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Article ; Online: Evidence of an intracellular creatine-sensing mechanism that modulates creatine biosynthesis via AGAT expression in human HAP1 cells.

Tropak, Michael B / Tkachyova, Ilona / Gu, Ray / Lee, Alex / Schulze, Andreas

2023 Volume 13, Issue 1, Page(s) 22392

Abstract: Cellular homeostasis of creatine (CT), integral part of the energy buffering and transducing system connecting intracellular sites of ATP production and utilization, comprises of mechanisms that increase CT, i.e., biosynthesis and cellular uptake, and CT- ...

Abstract	Cellular homeostasis of creatine (CT), integral part of the energy buffering and transducing system connecting intracellular sites of ATP production and utilization, comprises of mechanisms that increase CT, i.e., biosynthesis and cellular uptake, and CT-lowering processes, such as export and non-enzymatic conversion to creatinine. The biosynthesis of CT is controlled by negative feedback loop via suppression of the rate-limiting enzyme arginine:glycine amidinotransferase (AGAT). Although the regulatory mechanism involved is not well understood, AGAT suppression is successfully used in patients with guanidinoacetate methyltransferase (GAMT) deficiency to reduce the neurotoxic accumulation of the AGAT-mediated guanidinoacetate production by supplementing patients with CT. Utilizing the CT-dependent feedback loop for the upregulation of AGAT expression may well represent a therapeutic target for an additional CT deficiency syndrome, the CT transporter (CrT) defect, for which no effective treatment option is available so far. We have used CRISPR to tag the C-terminus of AGAT with a nanoluc luciferase (NLuc) reporter in HAP1 cells. A biphasic decay of AGAT-NLuc in response to increasing extracellular CT was observed, whereas the decrease in AGAT-NLuc expression was directly proportional to the rise in intracellular CT levels with an approximate IC50 of 1-2 mM. CRISPR generated HAP1 CrT null cells and HAP1 CrT null cells stably expressing a CrT-GFP fusion protein further demonstrated that the biphasic response to extracellular CT is mediated by a high-affinity (Km 9-10 µM) CrT dependent, saturable mechanism and a CrT independent, unsaturable uptake process. The direct response to intracellular CT suggests the existence of an intracellular CT sensing system enabling a dynamic cell response to changing CT concentration that is relevant for cellular CT homeostasis.
MeSH term(s)	Humans ; Amidinotransferases/metabolism ; Creatine/metabolism ; Guanidinoacetate N-Methyltransferase/genetics ; Language Development Disorders ; Movement Disorders
Chemical Substances	Amidinotransferases (EC 2.1.4.-) ; Creatine (MU72812GK0) ; Guanidinoacetate N-Methyltransferase (EC 2.1.1.2) ; glycine amidinotransferase (EC 2.1.4.1)
Language	English
Publishing date	2023-12-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-49860-1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evidence of an intracellular creatine-sensing mechanism that modulates creatine biosynthesis via AGAT expression in human HAP1 cells

Michael B. Tropak / Ilona Tkachyova / Ray Gu / Alex Lee / Andreas Schulze

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 16

Abstract: Abstract Cellular homeostasis of creatine (CT), integral part of the energy buffering and transducing system connecting intracellular sites of ATP production and utilization, comprises of mechanisms that increase CT, i.e., biosynthesis and cellular ... ...

Abstract	Abstract Cellular homeostasis of creatine (CT), integral part of the energy buffering and transducing system connecting intracellular sites of ATP production and utilization, comprises of mechanisms that increase CT, i.e., biosynthesis and cellular uptake, and CT-lowering processes, such as export and non-enzymatic conversion to creatinine. The biosynthesis of CT is controlled by negative feedback loop via suppression of the rate-limiting enzyme arginine:glycine amidinotransferase (AGAT). Although the regulatory mechanism involved is not well understood, AGAT suppression is successfully used in patients with guanidinoacetate methyltransferase (GAMT) deficiency to reduce the neurotoxic accumulation of the AGAT-mediated guanidinoacetate production by supplementing patients with CT. Utilizing the CT-dependent feedback loop for the upregulation of AGAT expression may well represent a therapeutic target for an additional CT deficiency syndrome, the CT transporter (CrT) defect, for which no effective treatment option is available so far. We have used CRISPR to tag the C-terminus of AGAT with a nanoluc luciferase (NLuc) reporter in HAP1 cells. A biphasic decay of AGAT-NLuc in response to increasing extracellular CT was observed, whereas the decrease in AGAT-NLuc expression was directly proportional to the rise in intracellular CT levels with an approximate IC50 of 1–2 mM. CRISPR generated HAP1 CrT null cells and HAP1 CrT null cells stably expressing a CrT-GFP fusion protein further demonstrated that the biphasic response to extracellular CT is mediated by a high-affinity (Km 9–10 µM) CrT dependent, saturable mechanism and a CrT independent, unsaturable uptake process. The direct response to intracellular CT suggests the existence of an intracellular CT sensing system enabling a dynamic cell response to changing CT concentration that is relevant for cellular CT homeostasis.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article: Lending a helping hand, screening chemical libraries for compounds that enhance beta-hexosaminidase A activity in GM2 gangliosidosis cells.

Tropak, Michael B / Mahuran, Don

The FEBS journal

2007 Volume 274, Issue 19, Page(s) 4951–4961

Abstract: Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and/or assembling into active oligomers in the ...

Abstract	Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and/or assembling into active oligomers in the endoplasmic reticulum. Many lysosomal storage diseases are candidates for enzyme enhancement therapy and have the additional advantage of requiring only 5-10% of normal enzyme levels to reduce and/or prevent substrate accumulation. Our long experience in working with the beta-hexosaminidase (EC 3.2.1.52) isozymes system and its associated deficiencies (Tay-Sachs and Sandhoff disease) lead us to search for possible enzyme enhancement therapy-agents that could treat the chronic forms of these diseases which express 2-5% residual activity. Pharmacological chaperones are enzyme enhancement therapy-agents that are competitive inhibitors of the target enzyme. Each of the known beta-hexosaminidase inhibitors (low microm IC50) increased mutant enzyme levels to >or= 10% in chronic Tay-Sachs fibroblasts and also attenuated the thermo-denaturation of beta-hexosaminidase. To expand the repertoire of pharmacological chaperones to more 'drug-like' compounds, we screened the Maybridge library of 50,000 compounds using a real-time assay for noncarbohydrate-based beta-hexosaminidase inhibitors and identified several that functioned as pharmacological chaperones in patient cells. Two of these inhibitors had derivatives that had been tested in humans for other purposes. These observations lead us to screen the NINDS library of 1040 Food and Drug Administration approved compounds for pharmacological chaperones. Pyrimethamine, an antimalarial drug with well documented pharmacokinetics, was confirmed as a beta-hexosaminidase pharmacological chaperone and compared favorably with our best carbohydrate-based pharmacological chaperone in patient cells with various mutant genotypes.
MeSH term(s)	Enzyme Inhibitors/pharmacology ; Gangliosidoses, GM2/enzymology ; Gangliosidoses, GM2/pathology ; Humans ; Models, Molecular ; beta-N-Acetylhexosaminidases/antagonists & inhibitors ; beta-N-Acetylhexosaminidases/metabolism
Chemical Substances	Enzyme Inhibitors ; beta-N-Acetylhexosaminidases (EC 3.2.1.52)
Language	English
Publishing date	2007-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/j.1742-4658.2007.06040.x
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Article: Lending a helping hand, screening chemical libraries for compounds that enhance β-hexosaminidase A activity in GM2 gangliosidosis cells

Tropak, Michael B / Mahuran, Don

FEBS journal. 2007 Oct., v. 274, no. 19

2007

Abstract	Enzyme enhancement therapy is an emerging therapeutic approach that has the potential to treat many genetic diseases. Candidate diseases are those associated with a mutant protein that has difficulty folding and/or assembling into active oligomers in the endoplasmic reticulum. Many lysosomal storage diseases are candidates for enzyme enhancement therapy and have the additional advantage of requiring only 5-10% of normal enzyme levels to reduce and/or prevent substrate accumulation. Our long experience in working with the β-hexosaminidase (EC 3.2.1.52) isozymes system and its associated deficiencies (Tay-Sachs and Sandhoff disease) lead us to search for possible enzyme enhancement therapy-agents that could treat the chronic forms of these diseases which express 2-5% residual activity. Pharmacological chaperones are enzyme enhancement therapy-agents that are competitive inhibitors of the target enzyme. Each of the known β-hexosaminidase inhibitors (low μ m IC₅₀) increased mutant enzyme levels to >= 10% in chronic Tay-Sachs fibroblasts and also attenuated the thermo-denaturation of β-hexosaminidase. To expand the repertoire of pharmacological chaperones to more 'drug-like' compounds, we screened the Maybridge library of 50 000 compounds using a real-time assay for noncarbohydrate-based β-hexosaminidase inhibitors and identified several that functioned as pharmacological chaperones in patient cells. Two of these inhibitors had derivatives that had been tested in humans for other purposes. These observations lead us to screen the NINDS library of 1040 Food and Drug Administration approved compounds for pharmacological chaperones. Pyrimethamine, an antimalarial drug with well documented pharmacokinetics, was confirmed as a β-hexosaminidase pharmacological chaperone and compared favorably with our best carbohydrate-based pharmacological chaperone in patient cells with various mutant genotypes.
Language	English
Dates of publication	2007-10
Size	p. 4951-4961.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/j.1742-4658.2007.06040.x
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Article ; Online: Pharmacological chaperones facilitate the post-ER transport of recombinant N370S mutant β-glucocerebrosidase in plant cells: evidence that N370S is a folding mutant.

Babajani, Gholamreza / Tropak, Michael B / Mahuran, Don J / Kermode, Allison R

Molecular genetics and metabolism

2012 Volume 106, Issue 3, Page(s) 323–329

Abstract: Gaucher disease is a prevalent lysosomal storage disease in which affected individuals inherit mutations in the gene (GBA1) encoding lysosomal acid β-glucosidase (glucocerebrosidase, GCase, EC 3.2.1.45). One of the most prevalent disease-causing ... ...

Abstract	Gaucher disease is a prevalent lysosomal storage disease in which affected individuals inherit mutations in the gene (GBA1) encoding lysosomal acid β-glucosidase (glucocerebrosidase, GCase, EC 3.2.1.45). One of the most prevalent disease-causing mutations in humans is a N370S missense mutation in the GCase protein. As part of a larger endeavor to study the fate of mutant human proteins expressed in plant cells, the N370S mutant protein along with the wild-type- (WT)-GCase, both equipped with a signal peptide, were synthesized in transgenic tobacco BY2 cells, which do not possess lysosomes. The enzymatic activity of plant-recombinant N370S GCase lines was significantly lower (by 81-95%) than that of the WT-GCase lines. In contrast to the WT-GCase protein, which was efficiently secreted from tobacco BY2 cells, and detected in large amounts in the culture medium, only a small proportion of the N370S GCase was secreted. Pharmacological chaperones such as N-(n-nonyl) deoxynojirimycin and ambroxol increased the steady-state mutant protein levels both inside the plant cells and in the culture medium. These findings contradict the assertion that small molecule chaperones increase N370S GCase activity (as assayed in treated patient cell lysates) by stabilizing the enzyme in the lysosome, and suggest that the mutant protein is impaired in its ability to obtain its functional folded conformation, which is a requirement for exiting the lumen of the ER.
MeSH term(s)	Biological Transport ; Catalytic Domain ; Cells, Cultured ; Endoplasmic Reticulum/metabolism ; Gaucher Disease/enzymology ; Gaucher Disease/genetics ; Glucosylceramidase/genetics ; Glucosylceramidase/metabolism ; Humans ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Mutation ; Plant Cells/metabolism ; Plants, Genetically Modified ; Protein Folding ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
Chemical Substances	Molecular Chaperones ; Recombinant Proteins ; Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2012-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2012.04.018
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Article ; Online: Synthesis, kinetic evaluation and cell-based analysis of C-alkylated isofagomines as chaperones of β-glucocerebrosidase.

Hill, Tara / Tropak, Michael B / Mahuran, Don / Withers, Stephen G

Chembiochem : a European journal of chemical biology

2011 Volume 12, Issue 14, Page(s) 2151–2154

MeSH term(s)	Alkylation ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Glucosylceramidase/antagonists & inhibitors ; Humans ; Imino Pyranoses/chemical synthesis ; Imino Pyranoses/chemistry ; Imino Pyranoses/pharmacology ; Kinetics
Chemical Substances	Enzyme Inhibitors ; Imino Pyranoses ; isofagomine ; Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2011-07-12
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2020469-3
ISSN	1439-7633 ; 1439-4227
ISSN (online)	1439-7633
ISSN	1439-4227
DOI	10.1002/cbic.201100332
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Article ; Online: Tailoring the specificity and reactivity of a mechanism-based inactivator of glucocerebrosidase for potential therapeutic applications.

Rempel, Brian P / Tropak, Michael B / Mahuran, Don J / Withers, Stephen G

Angewandte Chemie (International ed. in English)

2011 Volume 50, Issue 44, Page(s) 10381–10383

MeSH term(s)	Cells, Cultured ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Fibroblasts/drug effects ; Fibroblasts/enzymology ; Fluorine/chemistry ; Gaucher Disease/drug therapy ; Glucosylceramidase/antagonists & inhibitors ; Humans
Chemical Substances	Enzyme Inhibitors ; Fluorine (284SYP0193) ; Glucosylceramidase (EC 3.2.1.45)
Language	English
Publishing date	2011-09-13
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.201103924
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Article ; Online: Potent neuroprotection induced by remote preconditioning in a rat model of neonatal cerebral hypoxic-ischemic injury.

Tropak, Michael B / Shi, Hui / Li, Jing / Dai, Xiaojing / Redington, Andrew N / Askalan, Rand

The Journal of thoracic and cardiovascular surgery

2011 Volume 142, Issue 1, Page(s) 233–235

MeSH term(s)	Animals ; Animals, Newborn ; Brain/blood supply ; Brain/pathology ; Carotid Artery, Internal/surgery ; Cerebral Infarction/etiology ; Cerebral Infarction/pathology ; Cerebral Infarction/prevention & control ; Disease Models, Animal ; Hindlimb/blood supply ; Hypoxia-Ischemia, Brain/etiology ; Hypoxia-Ischemia, Brain/pathology ; Hypoxia-Ischemia, Brain/therapy ; Ischemic Preconditioning/methods ; Ligation ; Rats ; Reperfusion Injury/etiology ; Reperfusion Injury/pathology ; Reperfusion Injury/prevention & control
Language	English
Publishing date	2011-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	3104-5
ISSN	1097-685X ; 0022-5223
ISSN (online)	1097-685X
ISSN	0022-5223
DOI	10.1016/j.jtcvs.2011.04.003
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Article: Construction of a hybrid β-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo.

Tropak, Michael B / Yonekawa, Sayuri / Karumuthil-Melethil, Subha / Thompson, Patrick / Wakarchuk, Warren / Gray, Steven J / Walia, Jagdeep S / Mark, Brian L / Mahuran, Don

Molecular therapy. Methods & clinical development

2016 Volume 3, Page(s) 15057

Abstract: Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the α- or β-subunits of β-hexosaminidase A (HexA). Of the three Hex isozymes, only HexA can interact with its cofactor, the ...

Abstract	Tay-Sachs or Sandhoff disease result from mutations in either the evolutionarily related HEXA or HEXB genes encoding respectively, the α- or β-subunits of β-hexosaminidase A (HexA). Of the three Hex isozymes, only HexA can interact with its cofactor, the GM2 activator protein (GM2AP), and hydrolyze GM2 ganglioside. A major impediment to establishing gene or enzyme replacement therapy based on HexA is the need to synthesize both subunits. Thus, we combined the critical features of both α- and β-subunits into a single hybrid µ-subunit that contains the α-subunit active site, the stable β-subunit interface and unique areas in each subunit needed to interact with GM2AP. To facilitate intracellular analysis and the purification of the µ-homodimer (HexM), CRISPR-based genome editing was used to disrupt the HEXA and HEXB genes in a Human Embryonic Kidney 293 cell line stably expressing the µ-subunit. In association with GM2AP, HexM was shown to hydrolyze a fluorescent GM2 ganglioside derivative both in cellulo and in vitro. Gene transfer studies in both Tay-Sachs and Sandhoff mouse models demonstrated that HexM expression reduced brain GM2 ganglioside levels.
Language	English
Publishing date	2016-03-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1038/mtm.2015.57
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Article: 2-Acetamino-1,2-dideoxynojirimycin-lysine hybrids as hexosaminidase inhibitors.

Steiner, Andreas J / Schitter, Georg / Stütz, Arnold E / Wrodnigg, Tanja M / Tarling, Chris A / Withers, Stephen G / Mahuran, Don J / Tropak, Michael B

Tetrahedron, asymmetry

2012 Volume 20, Issue 6-8, Page(s) 832–835

Abstract: Cyclisation by double reductive amination of 2-acetamino-2-deoxy-D-xylo-hexos-5-ulose with N-2 protected L-lysine derivatives provided 2-acetamino-1,2-dideoxynojirimycin derivatives without any observable epimer formation at C-5. Modifications on the ... ...

Abstract	Cyclisation by double reductive amination of 2-acetamino-2-deoxy-D-xylo-hexos-5-ulose with N-2 protected L-lysine derivatives provided 2-acetamino-1,2-dideoxynojirimycin derivatives without any observable epimer formation at C-5. Modifications on the lysine moiety gave access to lipophilic derivatives that exhibited improved hexosaminidase inhibitory activities.
Language	English
Publishing date	2012-09-25
Publishing country	England
Document type	Journal Article
ZDB-ID	1015012-2
ISSN	0957-4166
ISSN	0957-4166
DOI	10.1016/j.tetasy.2009.02.015
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