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Nachrichten, Termine, Experten
Nachrichten, Termine, Experten
Abstract: The investigation of oxygen-insensitive nitrogen reductive drug metabolism in mitochondria resulted in the discovery of a completely unknown mammalian molybdenum enzyme in our laboratory. Upon reconstitution with the electron transport proteins cytochrome b5 and its reductase this molybdenum enzyme is capable of reducing N-hydroxylated compounds. Thus, it was named “mitochondrial amidoxime reducing component” (mARC), because initially the N-reduction of amidoxime structures was studied with this isolated enzyme. Besides xanthine oxidase, aldehyde oxidase and sulfite oxidase, mARC is the fourth human molybdenum enzyme.
Amidoxime prodrugs are used to make amidines orally available. As amidines are protonated under physiological conditions they are not absorbed from the gastro-intestinal tract. By introducing an oxygen atom at one of the nitrogens, the basicity is lowered, the structures are not protonated and are absorbed by diffusion. After absorption the amidoximes are reduced back by mARC to the active principle, the amidines.
In continuation of our drug metabolism studies a suitable in-vitro assay using the recombinant human enzymes was developed. Since mammalian genomes encode for two homologues mARC enzymes (mARC1/mARC2), both mARC enzymes were tested and are able to reduce N-hydroxylated compounds together with cytochrome b5 and its reductase in vitro. By RNA interference and knockout studies the involvement of mitochondrial cytochrome b5 and at least one mARC protein in the N-reductive pathway was confirmed. Using in-vitro assays of the recombinant enzymes or isolated mitochondria as well as cellular systems we clearly demonstrate that the mARC-containing system plays a major role in drug metabolism. For example, we show that this molybdenum enzyme system is able to reduce not only amidoximes but also oximes, hydroxylamines, sulfhydroxamic acids as well as N-oxides. Furthermore, it is involved in the detoxification of mutagenic N-hydroxylated DNA bases and hydroxylamines. Thus, mARC is very often the counterpart of P450 catalysed N-oxygenations. Unusual for xenobiotic metabolizing enzymes all tested extrahepatic tissues show high N-reductive activity by mARC. The aim of the lecture is to summarize our current knowledge of mARC with a special focus on drug metabolism.
Information on participating / attending:
Einladende: Prof. Dr. Andreas Link und
PD Dr. Heike Kahlert, Vorsitzende des Ortsverbandes der GDCh
hkahlert@uni-greifswald.de
Date:
07/09/2015 17:15 - 07/09/2015 18:15
Event venue:
Großer Hörsaal Biochemie
Felix-Hausdorff-Straße 4
17489 Greifswald
Mecklenburg-Vorpommern
Germany
Target group:
Scientists and scholars, Students
Relevance:
transregional, national
Subject areas:
Chemistry
Types of events:
Presentation / colloquium / lecture
Entry:
07/01/2015
Sender/author:
Sabine Köditz
Department:
Presse- und Informationsstelle
Event is free:
no
Language of the text:
German
URL of this event: http://idw-online.de/en/event51372
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