Dataset Information

Improving Metabolite Identification with DecoID for Database-Assisted Deconvolution of Metabolomic MS/MS Spectra

ABSTRACT:

Chimeric MS/MS spectra contain fragments from multiple precursor ions and therefore hinder compound identification in metabolomics. Historically, deconvolution of these chimeric spectra has been challenging and relied upon specific experimental methods that introduce variation in the ratios of precursor ions between multiple MS/MS scans. DecoID introduces a complementary, method-independent approach where database spectra are computationally mixed to match an experimentally acquired spectrum using LASSO regression. When applied to human plasma, DecoID increased the number of identified metabolites by over 30%.

INSTRUMENT(S): Liquid Chromatography MS - positive - hilic, Liquid Chromatography MS - negative - hilic

SUBMITTER: Ethan Stancliffe

PROVIDER: MTBLS2207 | MetaboLights | 2021-04-29

REPOSITORIES: MetaboLights

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Dataset's files

Source:

			Action	DRS
	MTBLS2207	Other
	FILES	Other
	a_MTBLS2207_LC-MS_negative_hilic_metabolite_profiling.txt	Txt
	a_MTBLS2207_LC-MS_positive_hilic_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt

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Publications

DecoID improves identification rates in metabolomics through database-assisted MS/MS deconvolution.

Stancliffe Ethan E Schwaiger-Haber Michaela M Sindelar Miriam M Patti Gary J GJ

Nature methods 20210708 7

Chimeric MS/MS spectra contain fragments from multiple precursor ions and therefore hinder compound identification in metabolomics. Historically, deconvolution of these chimeric spectra has been challenging and relied on specific experimental methods that introduce variation in the ratios of precursor ions between multiple tandem mass spectrometry (MS/MS) scans. DecoID provides a complementary, method-independent approach where database spectra are computationally mixed to match an experimentall ...[more]

PMID: 34239103

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Project description:Isopeptide crosslinked proteins can be the product of transglutaminase or of exposure to organophosphorus toxicants (OP). Transglutaminase links glutamine to lysine with loss of ammonia. OP toxicants induce a link between glutamic acid and lysine with loss of water. Our goal was to establish criteria to distinguish real from false isopeptide crosslinks reported by software searches of mass spectrometry data. We used fragmentation spectra of tryptic peptides from MAP-rich tubulin Sus scrofa as a test system for detection of naturally-occurring isopeptide crosslinks. Data were analyzed with Protein Prospector. Criteria for the assignments included the presence of at least 1 crosslink specific product ion, fragment ions from both peptides, Protein Prospector scores ≥20, and best fit of the MS/MS data to the crosslinked peptide as opposed to a linear peptide. Out of 301,364 spectra, 15 potential transglutaminase-type crosslinked peptide candidates were identified. Manual evaluation of these MS/MS spectra reduced the number to 1 valid crosslink between Q112 of NFH and K368 of Tau. Immunopurification with anti-isopeptide 81D1C2 confirmed that MAP-rich tubulin contained only one isopeptide. Support for this isopeptide bond was obtained by showing that transglutaminase was capable of incorporating dansyl-aminohexyl -QQIV into K368. A model of the KIETHK-QLEAHNR isopeptide was synthesized with the aid of transglutaminase. MS/MS spectra of the model validated our interpretation of the native isopeptide. An OP-induced isopeptide bond between K163 of tubulin alpha-1A and E158 of tubulin beta-4B was induced by treating MAP-rich tubulin with 100 µM chlorpyrifos oxon. This crosslink was supported by the criteria described above and by the presence of diethoxyphospho-lysine 163 in the tubulin alpha-1A peptide. The information obtained in this work is valuable for future studies that aim to understand why exposure to OP is associated with increased risk of neurodegenerative disease.