Biological Filtering and Substrate Promiscuity Prediction for Annotating Untargeted Metabolomics
Abstract
:1. Introduction
2. Methods
3. Results
3.1. Datasets, Reference Metabolic Models, and EMMs
3.2. Annotation Opportunities
3.3. Computational Time Required for Annotation
3.4. Experimental Validation of EMMF
4. Discussion and Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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(A) Experimental Data | (B) Metabolic Model | (C) Expanded Metabolic Model Using PROXIMAL | (D) Fold Change for EMM Relative to Metabolic Model | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Biological Sample | Dataset | MS Mode | Number of Measured Masses | Number of Reactions | Number of Metabolites | Number of Unique Masses | Number of Unique Operators | Number of Unique Derivatives | Number of Unique Derivative Masses | Number of Metabolites | Number of Unique Masses |
CHO cell | HilNeg | negative | 2502 | 1619 | 1353 | 775 | 2392 | 76745 | 17930 | 56.72 | 23.14 |
HilPos | positive | 3856 | |||||||||
SynNeg | negative | 5336 | |||||||||
gut microbiota | Neg | negative | 1651 | 1381 | 1307 | 779 | 2756 | 94186 | 23356 | 72.06 | 29.98 |
Pos | positive | 1657 |
Biological Sample | (A) Metabolites in Metabolic Model | (B) All EMM Derivatives | (C) EMM Derivatives with Previously Known Chemical IDs | (D) Using PubChem-based Filtering | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Number of Measured Masses Matched to Those in Metabolic Model | Percentage of Measured Masses Matched to Those in Metabolic Model | Number of Chemical Ids Associated with Measured Masses | Number of Masses Matched to Those in EMM | Percentage of Masses Matched to Those in EMM | Number of Unique Mass-Matched Derivatives in EMM But Not in The Model | Number of Masses Matched to Those with Previously Known Chemical IDs | Percentage of Masses Matched to Those with Previously Known Chemical IDs | Number of Previously Known Chemical IDs for EMM Derivatives that Mass-Match to Measurements | Number of Unique Mass Matches in PubChem | Number of Corresponding Chemical IDs Associated with Measured Masses | ||
CHO cell | HilNeg | 118 | 4.72% | 178 | 678 | 27.10% | 2,725 | 174 | 6.95% | 386 | 3,951,635 | 7,657,564 |
HilPos | 75 | 1.95% | 93 | 715 | 18.54% | 2,729 | 132 | 3.42% | 226 | 3,362,305 | 6,406,877 | |
SynNeg | 198 | 3.71% | 229 | 1,490 | 27.92% | 4,944 | 293 | 5.49% | 527 | 7,058,696 | 14,133,885 | |
gut microbiota | Neg | 51 | 3.09% | 131 | 445 | 26.95% | 2,470 | 77 | 4.66% | 207 | 2,448,238 | 5,192,205 |
Pos | 36 | 2.17% | 43 | 316 | 19.07% | 1,236 | 84 | 5.07% | 149 | 2,774,074 | 5,572,587 | |
Averages | 96 | 3.13% | 135 | 729 | 23.92% | 2,821 | 152 | 5.12% | 299 | 3,918,990 | 7,792,624 |
Biological Sample | KEGG | PubChem | |||||
---|---|---|---|---|---|---|---|
Number of EMMF Derivatives | Percentage of EMMF Derivatives with Nonzero CFM-ID scores | Average CFM-ID Score | Number of EMMF Derivatives | Percentage of EMMF Derivatives with Nonzero CFM-ID scores | Average CFM-ID Score | ||
CHO cell | HilNeg | 65 | 65% | 0.557 | 280 | 55% | 0.415 |
HilPos | 48 | 63% | 0.395 | 286 | 49% | 0.316 | |
SynNeg | 114 | 64% | 0.501 | 446 | 51% | 0.370 | |
gut microbiota | Neg | 252 | 16% | 0.631 | 197 | 53% | 0.484 |
Pos | 56 | 55% | 0.292 | 428 | 29% | 0.270 | |
Average | 53% | 0.475 | 47% | 0.396 |
Biological Sample | (A) Experimental Data | (B) In EMM And in KEGG | (C) In EMM And PubChem, And Not in KEGG | (D) Lower-Bound Fold Increase of Pubchem over KEGG | ||||
---|---|---|---|---|---|---|---|---|
Dataset | Number of Measured Masses | Number of Matched Masses | Number of Candidate Chemical IDs | Number of Matched Masses | Number of Candidate Chemical IDs | Number of Matched Masses | Number of Candidate Chemical IDs | |
CHO cell | HilNeg | 2502 | 56 | 93 | 118 | 200 | 2.11 | 2.15 |
HilPos | 3856 | 26 | 39 | 106 | 148 | 4.08 | 3.79 | |
SynNeg | 5336 | 88 | 122 | 205 | 283 | 2.33 | 2.32 | |
gut microbiota | Neg | 1651 | 25 | 47 | 52 | 113 | 2.08 | 2.40 |
Pos | 1657 | 23 | 28 | 61 | 93 | 2.65 | 3.32 | |
Average | 2.65 | 2.80 |
(A) Candidate Metabolites | (B) KEGG | (C) PubChem | (D) PROXIMAL | (E) | ||||
---|---|---|---|---|---|---|---|---|
Mass Measurement (Daltons) | Candidate Metabolite Identified by EMMF | Rank | Matches | Rank | Matches | Number of Reactions Used to Derive Operator | Number of ECs Associated with Reactions | Experimentally Validated? |
122.04 | Salicylaldehyde | 1 | 1 | 1 | 1 | 1 | 1 | No |
182.06 | 4-Hydroxyphenyllactate | 1 | 2 | 1 | 4 | 12 | 15 | Yes |
101.05 | Acetoacetamide | 1 | 1 | 2 | 3 | 1 | 1 | No |
117.79 | 5-Aminopentanoate | 1 | 2 | 1 | 5 | 4 | 4 | No |
132.04 | Glutarate | 1 | 1 | 3 | 6 | 12 | 11 | No |
167.06 | 3-Methoxyanthranilate | 1 | 1 | 2 | 3 | 8 | 2 | No |
152.05 | 2-Hydroxyphenylacetic acid | NA | 1 | 1 | 4 | 1 | 1 | No |
183.05 | 4-Pyridoxate | NA | 0 | 1 | 1 | 1 | 1 | No |
(A) EMMF | (B) CFMID | (C) GNPS | (D) HMDB | (E) PubChem | (F) MetFrag | ||||
---|---|---|---|---|---|---|---|---|---|
Mass Measurement (Daltons) | Candidate Metabolite | Score | Matched Compound ( Score) | Matched Compound (Score) | Number of Matches | Rank of Compound Identified by EMMF | # of Peaks Explained/ # of Peaks Used | Top Ranked Candidate | # of Peaks Explained/ # of Peaks Used |
122.04 | Salicylal | 0.596 | No Match | No Match | 241 | 27 | 4/8 | 2-cyclopenta-1,3-dien-1-yl-2-oxo-acetaldehyde | 4/8 |
182.06 | 4-Hydroxyphenyllactate | 0.717 | No Match | Homovanillic acid (0.43) | 1694 | 218 | 10/22 | methyl 2-hydroxy-2-phenyl-peroxyacetate | 11/22 |
101.05 | Acetoacetamide | 0.682 | Aminocyclopropane (0.92), L-threonine (0.90) | No Match | 445 | 331 | 1/2 | hydroxy N-isopropenylmethanimidate | 1/2 |
117.79 | 5-Aminopentanoate | 0.979 | No Match | L-Valine (0.44), Betaine (0.34), 5-Aminopentanoic acid (0.31) | 858 | 12 | 2/5 | 2-[ethyl(methyl)amino]acetic acid | 2/5 |
132.04 | Glutarate | 0.600 | No Match | Ethylmalonic acid (0.41) | N/A | ||||
167.06 | 3-Methoxyanthranilate | 0.949 | No Match | Mandelic acid (0.55), 3-Hydroxyphenylacetic acid (0.44), p-Hydroxyphenylacetic acid (0.40), Ortho-Hydroxyphenylacetic acid (0.19) | 1962 | 972 | 2/7 | (2-aminophenyl) peroxyacetate | 2/7 |
152.05 | 2-Hydroxyphenylacetic acid | 0.716 | 4-hydroxyphenylacetic acid (0.81) | No Match | 841 | 129 | 1/4 | methyl-phenyl-silyl-silane | 1/4 |
183.05 | 4-Pyridoxate | 0.870 | 4-Pyridoxate (0.76) | No Match | 1252 | 149 | 2/5 | 2-[1-(3-furyl)ethylideneamino]oxyacetic acid | 2/5 |
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Hassanpour, N.; Alden, N.; Menon, R.; Jayaraman, A.; Lee, K.; Hassoun, S. Biological Filtering and Substrate Promiscuity Prediction for Annotating Untargeted Metabolomics. Metabolites 2020, 10, 160. https://doi.org/10.3390/metabo10040160
Hassanpour N, Alden N, Menon R, Jayaraman A, Lee K, Hassoun S. Biological Filtering and Substrate Promiscuity Prediction for Annotating Untargeted Metabolomics. Metabolites. 2020; 10(4):160. https://doi.org/10.3390/metabo10040160
Chicago/Turabian StyleHassanpour, Neda, Nicholas Alden, Rani Menon, Arul Jayaraman, Kyongbum Lee, and Soha Hassoun. 2020. "Biological Filtering and Substrate Promiscuity Prediction for Annotating Untargeted Metabolomics" Metabolites 10, no. 4: 160. https://doi.org/10.3390/metabo10040160