Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0268596 (EMA)
 2,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of intact fibroblasts from a patients with glutaric aciduria type II with [2-14C]riboflavin showed normal synthesis of flavin mononucleotide and flavin adenine dinucleotide. This is taken as evidence for normal transport of riboflavin into the cells and normal activity of riboflavin kinase (EC 2.7.1.26) and flavin mononucleotide adenylyltransferase (EC 2.7.7.2). The ability of intact fibroblasts to oxidize 1-14C-fatty acids and [6-14C]lysine is impaired in the patient which together with the urinary excretion pattern of organic acids indicates a defective dehydrogenation of fatty acid acyl-CoAs and glutaryl-CoA. However, dehydrogenation of (C6-C10) fatty acid acyl-CoA derivatives and glutaryl-CoA was normal when the dehydrogenases were measured in fibroblast homogenate with artificial electron acceptors. In vivo, these dehydrogenases transfer their electrons to CoQ10 in the main electron transport chain via electron transfer flavoprotein and electron transfer flavoprotein dehydrogenase. Glutaric aciduria type II fibroblasts showed very diminished activity when the glutaryl-CoA dehydrogenase activity was measured without artificial electron acceptor but with intact endogenous electron transport system. As the NADH and succinate oxidation seems normal in glutaric aciduria type II patients, this is strong evidence for a defect in either the electron transfer flavoprotein or the electron transfer flavoprotein dehydrogenase.
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PMID:Glutaric aciduria type II: evidence for a defect related to the electron transfer flavoprotein or its dehydrogenase. 643 13

The previous biochemical evidence had suggested that glutaric aciduria type II (GA II) is due to deficient dehydrogenation of multiple short-chain acyl coenzyme A's (CoA's), bu the precise biochemical mechanism underlying this disease was unknown. We investigated substrate oxidation and in vitro activities of isovaleryl CoA- and butyryl CoA dehydrogenases as well as that of electron-transferring flavoprotein (ETF) in cultured skin fibroblasts from a patient with GA II. GA II cells have a markedly decreased ability to oxidize [1-14C]butyrate, [2-14C]lysine, and [2,14C]leucine (3, 9, and 9% of control values, respectively). Mitochondrial isovaleryl CoA- and butyryl CoA dehydrogenase activities in GA II cells were determined using a tritium release assay with [2,3-3H] acyl-CoA's as substrate. When an artificial electron acceptor, phenazine methosulfate (PMS) was not added in the assay media, these activities were 108 and 113% of controls, respectively. This represents the normal abilities of the dehydrogenases in GA II cells to bind the substrate and to catalyze tritium exchange between the bound substrate and solvent. When PMS was added to the assay mixture, these activities were 88 and 70% of control values, respectively, indicating that these enzymes can both dehydrogenate their substrates normally and then transfer electrons to an acceptor (PMS). ETF activity in mitochondrial sonic supernatants from GA II cells, as assessed by a newly devised method, was 159% of control values. These observations suggest that the acyl CoA dehydrogenases themselves and ETF are not defective in GA II. Therefore, the deficiency of another common gene product necessary for the function of all the affected acyl CoA dehydrogenases must be sought to explain the etiology of GA II.
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PMID:Glutaric aciduria type II: in vitro studies on substrate oxidation, acyl-CoA dehydrogenases, and electron-transferring flavoprotein in cultured skin fibroblasts. 720 50

To characterize the motilin receptors present in the chicken, the effects of chicken motilin (Phe-Val-Pro-Phe-Phe-Thr-Gln-Ser-Asp-Ile-Gln-Lys-Met-Gln-Glu-Lys-Glu-Arg -Asn-Lys-Gly-Gln), Leu13 porcine motilin, canine motilin and three erythromycin derivatives (EMA, EM523, GM611) on the contractility of the chicken gastrointestinal (GI) smooth muscles were investigated in vitro and compared with those in the rabbit duodenum. In the proventriculus longitudinal and circular muscle layers, chicken motilin (3 nM-1 microM) caused an atropine- and a tetrodotoxin-sensitive contraction (EC50 = 39-49 nM), and potentiated the EFS-induced contraction without affecting the responsiveness of acetylcholine. EM523 and GM611 (3-100 microM) contracted the proventriculus longitudinal muscle, and the maximum amplitudes of contraction were about 60% of that induced by chicken motilin. Chicken motilin (0.1 nM-100 nM) also caused contraction of the ileum (EC50 = 7 nM) through direct action on the smooth muscle cells. On the other hand, erythromycin derivatives showed only a weak contractile efficacy (about 20% of the maximum response of chicken motilin) even at high concentrations (10-100 microM). The rank order of potency in the ileum was chicken motilin > canine motilin > or = Leu13 porcine motilin > > GM611 > or = EM523 > or = EMA. GM109 slightly inhibited the ideal contractions induced by Leu13 porcine motilin at 100 microM (pA2 = 3.86). In the rabbit duodenum, chicken motilin was a full agonist with the same intrinsic activity as Leu13 porcine motilin, canine motilin and the erythromycin derivatives. However, the rank order of potency (Leu13 porcine motilin > or = canine motilin > chicken motilin > GM611 > or = EM523 > EMA) was different from that in the chicken ileum. In conclusion, chicken motilin causes an excitatory response in the chicken GI tract through activation of neural (proventriculus) and smooth muscle motilin receptors (ileum). The motilin receptor present in the ileum is different from that demonstrated in the rabbit intestine, because of a different rank order of motilin peptides in producing the contraction, low contracting activity of erythromycin derivatives and low antagonistic efficacy of GM109. Different pharmacological characteristics of the mechanical response induced by motilin peptides and erythromycin derivatives between the proventriculus and the ileum are discussed.
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PMID:Functional characterization of neural and smooth muscle motilin receptors in the chicken proventriculus and ileum. 941 90

Immunglobolin G (IgG)-based biopharmaceuticals are emerging on the pharmaceuticals market due to their high target selectivity in different diseases. In parallel, a growing interest by other companies to produce similar or highly similar follow-on biologics exits, once the patent of blockbuster biotherapeutics is about to expire. In correlation to their complex structure, an analytical challenge is facing the approval of these biosimilars. Health authorities (e.g. FDA and EMA) have issued several guidelines to define critical quality attributes during manufacturing process changes. In the current study, physicochemical characterization using state-of-the-art analytics was applied to analyse intact mass, post-translational modifications (PTMs) and higher order structure of Rituximab and one of its biosimilars. Intact mass analysis, middle-up approach as well as subunit analysis revealed similar glycoforms but additional lysine variants in the biosimilar. The N-glycosylation site was confirmed for both, the originator and the biosimilar. PTMs and higher order structure were confirmed to be similar. A special focus was given to N-glycosylation due to its potential to monitor the batch-to-batch consistency and alteration during the production bioprocess. Comparison of the N-glycosylation profiles obtained from three batches of the biosimilar and the reference product showed quantitative variations, although the N-glycans were qualitatively similar. Furthermore, a head-to-head comparability of functional properties was performed to investigate the impact of glycosylation alteration and PTMs on potency within the biosimilar batches and between originator and follow-on biodrug. The data affirm that the difference is still in the acceptable range for biosimilarity.
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PMID:Comparability study of Rituximab originator and follow-on biopharmaceutical. 2837 18

The role of epigenetic regulation is in large parts connected to cancer, but additionally, its therapeutic claim in neurological disorders has emerged. Inhibition of histone H3 lysine N-methyltransferase, especially G9a, has been recently shown to restore candidate genes from silenced parental chromosomes in the imprinting disorder Prader-Willi syndrome (PWS). In addition to this epigenetic approach, pitolisant as G-protein coupled histamine H3 receptor (H3R) antagonist has demonstrated promising therapeutic effects for Prader-Willi syndrome. To combine these pioneering principles of drug action, we aimed to identify compounds that combine both activities, guided by the pharmacophore blueprint for both targets. However, pitolisant as selective H3R inverse agonist with FDA and EMA-approval did not show the required inhibition at G9a. Pharmacological characterization of the prominent G9a inhibitor A-366, that is as well an inhibitor of the epigenetic reader protein Spindlin1, revealed its high affinity at H3R while showing subtype selectivity among subsets of the histaminergic and dopaminergic receptor families. This work moves prominent G9a ligands forward as pharmacological tools to prove for a potentially combined, symptomatic and causal, therapy in PWS by bridging the gap between drug development for G-protein coupled receptors and G9a as an epigenetic effector in a multi-targeting approach.
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PMID:Epigenetics meets GPCR: inhibition of histone H3 methyltransferase (G9a) and histamine H3 receptor for Prader-Willi Syndrome. 3278 17