit contacts in triosephosphate isomerase from two closely related pathogenic trypanosomes. , 1998, Journal of molecular biology.

[76]  T. Gefflaut,et al.  Slow reversible inhibitions of rabbit muscle aldolase with substrate analogues: synthesis, enzymatic kinetics and UV difference spectroscopy studies. , 1996, Bioorganic & medicinal chemistry.

[77]  G Vriend,et al.  Refined 1.83 A structure of trypanosomal triosephosphate isomerase crystallized in the presence of 2.4 M-ammonium sulphate. A comparison with the structure of the trypanosomal triosephosphate isomerase-glycerol-3-phosphate complex. , 1991, Journal of molecular biology.

[78]  A. Enayati,et al.  A scoping review of Chikungunya virus infection: epidemiology, clinical characteristics, viral co-circulation complications, and control , 2018, Acta Tropica.

[79]  C. Verlinde,et al.  Synthesis and Conformational Analysis of 2′‐Deoxy‐2′‐(3‐methoxybenzamido)adenosine, a rational‐designed inhibitor of trypanosomal glyceraldehyde phosphate dehydrogenase (GAPDH) , 1994 .

[80]  S. Beverley,et al.  Evolution of nuclear ribosomal RNAs in kinetoplastid protozoa: perspectives on the age and origins of parasitism. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[81]  Barbara M. Bakker,et al.  Metabolic control analysis of glycolysis in trypanosomes as an approach to improve selectivity and effectiveness of drugs. , 2000, Molecular and biochemical parasitology.

[82]  G. Petsko,et al.  Crystal structure of rabbit phosphoglucose isomerase, a glycolytic enzyme that moonlights as neuroleukin, autocrine motility factor, and differentiation mediator. , 2000, Biochemistry.

[83]  Barbara M. Bakker,et al.  Using Metabolic Control Analysis To Improve The Selectivity and Effectiveness of Drugs Against Parasitic Diseases , 2000 .

[84]  P. Evans,et al.  Structure and control of phosphofructokinase from Bacillus stearothermophilus , 1979, Nature.

[85]  F. Opperdoes,et al.  Glycolysis in Trypanosoma brucei. , 1980, European journal of biochemistry.

[86]  P. Michels,et al.  Metabolic compartmentation in African trypanosomes. , 1996, Parasitology today.

[87]  T. MANN,et al.  Advances in Enzymology , 1963, Nature.

[88]  M. Noble,et al.  The crystal structure of the “open” and the “closed” conformation of the flexible loop of trypanosomal triosephosphate isomerase , 1991, Proteins.

[89]  W G Hol,et al.  A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana. , 2000, Structure.

[90]  F. Opperdoes,et al.  The inhibition of pyruvate transport across the plasma membrane of the bloodstream form of Trypanosoma brucei and its metabolic implications. , 1995, The Biochemical journal.

[91]  C L Verlinde,et al.  Structure-based drug design: progress, results and challenges. , 1994, Structure.

[92]  M. Barrett,et al.  Recent advances in identifying and validating drug targets in trypanosomes and leishmanias. , 1999, Trends in microbiology.

[93]  F. Opperdoes,et al.  Molecular cloning and analysis of two tandemly linked genes for pyruvate kinase of Trypanosoma brucei. , 1991, European journal of biochemistry.

[94]  G J Davies,et al.  Activity and specificity of human aldolases. , 1991, Journal of molecular biology.

[95]  Barbara M. Bakker,et al.  Regulation and control of compartmentalized glycolysis in bloodstream formTrypanosoma brucei , 1995, Journal of bioenergetics and biomembranes.

[96]  F. Opperdoes,et al.  Stimulation of Trypanosoma brucei pyruvate kinase by fructose 2,6-bisphosphate. , 1985, European journal of biochemistry.

[97]  G Vriend,et al.  Structural and mutagenesis studies of leishmania triosephosphate isomerase: a point mutation can convert a mesophilic enzyme into a superstable enzyme without losing catalytic power. , 1999, Protein engineering.

[98]  Y. Sanejouand,et al.  Yeast hexokinase inhibitors designed from the 3-D enzyme structure rebuilding. , 1997, Journal of enzyme inhibition.

[99]  F. Opperdoes,et al.  Localization of nine glycolytic enzymes in a microbody‐like organelle in Trypanosoma brucei: The glycosome , 1977, FEBS letters.

[100]  F. Opperdoes,et al.  Selective inhibition of trypanosomal glyceraldehyde-3-phosphate dehydrogenase by protein structure-based design: toward new drugs for the treatment of sleeping sickness. , 1994, Journal of medicinal chemistry.

[101]  J. Janin,et al.  X-ray structure and catalytic mechanism of lobster enolase. , 1995, Biochemistry.

[102]  C L Verlinde,et al.  Crystal structure of glycosomal glyceraldehyde-3-phosphate dehydrogenase from Leishmania mexicana: implications for structure-based drug design and a new position for the inorganic phosphate binding site. , 1995, Biochemistry.

[103]  R. A. Zubillaga,et al.  Using evolutionary changes to achieve species-specific inhibition of enzyme action--studies with triosephosphate isomerase. , 1995, Chemistry & biology.

[104]  J. Martial,et al.  Crystal structure of recombinant human triosephosphate isomerase at 2.8 Å resolution. Triosephosphate isomerase‐related human genetic disorders and comparison with the trypanosomal enzyme , 1994, Protein science : a publication of the Protein Society.

[105]  Barbara M. Bakker,et al.  Glycolysis in Bloodstream Form Trypanosoma brucei Can Be Understood in Terms of the Kinetics of the Glycolytic Enzymes* , 1997, The Journal of Biological Chemistry.

[106]  K Harlos,et al.  Crystal structure of the binary complex of pig muscle phosphoglycerate kinase and its substrate 3‐phospho‐D‐glycerate , 1992, Proteins.

[107]  H. Watson,et al.  Twinning in crystals of human skeletal muscle D-glyceraldehyde-3-phosphate dehydrogenase. , 1976, Journal of molecular biology.

[108]  K. Nagai,et al.  Erratum to ``An antibiotic, ascofuranone, specifically inhibits respiration and in vitro growth of long slender bloodstream forms of Trypanosoma brucei brucei'': [Mol. Biochem. Parasitol. 81 (1996) 127–136] , 1997 .

[109]  A. Cornish-Bowden,et al.  Evolution and regulatory role of the hexokinases. , 1998, Biochimica et biophysica acta.