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 studied the components of the hepatic phenylalanine hydroxylating system in a child with phenylketonuria who showed substantial neurologic impairment despite early dietary control of elevated blood phenylalanine levels. Phenylalanine hydroxylase, dihydropteridine reductase and dihydrofolate reductase activities were normal. In contrast the level of hydroxylation cofactor, tetrahydrobiopterin, in liver was only 10 per cent of normal. In addition to this hepatic deficiency, serum and urinary levels of biopterin-like compounds were low, and the serum biopterin did not increase in response to a phenylalanine load as it does in normal and phenylketonuric subjects. The phenylalanine hydroxylase activity in this child, as determined by an in vivo tritium-release assay, was 2.3 per cent of the normal value. These results indicate that the child suffers from a variant form of phenylketonuria--a deficiency of a functional phenylalanine hydroxylating system secondary to a defect in biosynthesis of biopterin.
 ...
PMID:Hyperphenylalaninemia due to a deficiency of biopterin. A variant form of phenylketonuria. 68 51

E. coli Dihydropteridine reductase, known to have a pterin-independent oxidoreductase activity with potassium ferricyanide as electron donor, has now been shown to possess also dihydrofolate reductase activity. The kinetic parameters for dihydrofolate reductase activity have been determined. The ratio of the three activities, dihydropteridine reductase, dihydrofolate reductase and pterin-independent oxidoreductase activity is 1.0, 0.05 and 4.3, respectively. The enzyme, a flavoprotein which is unstable in the presence of dithiothreitol, was shown to be a monomer with a molecular mass of 25.7 kDa. The apparent lack of discrimination between hydride transfer from the pyridine nucleotide to N5 of the pterin in the dihydropteridine reductase reaction and C6 of folate in the dihydrofolate reaction suggested that the FAD prosthetic group may be involved in the hydride transfers. The flavoprotein inhibitor N,N- dimethylpropargylamine inhibited the dihydropteridine reductase and oxidoreductase reactions differently and did not affect the dihydrofolate reductase activity however.
 ...
PMID:Dihydropteridine reductase from Escherichia coli exhibits dihydrofolate reductase activity. 141 77

The structure of a binary complex of dihydropteridine reductase [DHPR; NAD(P)H:6,7-dihydropteridine oxidoreductase, EC 1.6.99.7] with its cofactor, NADH, has been solved and refined to a final R factor of 15.4% by using 2.3 A diffraction data. DHPR is an alpha/beta protein with a Rossmann-type dinucleotide fold for NADH binding. Insertion of an extra threonine residue in the human enzyme is associated with severe symptoms of a variant form of phenylketonuria and maps to a tightly linked sequence of secondary-structural elements near the dimer interface. Dimerization is mediated by a four-helix bundle motif (two helices from each protomer) having an unusual right-handed twist. DHPR is structurally and mechanistically distinct from dihydrofolate reductase, appearing to more closely resemble certain nicotinamide dinucleotide-requiring flavin-dependent enzymes, such as glutathione reductase.
 ...
PMID:Crystal structure of rat liver dihydropteridine reductase. 163 Oct 94

Transient neurologic dysfunction associated with high-dose methotrexate and citrovorum factor rescue (MTX-CF) has been previously reported. At the biochemical level, there are at least two important pathways in central nervous system metabolism which might be disturbed by MTX: MTX may deplete the cell of the de novo synthesis of purine nucleotides and thymidylate through its action on dihydrofolate reductase (DHFR), and also inhibit dihydropteridine reductase (DHPR), an enzyme maintaining the cofactor of phenylalanine-hydroxylase in its active tetrahydrogenated form (tetrahydrobiopterin), and hence interfere with the supply of the neurotransmitters derived from tyrosine and tryptophan. We describe such a neurologic disease in a patient with acute lymphoblastic leukemia (ALL) receiving chemotherapy. Significant increase in cerebrospinal fluid biopterins supports the hypothesis of an inhibition of dihydropteridine reductase by MTX, and provides additional suggestions in terms of etiology, diagnosis and treatment.
 ...
PMID:[Early neurotoxicity of high-dose of methotrexate and tetrahydrobiopterin deficiency]. 179 49

BALB/c mice were immunized with a synthetic co-factor of the aromatic amino acid hydroxylases, 6,7-dimethyl-5,6,7,8-tetrahydropterin, conjugated to albumin. Hybridoma cell lines isolated from the immunized mice secreted monoclonal antibodies reacting specifically with the pterin molecule and monoclonal antibodies which were found to bind phenylalanine hydroxylase. Several lines of evidence were consistent with the anti-phenylalanine hydroxylase antibodies being anti-idiotype antibodies mimicking the pterin molecule and binding to the pterin binding site of phenylalanine hydroxylase. (a) An anti-idiotype monoclonal antibody, NS7, when reimmunized into mice produced anti-pterin antibodies consistent with NS7 being an internal image anti-idiotypic antibody. (b) NS7 antibody was prevented from binding to phenylalanine hydroxylase when a competitive inhibitor of phenylalanine hydroxylase enzyme activity, 6,7-dimethyl-7,8-dihydropterin, was bound to phenylalanine hydroxylase. (c) NS7 antibody was shown to bind to a wide range of pterin-requiring enzymes: phenylalanine, tyrosine and tryptophan hydroxylases, dihydropteridine reductase, dihydrofolate reductase, and sepiapterin reductase. Thus the NS7 antibody has successfully mimicked a common portion of the pterin cofactors utilized by these enzymes and demonstrated structure homology in their pterin binding sites despite their diverse function and little amino acid sequence homology except among the three aromatic amino acid hydroxylases.
 ...
PMID:Structural similarities among enzyme pterin binding sites as demonstrated by a monoclonal anti-idiotypic antibody. 196 5

The natural killer-like cell line YT constitutively expresses GTP-cyclohydrolase activity whereas 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase are absent. The product, dihydroneopterin triphosphate, is dephosphorylated and oxidized causing neopterin to accumulate in the cells. The activities of the H4biopterin synthesizing enzymes are not controlled by IFN-gamma or the synergistic action of both IFN-gamma and IL-2 as has been shown for monocytes/macrophages (Huber C. et al. (1984) J. Exp. Med. 160, 310) and CD4+ T cells, respectively (Ziegler I. et al. (1990) J. Biol. Chem. 265, 17026). Sepiapterin reductase specifically is induced by incubation of the cells with sepiapterin, leaving GTP-cyclohydrolase, 6-pyruvoyltetrahydropterin synthase and other enzymes related to pteridine metabolism (dihydropteridine reductase, dihydrofolate reductase) unaffected. The data indicate that H4biopterin synthesis is individually regulated in the diverse cellular components of the immune system.
 ...
PMID:Control of pteridine biosynthesis in the natural killer-like cell line YT. 203 22

A child with dihydropteridine reductase (DHPR) deficiency developed signs of dopamine insufficiency after being given trimethoprim-sulfamethoxazole (TMP-SMX). She recovered function after the antibiotic was stopped, which suggests that it adversely influenced dopamine metabolism in the CNS. The authors speculate that TMP, a dihydrofolate reductase inhibitor, was the major cause of the patient's deterioration, and suggest that it and other dihydrofolate inhibitors, notably methotrexate, are contra-indicated for patients with DHPR deficiency.
 ...
PMID:Adverse effects of trimethoprim-sulfamethoxazole in a child with dihydropteridine reductase deficiency. 239 Oct 14

Monoclonal antibodies (mAbs) against antipterin immunoglobulin and dihydropteridine reductase (DHPR) and also polyclonal antibodies against human dihydrofolate reductase (DHFR) were obtained. The anti-idiotypic mAbs and anti-DHPR mAbs bind specifically to human DHFR, Escherichia coli DHFR, soybean seedling DHFR, and human DHPR in solid-phase immunoassays. Further, the mAbs bind to the native but not to the denatured forms of DHFRs. The monoclonal antibodies also inhibit the enzymatic activity of human DHFR but not that of human DHPR. Competitive solid-phase immunoassays show stoichiometric inhibition by methotrexate and partial inhibition by NADPH of mAb binding to human DHFR. Cyanogen bromide fragments derived from human DHFR (residues 15-52 and 53-111), containing several active site residues, bind partially to some of the monoclonal antibodies. Accordingly, polyclonal antibodies to peptide 53-111 of human DHFR cross-react to some extent with human DHPR. Data from competitive immunoassays in which the binding of the various mAbs was tested singly and in combination with other mAbs suggest that these antibodies bind to a common region on human DHFR. The results also indicate that the mAbs display some heterogeneity with respect to specific epitopes. These data suggest that despite the absence of significant amino acid sequence homologies among the various DHFRs and DHPR, they have a fundamentally similar topography at the site of binding of the pterin moiety that is recognized by the anti-idiotypic mAbs generated by pterin. In the relatively simple structure of the pterin ring system there are different substituent groups at positions C4 and C6 in methotrexate, 7,8-dihydrofolate, and 7,8-dihydrobiopterin, suggesting that these antibodies are specific for regions on various proteins that interact with the remainder of the pterin moiety. These mAbs and similar mAbs specified by substituent groups on pterin may thus be used as specific probes or inhibitors of various folate-dependent enzymes and transport proteins. They should also provide insights into some of the general features of antibody recognition of protein antigens.
 ...
PMID:Anti-idiotypic antibodies elicited by pterin recognize active site epitopes in dihydrofolate reductases and dihydropteridine reductase. 248 Jul 46

Deficiency of human dihydropteridine reductase (hDHPR) causes malignant hyperphenylalaninemia. We report the isolation of a cDNA clone for hDHPR that spans the complete coding region, and present the nucleotide sequence and the predicted amino acid sequence. The hDHPR protein does not share extensive homology with the enzymatically related protein human dihydrofolate reductase. Patients with hDHPR deficiency were analysed for the presence of hDHPR cross-reacting protein, mRNA encoding hDHPR, and chromosomal DNA rearrangements. The results show that this inherited error of metabolism can result from a variety of mutations. However, no major rearrangements were seen in 11 patients analysed by Southern blotting. Three RFLPs were found with the restriction endonucleases AvaII and MspI. These RFLPs are useful for prenatal diagnosis of hDHPR deficiency.
 ...
PMID:Human dihydropteridine reductase: characterisation of a cDNA clone and its use in analysis of patients with dihydropteridine reductase deficiency. 303 82

The cleavage of reductively alkylated rat liver dihydropteridine reductase with cyanogen bromide afforded a mixture of peptides, six of which (CB-1 to CB-6) were isolated and purified by C8 reverse-phase high performance liquid chromatography. Portions of peptides CB-1, CB-4, and CB-6 were sequenced by automated Edman degradation and high performance liquid chromatography and the carboxyl-terminal region by conventional procedures. Further proteolytic digestion of CB-6 and isolation of the products afforded a seven-amino acid peptide. A low degeneracy probe comprising 20 nucleotides was synthesized from the sequence of this peptide and was used to screen a rat liver cDNA expression library constructed in the vector lambda gt 10. Positive clones were isolated, and detailed examination of five of these by restriction endonucleases and dideoxy sequence analyses allowed identification of the entire coding region for dihydropteridine reductase. The gene was found to code for a protein of 240 amino acids (excluding the methionine initiator) of Mr = 25,420. Each of the sequences corresponding to the peptides CB-1, CB-4, CB-6, and the carboxyl terminus were identified in the deduced protein sequence. The rat enzyme is highly homologous to the human dihydropteridine reductase; the two proteins differ in only 10 amino acids, and all are conservative substitutions. In contrast, the sequence shows little homology with that of mammalian dihydrofolate reductase: reduced pyridine nucleotide-requiring enzymes with superficial mechanistic similarities.
 ...
PMID:Structural studies and isolation of cDNA clones providing the complete sequence of rat liver dihydropteridine reductase. 368 Feb 58


1 2 Next >>