Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A macromolecular binder of folic acid and folic acid derivatives has been identified in the particulate fraction of homogenates of rabbit choroid plexus. Within the choroid plexus, there are 2.3 nmol of folate-binding activity (binder) per g of tissue. The molecular weight of the folate binder complex, separated from the particulate fraction after solubilization with Triton X-100, was 340,000 to 400,000 by Sephadex gel filtration. The partially purified binder, when freed of endogenous folates, bound equivalent amounts of both [3H]folic acid and [methyl-14C]methyltetrahydrofolic acid per mg of protein. Folic acid, homofolic acid, 5-methyltetrahydrofolic acid, and to a lesser degree, methotrexate, inhibited the binding of both [3H]folic acid and [14C]methyltetrahydrofolic acid. Binding activity, which decreased below pH = 7.0, was unaffected by pretreatment with ribonuclease but was eliminated completely by papain and a protease (Streptomyces griseus). Although dihydrofolate reductase was present in choroid plexus, the binder was distinct from dihydrofolate reductase as judged by gel filtration and methotrexate sensitivity. This high affinity binder of folates may be responsible, in part, for the rapid, saturable uptake of folic acid and methyltetrahydrofolic acid by rabbit choroid plexus in vitro.
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PMID:Identification of folate binding macromolecule in rabbit choroid plexus. 1 98

The problem of inhibiting a specific enzyme of a pathogen without inhibiting the corresponding enzyme of the host is one which has intrigued medicinal chemists for years. While it is easy to find potent inhibitors of purified enzymes transforming these inhibitors into effective drugs, it still is a very poorly understood business. This report discusses studies with two enzymes, papain and dihydrofolate reductase, and the nonspecific (phi and MR correlated) interaction of ligands with them. The QSAR which has been developed for the inhibition of dihydrofolate reductase by triazines is compared with the QSAR which has been reported for the same inhibitors acting against S. aureus.
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PMID:The interaction of ligands with enzymes. A starting point in drug design. 11 68

Molecular recognition impinges upon many fields of biological chemistry, especially those involving catalytic processes. This review gives examples from studies at Strathclyde of both small and macromolecular systems. Mechanism-based enzyme inhibitors are described with reference to dihydrofolate reductase, dihydroorotate dehydrogenase, and cholesterol metabolism. Applications of molecular recognition related to synthetic transformations are discussed in terms of aromatic substitution, chemically modified papain, and catalytic antibodies for Diels-Alder reactions.
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PMID:Molecular recognition in applied enzyme chemistry. 176 26

Studies of the time course of methotrexate-derived antifolate activity (methotrexate activity) in plasma and skin of rats have been carried out to evaluate the hypothesis that the formation of therapeutically active poly-gamma-glutamyl conjugates of methotrexate in skin after systemic administration of the drug will result in the prolongation of methotrexate effects in skin. Such a finding may eventually bear on the use of the drug in the treatment of psoriasis. Three groups of 4 rats received a single i.v. dose of methotrexate, 5, 20, or 40 mg/kg, respectively. Serial skin and plasma samples were obtained over 48 h from each rat and analyzed for methotrexate activity by a dihydrofolate reductase enzyme inhibition assay. The values of pharmacokinetic parameters describing the disposition of the drug were calculated from plasma data using standard methods. Skin to plasma ratio of methotrexate activity was also calculated each time a skin sample was obtained. Pharmacokinetic parameter values and skin to plasma ratios were not significantly different between doses. Methotrexate activity declined biexponentially in plasma and skin. The terminal half-life in plasma (mean +/- SD) was 20.3 +/- 9.2 h. At early times, methotrexate activity in skin was less than plasma, but at later times activity in skin was an order of magnitude greater than that in plasma. In a preliminary study to determine whether the persistent activity in skin is associated with the presence of poly-gamma-glutamyl conjugates of methotrexate, a rat was dosed with tritiated methotrexate, 0.18 mg/kg, i.v., and skin was obtained 24 h later. Skin homogenate was treated with papain and applied to an anion-exchange column for cleanup prior to injection on a reversed-phase high-pressure liquid chromatography system. Methotrexate poly-gamma-glutamates were identified by elution with authentic standards and specific hydrolysis with carboxypeptidase G1.
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PMID:Persistence of antifolate activity in skin of rats following systemic administration of methotrexate. 669 Jun 31