Summary of Study ST002561

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001653. The data can be accessed directly via it's Project DOI: 10.21228/M81Q6Q This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002561
Study TitleMetabolomic profiling of PMM2-CDG zebrafish in presence and absence of epalrestat
Study SummaryAbnormal polyol metabolism has been predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has also been implicated in phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG), and epalrestat, an AR inhibitor, proposed as a potential therapy for this disorder. Given that the PMM enzyme is not closely connected to polyol metabolism, and, unlike in diabetes, PMM2-CDG does not present with hyperglycemia in blood, the increased polyol production, and the therapeutic mechanism of epalrestat in PMM2-CDG remained largely elusive. PMM2-CDG is caused by deficiency of the PMM enzyme and results in a depletion of mannose-1-P and guanosine diphosphate mannose (GDP-mannose), which is essential for glycosylation. Here, we show that apart from glycosylation abnormalities, PMM2 deficiency also leads to changes in intracellular glucose flux, which results in an increase in intracellular polyols. Targeting AR with epalrestat decreases polyol levels and increases GDP-mannose in vivo in pmm2 mutant zebrafish.
Institute
Mayo Clinic
Last NameRadenkovic
First NameSilvia
Address200 2nd Ave SW Rochester MN, USA
Emailradenkovic.silvia@mayo.edu
Phone507(77) 6-6107
Submit Date2023-04-14
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2023-07-18
Release Version1
Silvia Radenkovic Silvia Radenkovic
https://dx.doi.org/10.21228/M81Q6Q
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001653
Project DOI:doi: 10.21228/M81Q6Q
Project Title:Metabolomic profiling of PMM2-CDG zebrafish in presence and absence of epalrestat
Project Summary:Abnormal polyol metabolism has been predominantly associated with diabetes, where excess glucose is converted to sorbitol by aldose reductase (AR). Recently, abnormal polyol metabolism has also been implicated in phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG), and epalrestat, an AR inhibitor, proposed as a potential therapy for this disorder. Given that the PMM enzyme is not closely connected to polyol metabolism, and, unlike in diabetes, PMM2-CDG does not present with hyperglycemia in blood, the increased polyol production, and the therapeutic mechanism of epalrestat in PMM2-CDG remained largely elusive. PMM2-CDG is caused by deficiency of the PMM enzyme and results in a depletion of mannose-1-P and guanosine diphosphate mannose (GDP-mannose), which is essential for glycosylation. Here, we show that apart from glycosylation abnormalities, PMM2 deficiency also leads to changes in intracellular glucose flux, which results in an increase in intracellular polyols. Targeting AR with epalrestat decreases polyol levels and increases GDP-mannose in vivo in pmm2 mutant zebrafish.
Institute:Mayo Clinic
Last Name:Radenkovic
First Name:Silvia
Address:200 2nd Ave SW Rochester MN, USA
Email:radenkovic.silvia@mayo.edu
Phone:507(77) 6-6107
Funding Source:NIH, KU Leuven
Publications:Tracer metabolomics reveals the role of aldose reductase in glycosylation
Contributors:Silvia Radenkovic, Anna N. Ligezka, Sneha S. Mokashi, Karen Driesen, Lynn Dukes-Rimsky, Graeme Preston, Luckio F. Owuocha, Leila Sabbagh, Jehan Mousa, Christina Lam, Andrew Edmondson, Austin Larson, Matthew Schultz, Pieter Vermeersch, David Cassiman, Peter Witters, Lesa J. Beamer, Tamas Kozicz, Heather Flanagan-Steet, Bart Ghesquière, Eva Morava

Subject:

Subject ID:SU002662
Subject Type:Fish
Subject Species:Danio rerio
Taxonomy ID:7955
Genotype Strain:WT/PMM2 mutant sa10150
Age Or Age Range:6 dpf

Factors:

Subject type: Fish; Subject species: Danio rerio (Factor headings shown in green)

mb_sample_id local_sample_id Sample treatment
SA257651MCF001395_pmm4_ep1010µM Epalrestat
SA257652MCF001395_pmm3_ep1010µM Epalrestat
SA257653MCF001395_wt4_ep1010µM Epalrestat
SA257654wt4_ep1010µM Epalrestat
SA257655wt3_ep1010µM Epalrestat
SA257656MCF001428_wt1_ep1010µM Epalrestat
SA257657wt2_ep1010µM Epalrestat
SA257658pmm1_ep1010µM Epalrestat
SA257659pmm3_ep1010µM Epalrestat
SA257660MCF001395_pmm1_ep1010µM Epalrestat
SA257661MCF001395_wt2_ep1010µM Epalrestat
SA257662MCF001395_wt1_ep1010µM Epalrestat
SA257663MCF001395_pmm2_ep1010µM Epalrestat
SA257664MCF001395_wt3_ep1010µM Epalrestat
SA257665MCF001428_wt2_ep1010µM Epalrestat
SA257666pmm4_ep1010µM Epalrestat
SA257667pmm2_ep1010µM Epalrestat
SA257668wt1_ep1010µM Epalrestat
SA257669MCF001428_pmm2_ep1010µM Epalrestat
SA257670MCF001428_pmm1_ep1010µM Epalrestat
SA257671MCF001428_wt3_ep1010µM Epalrestat
SA257672MCF001428_pmm4_ep1010µM Epalrestat
SA257673MCF001027_wt1_ep1010µM Epalrestat
SA257674MCF001027_wt2_ep1010µM Epalrestat
SA257675MCF001027_pmm1_ep1010µM Epalrestat
SA257676MCF001428_pmm3_ep1010µM Epalrestat
SA257677MCF001428_wt4_ep1010µM Epalrestat
SA257678MCF001027_pmm2_ep1010µM Epalrestat
SA257679MCF001395_wt3_ep4040µM Epalrestat
SA257680MCF001395_wt4_ep4040µM Epalrestat
SA257681MCF001395_wt2_ep4040µM Epalrestat
SA257682MCF001395_wt1_ep4040µM Epalrestat
SA257683MCF001428_pmm4_ep4040µM Epalrestat
SA257684MCF001428_pmm3_ep4040µM Epalrestat
SA257685MCF001395_pmm4_ep4040µM Epalrestat
SA257686MCF001395_pmm2_ep4040µM Epalrestat
SA257687MCF001428_wt1_ep4040µM Epalrestat
SA257688MCF001428_wt2_ep4040µM Epalrestat
SA257689MCF001428_wt3_ep4040µM Epalrestat
SA257690pmm3_ep4040µM Epalrestat
SA257691MCF001428_pmm1_ep4040µM Epalrestat
SA257692MCF001395_pmm3_ep4040µM Epalrestat
SA257693MCF001428_pmm2_ep4040µM Epalrestat
SA257694MCF001395_pmm1_ep4040µM Epalrestat
SA257695pmm4_ep4040µM Epalrestat
SA257696wt1_ep4040µM Epalrestat
SA257697wt3_ep4040µM Epalrestat
SA257698MCF001027_pmm1_ep4040µM Epalrestat
SA257699MCF001027_pmm2_ep4040µM Epalrestat
SA257700MCF001027_pmm4_ep4040µM Epalrestat
SA257701MCF001027_pmm3_ep4040µM Epalrestat
SA257702MCF001027_wt3_ep4040µM Epalrestat
SA257703wt2_ep4040µM Epalrestat
SA257704pmm2_ep4040µM Epalrestat
SA257705MCF001027_wt1_ep4040µM Epalrestat
SA257706MCF001027_wt2_ep4040µM Epalrestat
SA257707pmm1_ep4040µM Epalrestat
SA257708MCF001027_wt3DMSO
SA257709wt1DMSO
SA257710MCF001428_wt3DMSO
SA257711wt2DMSO
SA257712MCF001027_pmm4DMSO
SA257713MCF001027_wt2DMSO
SA257714MCF001428_pmm2DMSO
SA257715MCF001027_pmm2DMSO
SA257716MCF001027_pmm1DMSO
SA257717MCF001428_wt2DMSO
SA257718MCF001027_wt4DMSO
SA257719MCF001428_pmm3DMSO
SA257720MCF001027_pmm3DMSO
SA257721MCF001428_pmm1DMSO
SA257722pmm1DMSO
SA257723pmm5DMSO
SA257724MCF001395_pmm1DMSO
SA257725MCF001395_pmm2DMSO
SA257726wt5DMSO
SA257727pmm6DMSO
SA257728pmm7DMSO
SA257729MCF001395_wt1DMSO
SA257730MCF001395_wt2DMSO
SA257731pmm8DMSO
SA257732MCF001395_wt3DMSO
SA257733MCF001395_wt4DMSO
SA257734pmm2DMSO
SA257735MCF001027_wt1DMSO
SA257736wt3DMSO
SA257737pmm3DMSO
SA257738MCF001395_pmm4DMSO
SA257739wt4DMSO
SA257740pmm4DMSO
SA257741MCF001395_pmm3DMSO
SA257742MCF001428_wt1DMSO
Showing results 1 to 92 of 92

Collection:

Collection ID:CO002655
Collection Summary:10 embryos per sample were homogenized by sonication in extraction buffer (80% MeOH, IS). The metabolites were then precipitated at -80 °C overnight, after which the samples were centrifuged at 15,000 rpm, 20 min, 4 °C. Next, the supernatant was transferred to a fresh Eppendorf tube. The samples were centrifuged again at 15,000 rpm, 20 min, 4 °C to remove any leftover impurities and transferred to a fresh MS vial. Finally, the samples were analyzed by LC/MS
Sample Type:Larvae
Storage Conditions:-80?

Treatment:

Treatment ID:TR002674
Treatment Summary:Zebrafish were treated with vehicle or 10 or 40 microM epalrestat

Sample Preparation:

Sampleprep ID:SP002668
Sampleprep Summary:10 embryos per sample were homogenized by sonication in extraction buffer (80% MeOH, IS). The metabolites were then precipitated at -80 °C overnight, after which the samples were centrifuged at 15,000 rpm, 20 min, 4 °C. Next, the supernatant was transferred to a fresh Eppendorf tube. The samples were centrifuged again at 15,000 rpm, 20 min, 4 °C to remove any leftover impurities and transferred to a fresh MS vial. Finally, the samples were analyzed by LC/MS
Processing Storage Conditions:-80?
Extraction Method:80 % MeOH with Internal standards (e.g. d27 myristic acid)

Combined analysis:

Analysis ID AN004221 AN004222
Analysis type MS MS
Chromatography type Reversed phase HILIC
Chromatography system Waters Acquity Agilent Infinity
Column C-18: Acquity UPLC -HSS T3 1. 8 µm; 2.1 x 150 mm, Waters Poroshell 120 HILIC-Z PEEK Column 2.1x 150mm, 5 um
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Focus
Ion Mode NEGATIVE NEGATIVE
Units AUC AUC

Chromatography:

Chromatography ID:CH003130
Chromatography Summary:Reverse phase, IP, C18 column
Instrument Name:Waters Acquity
Column Name:C-18: Acquity UPLC -HSS T3 1. 8 µm; 2.1 x 150 mm, Waters
Column Temperature:40
Flow Gradient:The gradient started with 5% of solvent B and 95% solvent A and remained at 5% B until 2 min post injection. A linear gradient to 37% B was carried out until 7 min and increased to 41% until 14 min. Between 14 and 26 minutes the gradient increased to 95% of B and remained at 95% B for 4 minutes. At 30 min the gradient returned to 5% B. The chromatography was stopped at 40 min.
Flow Rate:0.25 mL/min
Solvent A:100% water; 10mM tributylamine; 15mM acetic acid
Solvent B:100% methanol
Chromatography Type:Reversed phase
  
Chromatography ID:CH003131
Chromatography Summary:HILIC
Instrument Name:Agilent Infinity
Column Name:Poroshell 120 HILIC-Z PEEK Column 2.1x 150mm, 5 um
Column Temperature:25
Flow Gradient:A linear gradient was carried out starting with 90% solvent A and 10% solvent B. From 2 to 12 min the gradient changed to 60% B. The gradient was kept on 60% B for 3 minutes and followed by a decrease to 10% B. The chromatography was stopped at 25 min
Flow Rate:0.25 mL/min
Solvent A:100% acetonitrile
Solvent B:100% water; 10 mM sodium acetate, pH 9.3
Chromatography Type:HILIC

MS:

MS ID:MS003968
Analysis ID:AN004221
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:El-Maven polly, ThemoFisher Xcalibur, Metabolites were annotated using in-house metabolite library- elution time and m/z were considered
Ion Mode:NEGATIVE
  
MS ID:MS003969
Analysis ID:AN004222
Instrument Name:Thermo Q Exactive Focus
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:El-Maven polly, ThemoFisher Xcalibur Metabolites were annotated using in-house metabolite library- elution time and m/z were considered
Ion Mode:NEGATIVE
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