Role of the conserved active site residue tryptophan-24 of human dihydrofolate reductase as revealed by mutagenesis

Biochemistry ◽  
1991 ◽  
Vol 30 (5) ◽  
pp. 1432-1440 ◽  
Author(s):  
William A. Beard ◽  
James R. Appleman ◽  
Shaoming Huang ◽  
Tavner J. Delcamp ◽  
James H. Freisheim ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Active Site ◽  
Active Site Residue ◽  
Human Dihydrofolate Reductase

scholarly journals Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim.

2001 ◽  
Vol 48 (4) ◽  
pp. 903-916 ◽  
Author(s):  
W Nowak ◽  
V Cody ◽  
A Wojtczak
Keyword(s):  
Dihydrofolate Reductase ◽  
Active Site ◽  
Structural Changes ◽  
Energy Substitution ◽  
Energy Simulations ◽  
Detailed Computer ◽  
Human Dihydrofolate Reductase ◽  
Folate Cycle ◽  
Active Site Mutants

Dihydrofolate reductase (DHFR, EC 1.5.1.3) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The important L22F point mutation does affect PTX orientation but does not changethe binding energy. Simulations of the dynamics of binary hDHFR-PTX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results indicate structural changes in the enzyme induced by NADPH binding.

scholarly journals Probing the role of two hydrophobic active site residues in the human dihydrofolate reductase by site-directed mutagenesis

1989 ◽  
Vol 264 (34) ◽  
pp. 20786-20795
Author(s):  
B.I. Schweitzer ◽  
S Srimatkandada ◽  
H Gritsman ◽  
R Sheridan ◽  
R Venkataraghavan ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Active Site ◽  
Site Directed Mutagenesis ◽  
Directed Mutagenesis ◽  
Active Site Residues ◽  
Human Dihydrofolate Reductase

scholarly journals Crystallographic analysis reveals a novel second binding site for trimethoprim in active site double mutants of human dihydrofolate reductase

2011 ◽  
Vol 176 (1) ◽  
pp. 52-59 ◽  
Author(s):  
Vivian Cody ◽  
Jim Pace ◽  
Jennifer Piraino ◽  
Sherry F. Queener
Keyword(s):  
Binding Site ◽  
Dihydrofolate Reductase ◽  
Active Site ◽  
Crystallographic Analysis ◽  
Human Dihydrofolate Reductase

scholarly journals Correlations of Inhibitor Kinetics forPneumocystis jiroveciiand Human Dihydrofolate Reductase with Structural Data for Human Active Site Mutant Enzyme Complexes†‡

Biochemistry ◽  
2009 ◽  
Vol 48 (8) ◽  
pp. 1702-1711 ◽  
Author(s):  
Vivian Cody ◽  
Jim Pace ◽  
Jennifer Makin ◽  
Jennifer Piraino ◽  
Sherry F. Queener ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Active Site ◽  
Structural Data ◽  
Mutant Enzyme ◽  
Human Dihydrofolate Reductase ◽  
Enzyme Complexes ◽  
Inhibitor Kinetics

Role of the Active-Site Carboxylate in Dihydrofolate Reductase: Kinetic and Spectroscopic Studies of the Aspartate 26 .fwdarw. Asparagine Mutant of the Lactobacillus casei Enzyme

Biochemistry ◽  
1995 ◽  
Vol 34 (9) ◽  
pp. 2872-2882 ◽  
Author(s):  
J. Basran ◽  
M. G. Casarotto ◽  
I. L. Barsukov ◽  
G. C. K. Roberts
Keyword(s):  
Dihydrofolate Reductase ◽  
Active Site ◽  
Lactobacillus Casei ◽  
Spectroscopic Studies

Kinetic investigation of the functional role of phenylalanine-31 of recombinant human dihydrofolate reductase

Biochemistry ◽  
1990 ◽  
Vol 29 (27) ◽  
pp. 6428-6436 ◽  
Author(s):  
Jiu Tsair Tsay ◽  
James R. Appleman ◽  
William A. Beard ◽  
Neal J. Prendergast ◽  
Tavner J. Delcamp ◽  
...  
Keyword(s):  
Dihydrofolate Reductase ◽  
Functional Role ◽  
Kinetic Investigation ◽  
Human Dihydrofolate Reductase

Functional role of a non-active site residue Trp23 on the enzyme activity of Escherichia coli thioesterase I/protease I/lysophospholipase L1

2009 ◽  
Vol 1794 (10) ◽  
pp. 1467-1473 ◽  
Author(s):  
Li-Chiun Lee ◽  
Yi-Li Chou ◽  
Hong-Hwa Chen ◽  
Ya-Lin Lee ◽  
Jei-Fu Shaw
Keyword(s):  
Escherichia Coli ◽  
Enzyme Activity ◽  
Active Site ◽  
Functional Role ◽  
Active Site Residue

scholarly journals Inhibitors of Human Dihydrofolate Reductase: A Computational Design and Docking Studies Using Glide

2008 ◽  
Vol 5 (2) ◽  
pp. 263-270 ◽  
Author(s):  
Lingala Yamini ◽  
Manga Vijjulatha
Keyword(s):  
Dna Synthesis ◽  
Dihydrofolate Reductase ◽  
Active Site ◽  
Computational Design ◽  
Docking Studies ◽  
Vital Role ◽  
Essential Component ◽  
Tetrahydrofolic Acid ◽  
Human Dihydrofolate Reductase

Dihydrofolate reductase (DHFR) plays a vital role in the DNA synthesis by reducing dihydrofolic acid to tetrahydrofolic acid which is an essential component. Synthetic ligands like methotrexate (MTX), aminopterin (AMP) and their analogues act as potential anti metabolites by mimicking the coenzyme dihydrofolic acid (DHFA) they inhibit the activity of DHFR antagonistically. Several ligands which are similar to MTX analogues and 6, 8 substituted 2 – naphthyls (NAP) which can mimic the pteridyl group of DHFA have been computationally designed. These ligands were proposed to hinder the formation N5, N10 methylene tetrahydrofolic acid (THFA) coenzyme, which is essential for the DNA synthesis. The docking studies were done using grid, generated with the 0.9 Vander Waals scaling for non polar bonds in the active site of the receptor. These newly designed ligands such as 14 -21 ,23 and 28 have shown good docking scores and predicted activities when compared to already existing ligands MTX and its analogues.

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