32. Osborne MJ, Schnell J, Benkovic SJ, Dyson
HJ, Wright PE (2001) Backbone dynamics in
dihydrofolate reductase complexes: role of
loop flexibility in the catalytic mechanism.
Biochemistry 40(33):9846–9859
33. Oyen D, Fenwick RB, Stanfield RL, Dyson
HJ, Wright PE (2015) Cofactor-mediated
conformational dynamics promote product
release from Escherichia coli dihydrofolate
reductase via an allosteric pathway. J Am
Chem Soc 137(29):9459–9468
34. Abali EE, Skacel NE, Celikkaya H, Hsieh YC
(2008) Regulation of human dihydrofolate
reductase activity and expression. Vitam
Horm 79:267–292
35. PerkinElmer Informatics (2016) ChemDraw
Professional, 15.1.0.144
36. Tuttle LM, Dyson HJ, Wright PE (2014) Side
chain conformational averaging in human
dihydrofolate reductase. Biochemistry 53
(7):1134–1145
37. Bhabha G, Ekiert DC, Jennewein M, Zmasek
CM, Tuttle LM, Kroon G, Dyson HJ,
Godzik A, Wilson IA, Wright PE (2013)
Divergent evolution of protein conformational dynamics in dihydrofolate reductase.
Nat Struct Mol Biol 20(11):1243–1249
38. Anderson AC (2005) Targeting DHFR in
parasitic protozoa. Drug Discov Today 10
(2):121–128
39. Chanama M, Chitnumsub P, Yuthavong Y
(2005) Subunit complementation of thymidylate synthase in Plasmodium falciparum
bifunctional
dihydrofolate
reductasethymidylate synthase. Mol Biochem Parasitol
139(1):83–90
40. Yuvaniyama
J,
Chitnumsub
P,
Kamchonwongpaisan S, Vanichtanankul J,
Sirawaraporn W, Taylor P, Walkinshaw MD,
Yuthavong Y (2003) Insights into antifolate
resistance from malarial DHFR-TS structures.
Nat Struct Biol 10(5):357–365
41. Mokmak W, Chunsrivirot S, Hannongbua S,
Yuthavong Y, Tongsima S, Kamchonwongpaisan S (2014) Molecular dynamics of interactions between rigid and flexible antifolates
and
dihydrofolate
reductase
from
pyrimethamine-sensitive and pyrimethamineresistant Plasmodium falciparum. Chem Biol
Drug Des 84(4):450–461
42. Yuthavong Y, Yuvaniyama J, Chitnumsub P,
Vanichtanankul J, Chusacultanachai S,
Tarnchompoo B, Vilaivan T, Kamchonwongpaisan S (2005) Malarial (Plasmodium falciparum)
DHFR-thymidylate
synthasestructural basis for antifolate resistance and
development of effective inhibitors. Parasitology 130:249–259
43. Dunn SMJ, Batchelor JG, King RW (1978)
Kinetics of ligand binding to DHFR-binary
complex formation with NADPH and coenzyme
analogues.
Biochemistry
17
(12):2356–2363
44. Dunn SMJ, King RW (1980) Kinetics of ternary complex formation between DHFR,
coenzyme, and inhibitors. Biochemistry 19
(4):766–773
45. Cayley PJ, Dunn SMJ, King RW (1981)
Kinetics of substrate, coenzyme, and inhibitor
binding to E. coli DHFR. Biochemistry 20
(4):874–879
46. Reddish MJ, Vaughn MB, Fu R, Dyer RB
(2016) Ligand-dependent conformational
dynamics of Dihydrofolate Reductase. Biochemistry 55(10):1485–1493
47. Karabulut S, Sizochenko N, Orhan A, Leszczynski J (2016) A DFT-based QSAR study on
inhibition of human dihydrofolate reductase.
J Mol Graph Model 70:23–29
48. Schweitzer BI, Dicker AP, Bertino JR (1990)
Dihydrofolate reductase as a therapeutic target. FASEB J 4:2441–2452
49. Hashkes PJ, Becker ML, Cabral DA, Laxer
RM, Paller AS, Rabinovich CE, Turner D,
Zulian F (2014) Methotrexate: new uses for
an old drug. J Pediatr 164(2):231–236
50. Lv C, Zhao W, Guo R (2012) Methotrexate:
pharmacology, clinical application and adverse
effects. In: Castillo VS, Moyano LA (eds)
Methotrexate. Nova Science Publishers, Inc.,
New York, pp 217–226
51. Verma U, Verma N (2012) Methotrexate:
pharmacology, clinical uses and adverse
effects. In: Castillo VS, Moyano LA (eds)
Methotrexate. Nova Science Publishers, Inc.,
New York, pp 107–126
52. Falzone CJ, Wright PE, Benkovic SJ (1991)
Evidence for two interconverting protein isomers in the methotrexate complex of DHFR
from E. coli. Biochemistry 30:2184–2191
53. Appleman JR, Howell EE, Kraut J, Ku ¨hl M,
Blakely RL (1988) Role of Aspartate 27 in the
binding of methotrexate to DHFR from E
coli. J Biol Chem 263(19):9187–9198
54. Cannon WR, Garrison BJ, Benkovic SJ
(1997) Consideration of the pH dependent
inhibition of DHFR by methotrexate. J Mol
Biol 271:656–668
55. Mauldin RV (2009) Multi-timescale dynamic
effects of antifolate binding and mutations in
DHFR
216
Melanie Goldstein and Nina M. Goodey
HJ, Wright PE (2001) Backbone dynamics in
dihydrofolate reductase complexes: role of
loop flexibility in the catalytic mechanism.
Biochemistry 40(33):9846–9859
33. Oyen D, Fenwick RB, Stanfield RL, Dyson
HJ, Wright PE (2015) Cofactor-mediated
conformational dynamics promote product
release from Escherichia coli dihydrofolate
reductase via an allosteric pathway. J Am
Chem Soc 137(29):9459–9468
34. Abali EE, Skacel NE, Celikkaya H, Hsieh YC
(2008) Regulation of human dihydrofolate
reductase activity and expression. Vitam
Horm 79:267–292
35. PerkinElmer Informatics (2016) ChemDraw
Professional, 15.1.0.144
36. Tuttle LM, Dyson HJ, Wright PE (2014) Side
chain conformational averaging in human
dihydrofolate reductase. Biochemistry 53
(7):1134–1145
37. Bhabha G, Ekiert DC, Jennewein M, Zmasek
CM, Tuttle LM, Kroon G, Dyson HJ,
Godzik A, Wilson IA, Wright PE (2013)
Divergent evolution of protein conformational dynamics in dihydrofolate reductase.
Nat Struct Mol Biol 20(11):1243–1249
38. Anderson AC (2005) Targeting DHFR in
parasitic protozoa. Drug Discov Today 10
(2):121–128
39. Chanama M, Chitnumsub P, Yuthavong Y
(2005) Subunit complementation of thymidylate synthase in Plasmodium falciparum
bifunctional
dihydrofolate
reductasethymidylate synthase. Mol Biochem Parasitol
139(1):83–90
40. Yuvaniyama
J,
Chitnumsub
P,
Kamchonwongpaisan S, Vanichtanankul J,
Sirawaraporn W, Taylor P, Walkinshaw MD,
Yuthavong Y (2003) Insights into antifolate
resistance from malarial DHFR-TS structures.
Nat Struct Biol 10(5):357–365
41. Mokmak W, Chunsrivirot S, Hannongbua S,
Yuthavong Y, Tongsima S, Kamchonwongpaisan S (2014) Molecular dynamics of interactions between rigid and flexible antifolates
and
dihydrofolate
reductase
from
pyrimethamine-sensitive and pyrimethamineresistant Plasmodium falciparum. Chem Biol
Drug Des 84(4):450–461
42. Yuthavong Y, Yuvaniyama J, Chitnumsub P,
Vanichtanankul J, Chusacultanachai S,
Tarnchompoo B, Vilaivan T, Kamchonwongpaisan S (2005) Malarial (Plasmodium falciparum)
DHFR-thymidylate
synthasestructural basis for antifolate resistance and
development of effective inhibitors. Parasitology 130:249–259
43. Dunn SMJ, Batchelor JG, King RW (1978)
Kinetics of ligand binding to DHFR-binary
complex formation with NADPH and coenzyme
analogues.
Biochemistry
17
(12):2356–2363
44. Dunn SMJ, King RW (1980) Kinetics of ternary complex formation between DHFR,
coenzyme, and inhibitors. Biochemistry 19
(4):766–773
45. Cayley PJ, Dunn SMJ, King RW (1981)
Kinetics of substrate, coenzyme, and inhibitor
binding to E. coli DHFR. Biochemistry 20
(4):874–879
46. Reddish MJ, Vaughn MB, Fu R, Dyer RB
(2016) Ligand-dependent conformational
dynamics of Dihydrofolate Reductase. Biochemistry 55(10):1485–1493
47. Karabulut S, Sizochenko N, Orhan A, Leszczynski J (2016) A DFT-based QSAR study on
inhibition of human dihydrofolate reductase.
J Mol Graph Model 70:23–29
48. Schweitzer BI, Dicker AP, Bertino JR (1990)
Dihydrofolate reductase as a therapeutic target. FASEB J 4:2441–2452
49. Hashkes PJ, Becker ML, Cabral DA, Laxer
RM, Paller AS, Rabinovich CE, Turner D,
Zulian F (2014) Methotrexate: new uses for
an old drug. J Pediatr 164(2):231–236
50. Lv C, Zhao W, Guo R (2012) Methotrexate:
pharmacology, clinical application and adverse
effects. In: Castillo VS, Moyano LA (eds)
Methotrexate. Nova Science Publishers, Inc.,
New York, pp 217–226
51. Verma U, Verma N (2012) Methotrexate:
pharmacology, clinical uses and adverse
effects. In: Castillo VS, Moyano LA (eds)
Methotrexate. Nova Science Publishers, Inc.,
New York, pp 107–126
52. Falzone CJ, Wright PE, Benkovic SJ (1991)
Evidence for two interconverting protein isomers in the methotrexate complex of DHFR
from E. coli. Biochemistry 30:2184–2191
53. Appleman JR, Howell EE, Kraut J, Ku ¨hl M,
Blakely RL (1988) Role of Aspartate 27 in the
binding of methotrexate to DHFR from E
coli. J Biol Chem 263(19):9187–9198
54. Cannon WR, Garrison BJ, Benkovic SJ
(1997) Consideration of the pH dependent
inhibition of DHFR by methotrexate. J Mol
Biol 271:656–668
55. Mauldin RV (2009) Multi-timescale dynamic
effects of antifolate binding and mutations in
DHFR
216
Melanie Goldstein and Nina M. Goodey