42. Harwaldt P, Rahlfs S, Becker K (2002) Glutathione S-transferase of the malarial parasite
Plasmodium falciparum: characterization of a potential drug target. Biol Chem 383:821–830
43. Hiller N, Fritz-Wolf K et al (2006) Plasmodium falciparum glutathione S-transferase—
structural and mechanistic studies on ligand binding and enzyme inhibition. Protein Sci
15:281–289
44. Fritz-Wolf K, Becker A et al (2003) X-ray structure of glutathione S-transferase from the
malarial parasite Plasmodium falciparum. Proc Natl Acad Sci USA 100:13821–13826
45. Perbandt M, Eberle R et al (2015) High resolution structures of Plasmodium falciparum GST
complexes provide novel insights into the dimer-tetramer transition and a novel
ligand-binding site. J Struct Biol 191:365–375
46. Ahmad R, Srivastava AK (2008) Inhibition of glutathione-S-transferase from Plasmodium
yoelii by protoporphyrin IX, cibacron blue and menadione: implications and therapeutic
benefits. Parasitol Res 102:805–807
47. Miller RW, Kerr CT, Curry JR (1968) Mammalian dihydroorotate—ubiquinone reductase
complex. Can J Biochem 46:1099–1106
48. Chen JJ, Jones ME (1976) The cellular location of dihydroorotate dehydrogenase: relation to
de novo biosynthesis of pyrimidines. Arch Biochem Biophys 176:82–90
49. [a] Larsen JN, Jensen KF (1985) Nucleotide sequence of the pyrD gene of Escherichia coli
and characterization of the flavoprotein dihydroorotate dehydrogenase. Eur J Biochem
151:59–65; [b] LeBlanc SB, Wilson CM (1993) The dihydroorotate dehydrogenase gene
homologue of Plasmodium falciparum. Mol Biochem Parasitol 60:349–351
50. [a] Gardner MJ, Hall N et al. (2002) Genome sequence of the human malaria parasite
Plasmodium falciparum. Nature 419:498–511; [b] K. Vyas V, Ghate M (2011) Recent
developments in the medicinal chemistry and therapeutic potential of dihydroorotate
dehydrogenase (DHODH) inhibitors. Mini-Rev Med Chem 11:1039–1055
51. Krungkrai J (1995) Purification, characterization and localization of mitochondrial dihydroorotate dehydrogenase in Plasmodium falciparum, human malaria parasite. Biochim
Biophys Acta Gen Subj 1243:351–360
52. McRobert L, McConkey GA (2002) RNA Interference (RNAi) inhibits growth of
Plasmodium falciparum. Mol Biochem Parasitol 119:273–278
53. Baldwin J, Farajallah AM et al (2002) Malarial dihydroorotate dehydrogenase: substrate and
inhibitor specificity. J Biol Chem 277:41827–41834
54. Boa AN, Canavan SP et al (2005) Synthesis of brequinar analogue inhibitors of malaria
parasite dihydroorotate dehydrogenase. Bioorg Med Chem 13:1945–1967
55. Baldwin J, Michnoff CH et al (2005) High-throughput screening for potent and selective
inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem
280:21847–21853
56. Heikkilä T, Thirumalairajan S et al (2006) The first de novo designed inhibitors of
Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg Med Chem Lett 16:88–92
57. Phillips MA, Rathod PK (2010) Plasmodium dihydroorotate dehydrogenase: A promising
target for novel anti-malarial chemotherapy. Infect Disord Drug Targets 10:226–239
58. Löffler M, Fairbanks LD et al (2005) Pyrimidine pathways in health and disease. Trends Mol
Med 11:430–437
59. Fagan RL, Nelson MN, Pagano PM, Palfey BA (2006) Mechanism of flavin reduction in class
2 dihydroorotate dehydrogenases. Biochemistry 45:14926–14932
60. Liu S, Neidhardt EA et al (2000) Structures of human dihydroorotate dehydrogenase in
complex with antiproliferative agents. Structure 8:25–33
61. Fagan RL, Palfey BA (2009) Roles in binding and chemistry for conserved active site
residues in the class 2 dihydroorotate dehydrogenase from Escherichia coli. Biochemistry
48:7169–7178
62. Hurt DE, Widom J, Clardy J (2006) Structure of Plasmodium falciparum dihydroorotate
dehydrogenase with a bound inhibitor. Acta Crystallogr Sect D: Biol Crystallogr D62:312–323
63. Drozdetskiy A, Cole C, Procter J, Barton GJ (2015) JPred4: a protein secondary structure
prediction server. Nucleic Acids Res 43:W389–W394
218
S. Bhagat et al.
Plasmodium falciparum: characterization of a potential drug target. Biol Chem 383:821–830
43. Hiller N, Fritz-Wolf K et al (2006) Plasmodium falciparum glutathione S-transferase—
structural and mechanistic studies on ligand binding and enzyme inhibition. Protein Sci
15:281–289
44. Fritz-Wolf K, Becker A et al (2003) X-ray structure of glutathione S-transferase from the
malarial parasite Plasmodium falciparum. Proc Natl Acad Sci USA 100:13821–13826
45. Perbandt M, Eberle R et al (2015) High resolution structures of Plasmodium falciparum GST
complexes provide novel insights into the dimer-tetramer transition and a novel
ligand-binding site. J Struct Biol 191:365–375
46. Ahmad R, Srivastava AK (2008) Inhibition of glutathione-S-transferase from Plasmodium
yoelii by protoporphyrin IX, cibacron blue and menadione: implications and therapeutic
benefits. Parasitol Res 102:805–807
47. Miller RW, Kerr CT, Curry JR (1968) Mammalian dihydroorotate—ubiquinone reductase
complex. Can J Biochem 46:1099–1106
48. Chen JJ, Jones ME (1976) The cellular location of dihydroorotate dehydrogenase: relation to
de novo biosynthesis of pyrimidines. Arch Biochem Biophys 176:82–90
49. [a] Larsen JN, Jensen KF (1985) Nucleotide sequence of the pyrD gene of Escherichia coli
and characterization of the flavoprotein dihydroorotate dehydrogenase. Eur J Biochem
151:59–65; [b] LeBlanc SB, Wilson CM (1993) The dihydroorotate dehydrogenase gene
homologue of Plasmodium falciparum. Mol Biochem Parasitol 60:349–351
50. [a] Gardner MJ, Hall N et al. (2002) Genome sequence of the human malaria parasite
Plasmodium falciparum. Nature 419:498–511; [b] K. Vyas V, Ghate M (2011) Recent
developments in the medicinal chemistry and therapeutic potential of dihydroorotate
dehydrogenase (DHODH) inhibitors. Mini-Rev Med Chem 11:1039–1055
51. Krungkrai J (1995) Purification, characterization and localization of mitochondrial dihydroorotate dehydrogenase in Plasmodium falciparum, human malaria parasite. Biochim
Biophys Acta Gen Subj 1243:351–360
52. McRobert L, McConkey GA (2002) RNA Interference (RNAi) inhibits growth of
Plasmodium falciparum. Mol Biochem Parasitol 119:273–278
53. Baldwin J, Farajallah AM et al (2002) Malarial dihydroorotate dehydrogenase: substrate and
inhibitor specificity. J Biol Chem 277:41827–41834
54. Boa AN, Canavan SP et al (2005) Synthesis of brequinar analogue inhibitors of malaria
parasite dihydroorotate dehydrogenase. Bioorg Med Chem 13:1945–1967
55. Baldwin J, Michnoff CH et al (2005) High-throughput screening for potent and selective
inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J Biol Chem
280:21847–21853
56. Heikkilä T, Thirumalairajan S et al (2006) The first de novo designed inhibitors of
Plasmodium falciparum dihydroorotate dehydrogenase. Bioorg Med Chem Lett 16:88–92
57. Phillips MA, Rathod PK (2010) Plasmodium dihydroorotate dehydrogenase: A promising
target for novel anti-malarial chemotherapy. Infect Disord Drug Targets 10:226–239
58. Löffler M, Fairbanks LD et al (2005) Pyrimidine pathways in health and disease. Trends Mol
Med 11:430–437
59. Fagan RL, Nelson MN, Pagano PM, Palfey BA (2006) Mechanism of flavin reduction in class
2 dihydroorotate dehydrogenases. Biochemistry 45:14926–14932
60. Liu S, Neidhardt EA et al (2000) Structures of human dihydroorotate dehydrogenase in
complex with antiproliferative agents. Structure 8:25–33
61. Fagan RL, Palfey BA (2009) Roles in binding and chemistry for conserved active site
residues in the class 2 dihydroorotate dehydrogenase from Escherichia coli. Biochemistry
48:7169–7178
62. Hurt DE, Widom J, Clardy J (2006) Structure of Plasmodium falciparum dihydroorotate
dehydrogenase with a bound inhibitor. Acta Crystallogr Sect D: Biol Crystallogr D62:312–323
63. Drozdetskiy A, Cole C, Procter J, Barton GJ (2015) JPred4: a protein secondary structure
prediction server. Nucleic Acids Res 43:W389–W394
218
S. Bhagat et al.