Dihydrofolate reductases as targets for inhibitors

Hitchings, George H.; Smith, Sheila L.

doi:10.1016/0065-2571(80)90025-4

Cited by 60 publications

(37 citation statements)

References 41 publications

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“…Thus the antibacterial, trimethoprim (TMP) inhibits bacterial DHFR selectively, showing about 3000-fold less affinity for mammalian DHFRs [2]. Methotrexate (MTX) shows high affinity for a wide range of DHFRs from different species, including mammalian enzyme [3], and is used as an anti-cancer agent.…”

Section: Introductionmentioning

confidence: 99%

The structure of mouse L1210 dihydrofolate reductase‐drug complexes and the construction of a model of human enzyme

et al. 1987

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The structure of mouse L 1210 dihydrofolate reductase (DHFR) complexed with NADPH and trimethoprim has been refined at 2.0/~ resolution. The analogous complex with NADPH and methotrexate has been refined at 2.5 A resolution. These structures reveal for the first time details of drug interactions with a mammalian DHFR, which are compared with those observed from previous X-ray investigations of DHFR/inhibitor complexes. The refined L1210 structure has been used as the basis for the construction of a model of the human enzyme. There are only twenty-one sequence differences between mouse L1210 and human DHFRs, and all but two of these are located close to the molecular surface: a strong indication that the active sites are essentially identical in these two mammalian enzymes.

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Section: Introductionmentioning

confidence: 99%

The structure of mouse L1210 dihydrofolate reductase‐drug complexes and the construction of a model of human enzyme

et al. 1987

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“…6; see table 4 of ref. 7). Moreover, the enzyme from plasmid R67 is a tetramer composed of four chemically identical subunits, whereas all known DHFRs from bacterial and mammalian sources are monomers.…”

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confidence: 99%

Alpha-pyridine nucleotides as substrates for a plasmid-specified dihydrofolate reductase.

Smith¹,

Burchall²

1983

Proc. Natl. Acad. Sci. U.S.A.

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The a epimers of pyridine nucleotides are almost totally inactive as reductants in dehydrogenase reactions. In contrast, the R plasmid R67-specified dihydrofolate reductase (5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) isolated from trimethoprim-resistant Escherichia coli utilized a-NADPH and a-NADH in addition to the "normal" 3-epimers. The enzymes from bacterial and mammalian sources used only 13-NADPH and ,B-NADH. The K. value for ax-NADPH (16 ,uM) was 4-fold greater than that for .8-NADPH (4 ,AM), while the maximal velocity of the a-NADPH-catalyzed reaction was 70% of that seen with the .3-NADPH. P-NADP+ and a-NADP+ were competitive inhibitors of the R67 enzyme. Pyridine nucleotide analogues such as deamino-and acetyl-NADPH were used readily by bacterial, plasmid, and mammalian enzymes, whereas thio-NADPH was used only by the plasmid enzyme. These data suggest that the enzyme from R plasmid R67 possesses a pyridine nucleotide binding site different from that of other dihydrofolate reductases and dehydrogenases.

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“…It is used as a target for several antibacterial and antineoplastic (antitumor) drugs. The antibacterial activity of these drugs is due to selective inhibition of the enzyme from species to species (Baccarani et al, 1982;Hitchings and Smith, 1980). Unfortunately, the molecular mechanism of selective inhibition is not yet known, despite extensive efforts.…”

Section: Introductionmentioning

confidence: 99%

Molecular and crystal structure of 2-amino-4-(tricyclo[3.3.1.1.3,7]decyl-1)-6-N-methyl-piperazino-1,3,5-triazine

Hamodrakas

Hempel

Camerman

et al. 1992

Journal of Crystallographic and Spectroscopic Research

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The crystal and molecular structure of the title compound has been determined by X-ray diffraction. The compound crystallizes in the rhombohedral space group R3 with a = b = c = 17.804(9)A, a = /3 = 7 = 116.48(2) ~ and Z = 6. The structure was solved by direct methods and a full-matrix least-squares refinement converged to a final R = 0.061 for 1922 unique reflections. The adamantyl moiety is statically disordered in the crystal structure, and adopts two conformations related by the rotation of approximately 60 ~ about the C(4)--C(9) bond. A hydrogen bond between N(7) 9 9 9 N(21) arranges molecules into hexamers stacked along the threefold axis and provides for empty hydrophobic channels bounded by the adamantyl groups.

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Dihydrofolate reductases as targets for inhibitors

Cited by 60 publications

References 41 publications

The structure of mouse L1210 dihydrofolate reductase‐drug complexes and the construction of a model of human enzyme

The structure of mouse L1210 dihydrofolate reductase‐drug complexes and the construction of a model of human enzyme

Alpha-pyridine nucleotides as substrates for a plasmid-specified dihydrofolate reductase.

Molecular and crystal structure of 2-amino-4-(tricyclo[3.3.1.1.3,7]decyl-1)-6-N-methyl-piperazino-1,3,5-triazine

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