Summary of Study ST002562

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.

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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 IDST002562
Study TitleMetabolomic profiling of PMM2-CDG patient fibroblasts 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 both in vitro in patient-derived fibroblasts.
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:SU002663
Subject Type:Cultured cells
Subject Species:Homo sapiens
Taxonomy ID:9606
Genotype Strain:WT/PMM2-CDG
Age Or Age Range:5-45
Gender:Male and female

Factors:

Subject type: Cultured cells; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Genotype Treatment
SA257743SR50PMM2-CDG 10microM epalrestat
SA257744SR81PMM2-CDG 10microM epalrestat
SA257745SR49PMM2-CDG 10microM epalrestat
SA257746SR51PMM2-CDG 10microM epalrestat
SA257747SR20PMM2-CDG 10microM epalrestat
SA257748SR52PMM2-CDG 10microM epalrestat
SA257749SR01PMM2-CDG 10microM epalrestat
SA257750SR84PMM2-CDG 10microM epalrestat
SA257751SR35PMM2-CDG 10microM epalrestat
SA257752SR36PMM2-CDG 10microM epalrestat
SA257753SR34PMM2-CDG 10microM epalrestat
SA257754SR33PMM2-CDG 10microM epalrestat
SA257755SR83PMM2-CDG 10microM epalrestat
SA257756SR82PMM2-CDG 10microM epalrestat
SA257757SR19PMM2-CDG 10microM epalrestat
SA257758SR18PMM2-CDG 10microM epalrestat
SA257759SR67PMM2-CDG 10microM epalrestat
SA257760SR66PMM2-CDG 10microM epalrestat
SA257761SR04PMM2-CDG 10microM epalrestat
SA257762SR03PMM2-CDG 10microM epalrestat
SA257763SR02PMM2-CDG 10microM epalrestat
SA257764SR65PMM2-CDG 10microM epalrestat
SA257765SR68PMM2-CDG 10microM epalrestat
SA257766SR17PMM2-CDG 10microM epalrestat
SA257767SR71PMM2-CDG Vehicle
SA257768SR72PMM2-CDG Vehicle
SA257769SR54PMM2-CDG Vehicle
SA257770SR70PMM2-CDG Vehicle
SA257771SR53PMM2-CDG Vehicle
SA257772SR69PMM2-CDG Vehicle
SA257773SR55PMM2-CDG Vehicle
SA257774SR38PMM2-CDG Vehicle
SA257775SR40PMM2-CDG Vehicle
SA257776SR39PMM2-CDG Vehicle
SA257777SR56PMM2-CDG Vehicle
SA257778SR37PMM2-CDG Vehicle
SA257779SR86PMM2-CDG Vehicle
SA257780SR21PMM2-CDG Vehicle
SA257781SR22PMM2-CDG Vehicle
SA257782SR23PMM2-CDG Vehicle
SA257783SR88PMM2-CDG Vehicle
SA257784SR08PMM2-CDG Vehicle
SA257785SR05PMM2-CDG Vehicle
SA257786SR06PMM2-CDG Vehicle
SA257787SR07PMM2-CDG Vehicle
SA257788SR24PMM2-CDG Vehicle
SA257789SR87PMM2-CDG Vehicle
SA257790SR85PMM2-CDG Vehicle
SA257791SR75WT 10microM epalrestat
SA257792SR76WT 10microM epalrestat
SA257793SR28WT 10microM epalrestat
SA257794SR12WT 10microM epalrestat
SA257795SR25WT 10microM epalrestat
SA257796SR11WT 10microM epalrestat
SA257797SR42WT 10microM epalrestat
SA257798SR09WT 10microM epalrestat
SA257799SR10WT 10microM epalrestat
SA257800SR60WT 10microM epalrestat
SA257801SR59WT 10microM epalrestat
SA257802SR27WT 10microM epalrestat
SA257803SR26WT 10microM epalrestat
SA257804SR73WT 10microM epalrestat
SA257805SR44WT 10microM epalrestat
SA257806SR74WT 10microM epalrestat
SA257807SR58WT 10microM epalrestat
SA257808SR57WT 10microM epalrestat
SA257809SR43WT 10microM epalrestat
SA257810SR41WT 10microM epalrestat
SA257811SR78WT Vehicle
SA257812SR79WT Vehicle
SA257813SR80WT Vehicle
SA257814SR77WT Vehicle
SA257815SR45WT Vehicle
SA257816SR29WT Vehicle
SA257817SR30WT Vehicle
SA257818SR16WT Vehicle
SA257819SR15WT Vehicle
SA257820SR13WT Vehicle
SA257821SR14WT Vehicle
SA257822SR31WT Vehicle
SA257823SR32WT Vehicle
SA257824SR62WT Vehicle
SA257825SR63WT Vehicle
SA257826SR61WT Vehicle
SA257827SR48WT Vehicle
SA257828SR46WT Vehicle
SA257829SR47WT Vehicle
SA257830SR64WT Vehicle
Showing results 1 to 88 of 88

Collection:

Collection ID:CO002656
Collection Summary:Cells were washed with PBS, cells were incubated with extraction buffer for 2min before scraping and transferring to a fresh eppendorf. Samples were precipitated overnight at -80, then they were centrifuged at max rpm, 20min, 4 degrees C and supernatant transferred to an M/S vial.
Sample Type:Fibroblasts
Storage Conditions:-80℃

Treatment:

Treatment ID:TR002675
Treatment Summary:Cells were treated with vehicle or 10 microM epalrestat

Sample Preparation:

Sampleprep ID:SP002669
Sampleprep Summary:Metabolites were extracted with 80% Methanol and IS (d27 myristic acid)
Processing Storage Conditions:-80℃
Extract Storage:-80℃

Combined analysis:

Analysis ID AN004223
Analysis type MS
Chromatography type Reversed phase
Chromatography system Waters Acquity
Column C-18: Acquity UPLC -HSS T3 1. 8 μm; 2.1 x 150 mm, Waters
MS Type ESI
MS instrument type Orbitrap
MS instrument name Thermo Q Exactive Orbitrap
Ion Mode NEGATIVE
Units AUC

Chromatography:

Chromatography ID:CH003132
Chromatography Summary:C18 iP REVERSE PHASE
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

MS:

MS ID:MS003970
Analysis ID:AN004223
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:El-Maven polly, ThermoFisher Xcalibur, Metabolites were annotated based on the in-house metabolite library- elution time and m/z values
Ion Mode:NEGATIVE
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