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)

We sought to investigate enzyme response appearing subsequent to sub-conjunctival administration of the Coxsackie B3 virus. This virus stimulates oxidising enzymes, diaphorase and leucin aminopeptidase, dihydrofolate reductase, and adenosinetriphosphatase. The most typical enzyme changes are been in the chorion of the conjunctival mucose and the corneal parenchyma there by showing that the virus, triggers local immune defence mechanisms. The appearance of highly active Langerhans cells around Bowman membrane and corneal tissue proves that the virus injected greatly stimulates the mobilisation of local immune mechanisms.
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PMID:[Ocular histoenzymatic research on an experimental viral attack]. 132 34

In an effort to improve the selectivity of the anticancer drug methotrexate (MTX), a series of potential prodrugs in which the 2-amino group was acylated with various alpha-amino acids (as well as L-pyroglutamic acid) was synthesized. Such derivatives are anticipated to be hydrolysed to MTX by appropriate aminopeptidases localized (over-expressed naturally or targeted as anti-tumor antibody conjugates) in the vicinity of the tumor. The L-leucyl, L-valyl, L-isoleucyl, D-alanyl and L-pyroglutamyl derivatives were assessed as to their suitability as prodrugs. Except for the L-pyroglutamyl compound, all derivatives decomposed slowly when incubated in phosphate buffer, pH 7.3; the formation of MTX was minimal. No major differences were observed when serum was included in the incubation medium, except for the L-leucyl compound, which was hydrolysed to MTX. The L-leucyl, L-valyl and L-isoleucyl derivatives were hydrolysed readily to MTX by aminopeptidase M (EC 3.4.11.2), while the L-pyroglutamyl and D-alanyl compounds were activated by pyroglutamate aminopeptidase (EC 3.4.19.3) (from Bacillus amyloliquefaciens) and D-aminopeptidase (from Ochrobactrum anthropi), respectively. When tested for inhibition of the target enzyme dihydrofolate reductase (DHFR; EC 1.5.1.3), 2-L-valyl-MTX showed inhibition two orders of magnitude poorer than that given by MTX, in agreement with the expectation that acylation of the 2-amino group reduces binding to DHFR. After treatment of this derivative with aminopeptidase M, the extent of inhibition correlated with the amount of MTX formed. MTX derivatives alone or in combination with the complementary peptidase were tested for cytotoxicity on murine L1210 cells in culture. The above-listed derivatives were considerably less cytotoxic than MTX, except for the L-leucyl derivative which showed considerable cytotoxicity. When the appropriate exogenous peptidase was included, the cytotoxicity of the activated prodrugs approached that of MTX. These results indicate that 2-L-leucyl-MTX is unsuitable as a prodrug since it is activated prematurely by serum enzymes. Although the L-valyl and L-isoleucyl derivatives do not hydrolyse to MTX in serum and are readily activated, they are not ideal prodrugs since they decompose under physiological conditions; the properties of the decomposition product will have a bearing on the ultimate suitability of these compounds. 2-L-Pyroglutamyl-MTX is the best candidate prodrug, showing stability and ready activation by the appropriate aminopeptidase.
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PMID:Activation and cytotoxicity of 2-alpha-aminoacyl prodrugs of methotrexate. 787 63

The molecular karyotype of a murine isolate of Encephalitozoon cuniculi, a microsporidian with a wide range of mammalian hosts, comprises eleven chromosomes ranging in size between 217 and 315 kb. To determine specific chromosomal markers, a partial genomic library was constructed and cloned DNA fragments were hybridized to chromosomal bands separated by pulsed-field gel electrophoresis. Most probes were assigned to single chromosomes, indicating prevalence of low-copy number nucleotide sequences within the very small genome of E. cuniculi (2.9 Mb). A few probes were shown to hybridize to all chromosomes. These repetitive DNA fragments corresponded to either rRNA genes or some non-coding regions whose sequences were characterized by short micro- and minisatellites. The chromosomal locations of beta-tubulin genes and six newly identified protein-encoding genes were determined. Genes encoding dihydrofolate reductase, thymidylate synthase, serine hydroxymethyl transferase, a cdc2 kinase-like protein and helicase ERCC6-like protein were each located on a single chromosome whereas genes for both beta-tubulin and aminopeptidase were on two different chromosomes. The mapping will serve as a reference for further analysis of intraspecific karyotype polymorphism in different isolates from different host species.
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PMID:Mapping of repetitive and non-repetitive DNA probes to chromosomes of the microsporidian Encephalitozoon cuniculi. 921 May 86

Belonging to a large group of parasitic amitochondrial protozoans (Microspora), Encephalitozoon cuniculi infects humans and other mammals. Because of its medical importance and small genome size (2.9 Mbp), we are systematically sequencing its smallest (217 kbp) chromosome. The shotgun cloning strategy now has produced the sequence of randomly dispersed contigs representing more than 180 kbp of this chromosome. The present report describes analysis of the 4.3 kbp contig, which includes the complete coding regions of dihydrofolate reductase (DHFR), thymidylate synthase (TS), and serine hydroxymethyl transferase (SHMT) genes and the partial coding region of an aminopeptidase (AP) gene. In contrast to the other reported protozoan genes, DHFR and TS are encoded by two different open reading frames (ORFs). The SHMT gene is the first one identified in a protozoan and corresponds to the cytosolic form of the enzyme. No introns were detected, and the intergenic noncoding regions do not exceed 50 bp. The mean GC content is close to 60%, and there is a G or C third-base codon bias. Transcription and translation initiation signals also are analyzed, and a model for the mRNA-ssu rRNA interactions is proposed.
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PMID:First report on the systematic sequencing of the small genome of Encephalitozoon cuniculi (Protozoa, Microspora): gene organization of a 4.3 kbp region on chromosome I. 1101 7