Summary of Study ST002566

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 IDST002566
Study TitleMetabolomic profiling of PMM2-CDG patient fibroblasts
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.
Institute
Mayo Clinic
Last NameRadenkovic
First NameSilvia
Address200 2nd Ave SW Rochester MN, USA
Emailradenkovic.silvia@mayo.edu
Phone507(77) 6-6107
Submit Date2023-04-18
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2023-07-19
Release Version1
Silvia Radenkovic Silvia Radenkovic
https://dx.doi.org/10.21228/M81Q6Q
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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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:SU002667
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
SA257951SR02 (9)PMM2-CDG
SA257952SR02 (8)PMM2-CDG
SA257953SR02 (10)PMM2-CDG
SA257954SR02 (11)PMM2-CDG
SA257955SR02 (12)PMM2-CDG
SA257956SR02 (7)PMM2-CDG
SA257957SR02 (6)PMM2-CDG
SA257958SR02 (2)PMM2-CDG
SA257959SR02 (3)PMM2-CDG
SA257960SR02 (4)PMM2-CDG
SA257961SR01 (1)PMM2-CDG
SA257962SR03 (1)PMM2-CDG
SA257963SR03 (2)PMM2-CDG
SA257964SR03 (9)PMM2-CDG
SA257965SR03 (10)PMM2-CDG
SA257966SR03 (11)PMM2-CDG
SA257967SR03 (12)PMM2-CDG
SA257968SR03 (8)PMM2-CDG
SA257969SR03 (7)PMM2-CDG
SA257970SR03 (3)PMM2-CDG
SA257971SR03 (4)PMM2-CDG
SA257972SR03 (5)PMM2-CDG
SA257973SR03 (6)PMM2-CDG
SA257974SR02 (1)PMM2-CDG
SA257975SR02 (5)PMM2-CDG
SA257976SR01 (5)PMM2-CDG
SA257977SR01 (6)PMM2-CDG
SA257978SR01 (15)PMM2-CDG
SA257979SR01 (16)PMM2-CDG
SA257980SR01 (17)PMM2-CDG
SA257981SR01 (7)PMM2-CDG
SA257982SR01 (8)PMM2-CDG
SA257983SR01 (12)PMM2-CDG
SA257984SR01 (14)PMM2-CDG
SA257985SR01 (11)PMM2-CDG
SA257986SR01 (10)PMM2-CDG
SA257987SR01 (9)PMM2-CDG
SA257988SR01 (18)PMM2-CDG
SA257989SR01 (19)PMM2-CDG
SA257990SR01 (13)PMM2-CDG
SA257991SR01 (2)PMM2-CDG
SA257992SR01 (3)PMM2-CDG
SA257993SR01 (20)PMM2-CDG
SA257994SR01 (4)PMM2-CDG
SA257995SR03 (19)WT
SA257996SR03 (20)WT
SA257997SR03 (18)WT
SA257998SR03 (15)WT
SA257999SR03 (13)WT
SA258000SR03 (14)WT
SA258001SR03 (16)WT
SA258002SR03 (17)WT
SA258003SR02 (18)WT
SA258004SR01 (26)WT
SA258005SR01 (25)WT
SA258006SR01 (24)WT
SA258007SR01 (32)WT
SA258008SR01 (31)WT
SA258009SR01 (28)WT
SA258010SR01 (29)WT
SA258011SR01 (30)WT
SA258012SR01 (23)WT
SA258013SR01 (22)WT
SA258014SR02 (17)WT
SA258015SR01 (27)WT
SA258016SR02 (19)WT
SA258017SR02 (16)WT
SA258018SR02 (15)WT
SA258019SR01 (21)WT
SA258020SR02 (13)WT
SA258021SR02 (14)WT
SA258022SR02 (20)WT
Showing results 1 to 72 of 72

Collection:

Collection ID:CO002660
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:TR002679
Treatment Summary:Cells were grown in medium with 13c glucose or 12c glucose

Sample Preparation:

Sampleprep ID:SP002673
Sampleprep Summary:Metabolites were extracted with 80% Methanol and IS (d27 myristic acid)
Processing Storage Conditions:-80℃
Extract Storage:-80℃

Combined analysis:

Analysis ID AN004227
Analysis type MS
Chromatography type Reversed phase
Chromatography system Waters Acquity
Column Waters ACQUITY UPLC HSS T3 (150 x 2.1mm,1.8um)
MS Type ESI
MS instrument type Orbitrap
MS instrument name Thermo Q Exactive Orbitrap
Ion Mode NEGATIVE
Units AUC

Chromatography:

Chromatography ID:CH003136
Chromatography Summary:C18 iP REVERSE PHASE
Instrument Name:Waters Acquity
Column Name:Waters ACQUITY UPLC HSS T3 (150 x 2.1mm,1.8um)
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:MS003974
Analysis ID:AN004227
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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