#METABOLOMICS WORKBENCH RCulpHill_20190813_084937 DATATRACK_ID:1799 STUDY_ID:ST001243 ANALYSIS_ID:AN002066 PROJECT_ID:PR000831 VERSION 1 CREATED_ON August 19, 2019, 8:36 pm #PROJECT PR:PROJECT_TITLE Trisomy 21 activates the kynurenine pathway via increased dosage of interferon PR:PROJECT_TITLE receptors PR:PROJECT_SUMMARY Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological PR:PROJECT_SUMMARY function by unknown mechanisms. We report here a large metabolomics study of PR:PROJECT_SUMMARY plasma and cerebrospinal fluid showing that people with DS produce elevated PR:PROJECT_SUMMARY levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent PR:PROJECT_SUMMARY immunosuppressive and neurotoxic properties, respectively. We demonstrate that PR:PROJECT_SUMMARY immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the PR:PROJECT_SUMMARY kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. PR:PROJECT_SUMMARY Furthermore, we show positive correlations among levels of IFN-inducible PR:PROJECT_SUMMARY cytokines and KP dysregulation. Using metabolic tracing assays, we determine PR:PROJECT_SUMMARY that IFN stimulation causes IDO1 overexpression and kynurenine overproduction in PR:PROJECT_SUMMARY cells with T21, dependent on overexpression of IFN receptors encoded on PR:PROJECT_SUMMARY chromosome 21. Finally, we show a mouse model of DS carrying triplication of the PR:PROJECT_SUMMARY IFN receptors exhibits KP dysregulation. Altogether, these results reveal a PR:PROJECT_SUMMARY mechanism by which T21 could drive immunosuppression and neurotoxicity in DS. PR:INSTITUTE University of Colorado Denver PR:LAST_NAME Culp-Hill PR:FIRST_NAME Rachel PR:ADDRESS 12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA PR:EMAIL rachel.hill@cuanschutz.edu PR:PHONE 303-724-5798 #STUDY ST:STUDY_TITLE Global Metabolic Analysis Trisomy 21 - Cohort 1 ST:STUDY_SUMMARY Global metabolic analysis of plasma from individuals with and without trisomy ST:STUDY_SUMMARY 21. ST:INSTITUTE University of Colorado Denver ST:LAST_NAME Culp-Hill ST:FIRST_NAME Rachel ST:ADDRESS 12801 E 17th Ave L18-9403D, Aurora, Colorado, 80045, USA ST:EMAIL rachel.hill@cuanschutz.edu ST:PHONE 303-724-5798 #SUBJECT SU:SUBJECT_TYPE Human SU:SUBJECT_SPECIES Homo sapiens SU:TAXONOMY_ID 9606 SU:AGE_OR_AGE_RANGE 0.5 - 76.5 SU:GENDER Male and female #SUBJECT_SAMPLE_FACTORS: SUBJECT(optional)[tab]SAMPLE[tab]FACTORS(NAME:VALUE pairs separated by |)[tab]Additional sample data SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-4 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-8 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-15 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-16 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-17 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-19 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-20 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-31 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-32 Cohort:D21 SUBJECT_SAMPLE_FACTORS - Nexus_D21_4pos-35 Cohort:D21 SUBJECT_SAMPLE_FACTORS - 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Nexus_T21_4neg-53 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-54 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-55 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-56 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-57 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-58 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-59 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-61 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-62 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-69 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-70 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-81 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-92 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-94 Cohort:T21 SUBJECT_SAMPLE_FACTORS - Nexus_T21_4neg-97 Cohort:T21 #COLLECTION CO:COLLECTION_SUMMARY All human subjects in this study were consented according to Colorado Multiple CO:COLLECTION_SUMMARY Institutional Review Board (COMIRB)-approved protocols. Written informed consent CO:COLLECTION_SUMMARY was obtained from parents or guardians of participants under the age of 18, and CO:COLLECTION_SUMMARY assent was obtained from participants over the age of 7 who were cognitively CO:COLLECTION_SUMMARY able to assent. Deidentified plasma samples for Cohort 1 were obtained from the CO:COLLECTION_SUMMARY Translational Nexus Clinical Data Registry and Biobank (University of Colorado CO:COLLECTION_SUMMARY Anschutz Medical Campus, COMIRB 08-1276). Additional plasma and WBC samples were CO:COLLECTION_SUMMARY obtained through the Crnic’s Institute Human Trisome Project (University of CO:COLLECTION_SUMMARY Colorado Anschutz Medical Campus, COMIRB 15-2170, www.trisome.org). Plasma was CO:COLLECTION_SUMMARY collected in Vacutainer tubes (EDTA–purple capped or Lithium heparin–light CO:COLLECTION_SUMMARY green capped) and stored at -80°C. Participant medical history was collected by CO:COLLECTION_SUMMARY the respective biobanks. CO:SAMPLE_TYPE Blood (plasma) #TREATMENT TR:TREATMENT_SUMMARY N/A #SAMPLEPREP SP:SAMPLEPREP_SUMMARY For plasma analyses, a volume of 20μL of was extracted in 480μL of ice-cold SP:SAMPLEPREP_SUMMARY methanol:acetonitrile:water (5:3:2). Subsequently, these solutions were vortexed SP:SAMPLEPREP_SUMMARY for 30 minutes at 4°C.Insoluble proteins were pelleted by centrifugation (10 SP:SAMPLEPREP_SUMMARY minutes at 4°C and 12,000 g) and supernatants were collected and stored at SP:SAMPLEPREP_SUMMARY -80°C until analysis. For quantitative analysis of kynurenine pathway (KP) SP:SAMPLEPREP_SUMMARY metabolites, supernatants were spun in a Speedvac until dry and resuspended in SP:SAMPLEPREP_SUMMARY 0.1% formic acid in water as previously described (PMID: 30213797, 30143553). #CHROMATOGRAPHY CH:CHROMATOGRAPHY_SUMMARY UHPLC-MS metabolomics analyses were performed using a Vanquish UHPLC system CH:CHROMATOGRAPHY_SUMMARY coupled online to a Q Exactive mass spectrometer (Thermo Fisher, Bremen, CH:CHROMATOGRAPHY_SUMMARY Germany). Samples were resolved over a Kinetex C18 column (2.1x150 mm, 1.7μm; CH:CHROMATOGRAPHY_SUMMARY Phenomenex, Torrance, CA, USA) at 45°C using a 4 minute gradient at CH:CHROMATOGRAPHY_SUMMARY 450μL/minute from 0-100% B (A: 95% water/5% acetonitrile, 5mM NH4OAc; B: 95% CH:CHROMATOGRAPHY_SUMMARY acetonitrile/5% water, 5mM NH4OAc) for negative mode. To monitor possible CH:CHROMATOGRAPHY_SUMMARY technical variability, aliquots of each of the individual samples were combined CH:CHROMATOGRAPHY_SUMMARY to make technical replicates, which were run after every 15 samples. CH:CHROMATOGRAPHY_SUMMARY Additionally, in each experiment, several lysis solution aliquots were run as CH:CHROMATOGRAPHY_SUMMARY blanks for artifact identification. CH:CHROMATOGRAPHY_TYPE Reversed phase CH:INSTRUMENT_NAME Thermo Vanquish CH:COLUMN_NAME Phenomenex Kinetex C18 (150 x 2.1mm, 2.6 um) CH:FLOW_GRADIENT 0-100% B CH:FLOW_RATE 450uL/min CH:COLUMN_TEMPERATURE 45 CH:METHODS_FILENAME 4MMneg_method.pdf CH:SOLVENT_A 95% water/5% acetonitrile, 1mM NH4OAc CH:SOLVENT_B 95% acetonitrile/5% water, 1mM NH4OAc #ANALYSIS AN:ANALYSIS_TYPE MS AN:LABORATORY_NAME D'Alessandro Lab AN:OPERATOR_NAME Rachel Culp-Hill #MS MS:INSTRUMENT_NAME Thermo Q Exactive Orbitrap MS:INSTRUMENT_TYPE Orbitrap MS:MS_TYPE ESI MS:ION_MODE NEGATIVE MS:MS_COMMENTS The Q Exactive mass spectrometer (Thermo Fisher Scientific, San Jose, CA, USA) MS:MS_COMMENTS was operated in negative ion mode using electrospray ionization, scanning in MS:MS_COMMENTS Full MS mode (1μscan) from 65 to 975 m/z at 70,000 resolution, with 4 kV spray MS:MS_COMMENTS voltage, 45 sheath gas, 15 auxiliary gas. MS analysis and data elaboration were MS:MS_COMMENTS performed as described74,75. Calibration was performed prior to analysis using MS:MS_COMMENTS the PierceTM Negative Ion Calibration Solution (Thermo Fisher Scientific). #MS_METABOLITE_DATA MS_METABOLITE_DATA:UNITS relative abundance MS_METABOLITE_DATA_START Samples Nexus_D21_4neg-4 Nexus_D21_4neg-8 Nexus_D21_4neg-15 Nexus_D21_4neg-16 Nexus_D21_4neg-17 Nexus_D21_4neg-19 Nexus_D21_4neg-20 Nexus_D21_4neg-31 Nexus_D21_4neg-32 Nexus_D21_4neg-35 Nexus_D21_4neg-36 Nexus_D21_4neg-38 Nexus_D21_4neg-41 Nexus_D21_4neg-42 Nexus_D21_4neg-44 Nexus_D21_4neg-45 Nexus_T21_4neg-49 Nexus_D21_4neg-51 Nexus_D21_4neg-60 Nexus_D21_4neg-63 Nexus_D21_4neg-64 Nexus_D21_4neg-65 Nexus_D21_4neg-66 Nexus_D21_4neg-67 Nexus_D21_4neg-68 Nexus_D21_4neg-71 Nexus_D21_4neg-72 Nexus_D21_4neg-73 Nexus_D21_4neg-74 Nexus_D21_4neg-75 Nexus_D21_4neg-76 Nexus_D21_4neg-77 Nexus_D21_4neg-78 Nexus_D21_4neg-79 Nexus_D21_4neg-80 Nexus_D21_4neg-82 Nexus_D21_4neg-83 Nexus_D21_4neg-84 Nexus_D21_4neg-85 Nexus_D21_4neg-86 Nexus_D21_4neg-87 Nexus_D21_4neg-88 Nexus_D21_4neg-89 Nexus_D21_4neg-90 Nexus_D21_4neg-91 Nexus_D21_4neg-93 Nexus_D21_4neg-95 Nexus_D21_4neg-96 Nexus_D21_4neg-98 Nexus_T21_4neg-1 Nexus_T21_4neg-2 Nexus_T21_4neg-3 Nexus_T21_4neg-5 Nexus_T21_4neg-6 Nexus_T21_4neg-7 Nexus_T21_4neg-9 Nexus_T21_4neg-10 Nexus_T21_4neg-11 Nexus_T21_4neg-12 Nexus_T21_4neg-13 Nexus_T21_4neg-14 Nexus_T21_4neg-18 Nexus_T21_4neg-21 Nexus_T21_4neg-22 Nexus_T21_4neg-23 Nexus_T21_4neg-24 Nexus_T21_4neg-25 Nexus_T21_4neg-26 Nexus_T21_4neg-27 Nexus_T21_4neg-28 Nexus_T21_4neg-29 Nexus_T21_4neg-30 Nexus_T21_4neg-33 Nexus_T21_4neg-34 Nexus_T21_4neg-37 Nexus_T21_4neg-39 Nexus_T21_4neg-40 Nexus_T21_4neg-46 Nexus_T21_4neg-47 Nexus_T21_4neg-48 Nexus_T21_4neg-43 Nexus_T21_4neg-50 Nexus_T21_4neg-52 Nexus_T21_4neg-53 Nexus_T21_4neg-54 Nexus_T21_4neg-55 Nexus_T21_4neg-56 Nexus_T21_4neg-57 Nexus_T21_4neg-58 Nexus_T21_4neg-59 Nexus_T21_4neg-61 Nexus_T21_4neg-62 Nexus_T21_4neg-69 Nexus_T21_4neg-70 Nexus_T21_4neg-81 Nexus_T21_4neg-92 Nexus_T21_4neg-94 Nexus_T21_4neg-97 Factors Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:T21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:D21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Cohort:T21 Urate 44908820.00 29599500.00 52805860.00 33858170.00 45129600.00 64339100.00 53656840.00 48018850.00 37656400.00 57860720.00 50850410.00 33427610.00 48285920.00 41425290.00 51041460.00 62431620.00 35207900.00 61758360.00 49435920.00 37183060.00 55363830.00 44902340.00 32592610.00 61433760.00 70608130.00 30452160.00 51150550.00 52111720.00 34998080.00 40390400.00 49063020.00 63050610.00 37607900.00 40024000.00 52295880.00 40701440.00 48061260.00 31086410.00 31702860.00 38026300.00 55096920.00 42060940.00 50933460.00 46695830.00 55111340.00 35511780.00 43246690.00 40591440.00 42682450.00 28872840.00 25251100.00 34714460.00 36964290.00 24431690.00 35328720.00 28598420.00 37950440.00 35096980.00 56403480.00 35017430.00 40733990.00 52361090.00 52394430.00 55895390.00 36994650.00 53203970.00 50782720.00 50112670.00 54233260.00 34278450.00 38564930.00 44323940.00 54430780.00 46462680.00 40552360.00 59166510.00 38072030.00 48958650.00 75461050.00 38547730.00 65599030.00 61535760.00 59668430.00 52428580.00 70352150.00 57357570.00 49513060.00 36476100.00 57366040.00 50594050.00 42880040.00 50859420.00 64138200.00 75154010.00 48363660.00 29809110.00 44882880.00 45542660.00 2',3'-Cyclic CMP 67980.16 57208.99 114250.90 143886.80 93080.30 89930.72 92648.04 106580.30 40295.59 82338.79 144789.10 81974.89 49048.79 83358.62 101479.30 109607.50 116464.60 75802.12 112762.40 114752.00 107902.20 135023.70 206347.90 97705.16 96250.30 146933.30 118315.80 142494.90 189189.80 171012.00 114238.10 66707.30 140839.50 92034.96 90834.62 108436.70 86842.02 177250.80 133930.00 117234.90 96752.96 104648.50 87637.91 176724.30 94878.37 144438.00 144103.60 109402.20 117780.30 80915.71 111169.40 107585.20 99290.96 88983.66 102505.00 100056.70 103456.60 69753.94 107079.10 82743.62 138710.70 142579.00 91833.94 83807.98 107525.20 106048.00 118256.40 92154.09 128832.40 110603.30 79090.59 106955.00 134267.80 131149.90 167753.50 97134.76 192726.00 96945.71 70974.41 117295.00 64473.69 150523.70 154439.10 173199.40 96990.69 173289.10 210821.70 119363.80 80905.16 238615.60 171514.30 69861.79 116748.70 34729.50 144411.80 132900.20 130323.40 131588.50 Phosphate NA 1113910.00 555969.40 1700104.00 682868.30 919591.80 391498.80 1384682.00 1057112.00 NA 606043.10 633983.60 NA 848412.50 NA NA 2483482.00 1362204.00 1122917.00 NA 187706.90 1522261.00 2053578.00 326445.10 965107.00 984648.20 281995.50 643668.80 928910.50 267009.60 1263901.00 796721.70 953056.70 1216737.00 NA 758235.30 NA 538265.70 NA 1752115.00 621428.00 515532.20 NA 927680.50 190886.90 583690.90 NA 494848.70 1004094.00 942694.90 1954062.00 1157368.00 1758515.00 2022350.00 1310191.00 1349026.00 1184371.00 1656622.00 326952.80 856952.80 1519698.00 1940416.00 931633.00 459671.60 1298220.00 373285.20 1891284.00 1663760.00 1444680.00 700888.80 1588892.00 NA 1293693.00 443061.90 977825.20 1606773.00 786044.00 248238.00 1173681.00 1014873.00 597040.10 1701254.00 541440.80 1678833.00 NA 991502.40 463682.10 1119793.00 1385223.00 621369.10 1900834.00 667232.50 NA 291917.60 1299450.00 1795127.00 1128354.00 1168162.00 D-Glucose 1403384.00 1245055.00 2227760.00 2249844.00 1017714.00 1879193.00 2408456.00 2804662.00 1878580.00 2060345.00 2163177.00 2002792.00 1748711.00 2221715.00 4032618.00 1604859.00 2070294.00 2318884.00 2091020.00 1702923.00 2605274.00 2132465.00 1251369.00 1894978.00 1857539.00 1539682.00 1739132.00 2039717.00 2014584.00 1688701.00 1881190.00 1914962.00 1710569.00 2034776.00 1866990.00 2330193.00 2320520.00 1843874.00 1930070.00 1608848.00 2070735.00 1977588.00 2179676.00 1608234.00 1921686.00 1627205.00 1878131.00 1949180.00 2451995.00 1259749.00 893712.20 1389862.00 1631266.00 1618651.00 1765241.00 1651246.00 1666074.00 1425405.00 1943416.00 1365504.00 1457919.00 1656547.00 2099153.00 1894753.00 2284848.00 1289619.00 1558361.00 1948940.00 2419780.00 1931965.00 2129622.00 1583698.00 1765384.00 1707730.00 2384577.00 1595483.00 1518773.00 1853280.00 1823194.00 1856132.00 1534414.00 1761879.00 1977220.00 2283986.00 1811038.00 2142082.00 2392938.00 2972600.00 1805682.00 1697618.00 2209637.00 2976081.00 2189240.00 1904280.00 1906521.00 1920236.00 1831940.00 2327939.00 Pyruvate 2182120.00 2475665.00 2884743.00 2362617.00 1395734.00 4926238.00 4047847.00 4993584.00 2438120.00 2803944.00 4659456.00 2998510.00 2655401.00 2944107.00 3282510.00 3435302.00 2791599.00 3420691.00 3888819.00 2592836.00 4097899.00 1584164.00 890949.10 3193764.00 4392074.00 3932602.00 3059385.00 4906508.00 4681928.00 2897646.00 2247927.00 1779684.00 3779041.00 2913615.00 2823110.00 4363290.00 4254004.00 3563856.00 2659190.00 3266947.00 3181925.00 3494958.00 1056453.00 2235555.00 4371614.00 2480283.00 3043420.00 2257016.00 4077964.00 3331084.00 829910.50 2811712.00 2880953.00 1890701.00 4152659.00 4166024.00 2716301.00 2689123.00 1355844.00 3275068.00 2354755.00 4090787.00 2419042.00 3570790.00 2340948.00 2170333.00 2822493.00 3606196.00 5658040.00 1980172.00 4631330.00 858459.30 4703336.00 822362.40 3623740.00 1560667.00 2381433.00 4113255.00 2095459.00 1851891.00 2485196.00 3286565.00 2789452.00 3059945.00 3677549.00 3947815.00 2637321.00 4879442.00 1679242.00 2911162.00 3267228.00 2743762.00 4158988.00 3708226.00 3340649.00 3598164.00 3542290.00 6246754.00 Lactate 16751510.00 16614220.00 19176020.00 19271500.00 42745750.00 28154470.00 23678460.00 24410410.00 17535620.00 17225110.00 27303440.00 19153160.00 21842630.00 21876360.00 23409420.00 22904390.00 22025260.00 23450370.00 27292830.00 26716820.00 22917820.00 28543230.00 23595150.00 26347910.00 25172800.00 30975740.00 26919980.00 35592390.00 30712830.00 32806990.00 28057870.00 27909600.00 33906570.00 28012730.00 33286550.00 27011320.00 21632570.00 26659860.00 24394120.00 26765010.00 27811460.00 34877410.00 19111370.00 24391550.00 22381570.00 20357040.00 27290370.00 22415730.00 24962530.00 22092550.00 25440910.00 22061200.00 15320750.00 19140310.00 28955220.00 23373780.00 21914980.00 19150260.00 17742730.00 39894640.00 23223820.00 29859600.00 19989460.00 20325140.00 23456840.00 20103120.00 22611490.00 24628210.00 39343820.00 17516690.00 20725700.00 22204450.00 24982290.00 25574510.00 27530610.00 32887130.00 26803630.00 28434900.00 27263130.00 22116810.00 26321480.00 27366340.00 24030270.00 32120550.00 25648690.00 26611080.00 53267190.00 29671790.00 29377050.00 24125100.00 24512780.00 36667270.00 32574070.00 26575140.00 27023020.00 22465050.00 23601540.00 44250060.00 Mannitol 24967.86 49471.41 18199.51 15602.90 269238.50 9583.21 12773.28 11449.81 10384.47 92717.26 11867.08 19174.42 12706.78 6278.34 8242.05 5580.85 7989.69 86761.30 33796.68 118742.80 11866.20 7206.48 2261.19 18375.06 9616.02 15183.75 40994.18 13810.16 22729.02 13069.07 10787.63 6577.67 12252.28 6703.58 37254.32 35595.39 14845.87 9900.51 3443.15 6127.50 16108.22 5463.63 6079.54 5994.69 11151.84 2409.66 26495.02 25361.76 28346.96 69875.50 6632.50 1907.44 22714.66 26578.32 5142.13 25636.08 1684935.00 114868.60 12198.25 22534.03 14709.88 155150.40 16935.92 273143.00 55909.11 31661.12 23352.84 138040.80 257855.80 14747.98 38114.61 17303.95 20397.03 52186.11 22594.24 16786.88 15868.50 45836.98 23838.30 18103.93 35812.84 23471.15 87264.71 18318.59 7486.90 50823.27 11313.25 37180.49 17824.62 10668.63 36939.37 33409.30 12297.98 84963.17 15246.53 6271.93 20691.73 33229.33 D-Ribose 531367.90 106996.20 554109.90 223147.40 222683.90 354627.00 451094.60 464638.10 254612.30 310650.50 424547.50 408827.50 296206.60 715372.20 310208.30 180967.40 306716.50 239391.50 672323.20 372790.20 205832.30 316788.20 97592.38 261266.80 272868.00 231915.10 203691.10 234937.30 470504.20 296697.60 333135.70 198057.20 181871.20 231065.70 200862.60 544379.60 1219038.00 283754.80 253878.50 147711.50 297645.80 209458.60 275451.00 265088.60 314385.00 130168.80 466882.90 201446.30 403074.10 428169.80 151277.60 327940.00 541066.90 708196.20 305061.80 447629.50 391762.40 375000.60 365554.70 224231.80 151393.10 504990.80 470255.10 562003.70 934528.20 530013.80 639495.20 506752.20 650859.70 224049.90 1382972.00 255775.90 427279.00 386196.70 588900.80 561741.40 344702.80 262645.00 469126.30 339231.80 253031.50 495161.50 602007.40 272674.60 336679.10 699658.80 319776.60 358089.80 376526.80 316694.20 387732.80 388994.20 566248.00 204730.70 424942.50 328001.20 570132.70 550595.30 Citrate 4819904.00 5042362.00 9426997.00 12468950.00 6765294.00 9341572.00 8418933.00 11112340.00 3841034.00 9269971.00 11537990.00 6184352.00 5338837.00 8857727.00 16059380.00 9138120.00 10723480.00 8578478.00 10964750.00 5713960.00 7801382.00 9429084.00 13155850.00 8912541.00 9566560.00 11081870.00 11643480.00 14215870.00 11173580.00 14013880.00 9106523.00 7547328.00 11235480.00 10044770.00 8372216.00 9125239.00 6765172.00 14140660.00 8676431.00 8562727.00 9604838.00 10617500.00 7126110.00 11795630.00 7084028.00 9745136.00 10178970.00 7231066.00 7673916.00 9343676.00 10619070.00 10209240.00 10767750.00 8996193.00 12411270.00 8075382.00 9551909.00 6840720.00 10013180.00 5917358.00 12342540.00 13753020.00 11369620.00 10022030.00 11721790.00 10925060.00 11446600.00 10144650.00 14711540.00 8228466.00 7949162.00 7769542.00 10714070.00 11055470.00 12206240.00 9830709.00 14863740.00 7759784.00 8405745.00 13459310.00 6575660.00 15947740.00 13511650.00 12849480.00 8497449.00 16794070.00 18869000.00 13727170.00 8669156.00 15816630.00 16317860.00 8081280.00 11655120.00 5458944.00 14883240.00 9969264.00 8013994.00 11126830.00 2-Oxoglutarate 684869.80 534128.10 1092648.00 1047573.00 1217235.00 859271.90 1908185.00 1014226.00 774090.20 674926.40 974832.20 635688.80 614036.00 785298.50 870388.50 615926.00 1617674.00 491541.50 2144223.00 691386.10 903905.70 925166.20 807409.20 844069.40 803322.20 968588.00 897819.80 1361794.00 1415522.00 961348.70 1009927.00 885581.80 1143379.00 971517.50 954853.00 1273786.00 1139675.00 753122.70 608736.60 731913.80 1129783.00 730685.30 740077.00 1240939.00 1788528.00 1355603.00 1177209.00 700814.80 944037.10 813470.00 606448.70 1017750.00 971941.00 660599.60 1162948.00 736253.00 1022940.00 603079.20 761640.80 655514.60 718396.30 931725.80 991149.30 1029797.00 1217186.00 1287458.00 784185.80 679894.10 1397939.00 710007.50 1068457.00 662998.50 3591419.00 2043512.00 1436362.00 501399.70 778036.80 770982.80 776973.50 645783.70 876861.50 3663297.00 1943556.00 1264023.00 1197368.00 1390962.00 1402699.00 1145484.00 1124365.00 1521334.00 1231323.00 1338147.00 721158.90 1065154.00 1119936.00 1048894.00 875801.60 1282867.00 Succinate 93786.77 175781.60 246946.20 224872.60 214524.30 215853.20 168427.30 254679.90 208550.00 234635.00 269722.30 268058.80 205302.50 222877.20 274887.20 208219.00 221661.90 267906.30 157693.70 233686.30 133893.70 200380.30 231974.50 306443.00 205454.20 279559.60 231766.20 277870.20 225049.50 241344.00 277561.10 229899.90 232894.20 229179.00 321870.50 215996.50 256813.20 238005.20 203625.80 253088.70 208513.70 282394.40 212279.80 235913.30 231321.10 208730.10 202414.80 231637.50 206236.60 259887.00 248548.50 201020.30 153697.00 245534.10 250500.30 222389.90 293313.80 175965.60 179095.60 167676.60 226941.30 261001.10 232270.30 250189.60 289075.80 189224.10 301559.60 234061.80 304644.30 195051.60 175430.70 257530.10 222650.50 272909.50 265380.10 251622.80 261091.20 324177.90 259308.20 258670.50 208412.10 211037.20 338722.00 365413.20 234862.90 318208.20 772285.20 313363.40 297410.60 303390.60 345491.10 234474.40 278847.10 254404.30 282113.90 298210.00 298830.60 337630.60 Fumarate 224707.20 120798.00 160941.20 199672.50 127268.70 65611.15 138489.90 162438.00 71591.71 178875.90 194853.30 234031.90 256998.30 116299.20 99096.72 207678.80 106803.90 65858.45 260245.70 179130.00 250750.10 228828.20 182040.90 139980.10 169218.70 136492.30 272431.50 253466.70 427539.70 161985.00 264837.30 313272.90 244310.50 325898.50 223512.50 415892.20 316986.90 277315.80 151870.10 223269.60 505812.80 463912.30 234423.20 183599.50 214365.60 197681.90 386144.30 1682354.00 292135.20 199384.10 215965.50 343379.00 295020.20 361484.20 289616.30 377222.00 263376.00 277620.30 97294.15 166614.40 61792.68 156532.10 133585.00 183862.70 265777.80 269241.90 221040.80 194882.30 459992.40 291488.90 479826.10 243134.10 333107.10 102845.70 466931.30 316885.40 377578.00 242414.10 278575.30 196514.10 308598.40 379741.70 256859.50 401638.60 227717.00 529107.20 266214.80 525757.60 141047.80 355060.60 330950.70 232346.70 325216.30 195592.50 327750.50 305909.20 338372.50 440034.80 Malate 352996.00 414393.00 859088.80 1093634.00 989496.80 941800.10 740185.60 1256572.00 387863.00 714580.80 1092678.00 508796.30 453341.60 724151.20 1378032.00 689342.50 949763.80 867361.80 1031084.00 648586.00 471287.60 700093.30 764489.50 843856.20 855309.80 1202882.00 1123382.00 1481377.00 1637276.00 1188684.00 1249639.00 984148.70 1305692.00 1281956.00 1046966.00 1346332.00 931500.70 1122771.00 579810.40 746201.80 1307467.00 1106453.00 556104.20 938962.50 783471.50 677411.20 1004554.00 9510141.00 948697.30 987697.00 1633566.00 1379718.00 931400.70 769369.50 1163632.00 861112.80 1270977.00 633619.40 815091.20 733948.10 913561.20 1222394.00 1086594.00 849610.40 2358330.00 1137955.00 740901.70 794703.30 1470111.00 728936.70 1097321.00 877610.30 1439546.00 637407.40 1523359.00 1072959.00 880858.80 841868.20 1093432.00 980976.20 738848.20 1461524.00 1171857.00 1556706.00 1025405.00 1872112.00 3011304.00 1377636.00 820356.30 965454.00 1562124.00 1108066.00 1239179.00 660157.60 1409199.00 1024792.00 1030964.00 1758605.00 Oxaloacetate 151916.70 175769.50 239498.60 160375.10 194272.60 221336.10 239489.30 288838.50 195659.70 282973.50 208211.40 232459.80 212946.20 239075.80 273065.30 262514.30 255338.10 216984.90 256707.40 235664.30 215868.60 259595.50 232487.40 200711.30 221787.20 228026.60 197769.00 219041.50 197003.30 245582.50 262259.60 226971.70 214815.20 280287.00 262961.10 161029.40 238383.30 223081.10 200161.60 188781.60 250315.70 222003.50 261682.60 266697.10 262179.20 225847.50 240032.10 245918.00 208473.30 138207.90 139134.70 157996.80 175014.20 169172.40 201655.00 187417.30 229948.10 222216.00 195746.50 164114.60 187579.00 237556.90 249685.90 257423.10 223565.30 252048.00 167352.00 235995.80 243984.50 260929.60 271500.50 174461.50 209418.10 212997.90 277773.00 216774.20 252056.40 217018.10 227594.30 218516.70 255272.00 233470.60 231021.10 273052.80 241112.50 270046.10 241142.90 243134.20 232448.30 242882.10 246710.90 245017.30 194103.90 204392.40 251337.20 206187.70 190253.60 168726.00 2-Hydroxyglutarate 554205.10 569457.80 750413.80 689641.10 611540.90 796600.50 730151.00 838309.30 689738.20 834421.20 814959.10 704397.10 606410.30 856441.20 1068934.00 817482.50 907562.80 869008.30 847420.60 615485.80 805483.30 816775.80 734088.30 793998.80 725627.00 948567.80 970909.70 938903.20 855626.40 916208.80 737642.30 841271.60 906524.00 914495.30 772104.80 755886.90 756502.60 800706.20 687323.70 692545.40 781171.90 721312.30 634997.60 829743.00 775577.90 860295.50 748776.60 718199.60 698896.70 631572.00 589709.10 498927.40 707763.50 701923.50 555759.80 698222.60 734576.30 760255.70 684022.50 575782.40 686643.50 770755.80 876419.80 858169.60 978358.00 706528.80 810980.80 844375.70 946919.80 629480.40 746900.30 647423.20 870984.00 732909.40 873464.80 841114.00 807905.60 842829.70 881840.30 984719.20 866345.50 1058252.00 933631.70 764062.00 856152.40 1040014.00 860160.30 907441.50 812373.10 840897.70 1028560.00 897192.00 925785.00 809094.20 1002482.00 943350.00 843316.80 976341.30 alpha-D-Ribose 1-phosphate 16594.67 14601.14 32406.84 40457.84 29332.61 27915.51 37770.82 65604.12 22220.48 40185.09 32473.46 23109.28 28660.66 33175.34 99945.69 22094.96 28526.06 29009.60 26641.17 18801.05 43072.05 40153.78 16808.38 19413.84 28673.27 17200.16 24562.14 26645.91 42063.73 26038.79 28735.06 28079.67 29449.71 30273.79 45369.07 35022.86 21362.52 18931.56 22757.46 16946.40 25381.77 19129.63 29881.34 17381.10 22892.06 25101.44 21402.86 18929.80 23551.99 10820.85 8870.15 22914.17 17776.45 20122.24 25295.34 24575.58 20161.72 14816.60 37305.16 25440.05 14761.73 26598.33 32781.55 23650.57 33558.72 17202.88 21083.10 27432.54 29726.61 41471.39 31198.48 21821.22 24777.38 21004.13 34114.47 26182.85 16110.54 15690.00 25679.88 22330.37 33251.42 32763.93 30010.59 40076.06 35580.14 28345.17 37418.21 30925.50 23396.18 26462.80 32367.72 48917.79 31470.71 25988.32 24548.79 29692.19 20493.24 34863.98 Ascorbate 9519548.00 6954180.00 4828864.00 6122848.00 3061635.00 212416.80 4194606.00 2263118.00 1047400.00 7225388.00 9436338.00 13565880.00 16017840.00 1748748.00 532553.00 11058450.00 273396.00 199837.20 8052288.00 7313296.00 12285560.00 11934090.00 7791592.00 5161166.00 7354746.00 3848573.00 12677720.00 6144548.00 28811460.00 4858276.00 10211800.00 17056070.00 11112550.00 17490740.00 9462699.00 20487820.00 14926070.00 11921940.00 11336120.00 10141820.00 31678050.00 26179640.00 13031770.00 7013926.00 7184576.00 6427970.00 21517680.00 12824840.00 14132760.00 9511573.00 6013536.00 22544360.00 14711480.00 22783170.00 13544410.00 23966960.00 11876780.00 14796560.00 1328389.00 6777164.00 80321.70 1196801.00 4014826.00 8461973.00 5789226.00 16635800.00 11664150.00 10748620.00 28762250.00 19109740.00 29770870.00 12571370.00 12449060.00 1465967.00 25537920.00 15577610.00 22263110.00 12186240.00 16076960.00 9135813.00 13250890.00 16678940.00 10016920.00 20265550.00 8963724.00 31091510.00 4047281.00 30225310.00 4137581.00 17637140.00 16948430.00 9923744.00 16675640.00 9513057.00 17410890.00 18766420.00 17921420.00 18893210.00 Dehydroascorbate 315382.40 236650.70 408240.90 516422.40 196469.40 514633.20 290912.20 354105.90 209214.60 380542.50 414068.70 325378.60 304561.80 318152.80 507565.80 382024.20 429411.10 428462.40 475316.70 299064.60 386971.50 403215.40 411919.20 419208.20 463037.00 377576.00 506652.10 578411.60 568484.80 537033.90 479713.30 409047.00 478653.80 441315.20 432633.00 452320.10 372765.00 461208.60 343924.00 293112.50 435500.00 470426.90 339618.70 515687.70 386142.80 307016.40 508934.90 443438.90 418783.70 447006.40 504293.30 524560.60 592978.70 525978.20 429217.00 452043.40 519530.40 459321.10 391921.70 290989.00 444055.90 608233.90 454902.80 519381.50 443050.80 520524.00 525110.80 427824.10 761670.60 431484.70 521646.80 401627.60 545487.10 337409.00 653693.60 419993.30 567273.20 332691.50 419951.20 572770.20 378671.60 686962.60 568306.30 567150.10 436245.10 810438.80 611790.50 656732.90 345134.50 645430.10 682595.20 394251.20 521003.00 283606.90 732210.80 505181.50 501343.20 574242.20 1-4-beta-D-Xylan 52671.83 41337.73 59135.31 80500.91 37067.25 58309.38 83746.28 37329.69 65752.02 71593.49 71352.23 81044.02 64981.80 68232.77 149836.00 60034.96 70804.46 80618.62 59887.58 62262.81 94515.69 79897.49 50645.56 60443.64 79485.38 44448.80 58682.86 70781.55 95934.94 51996.19 65728.58 74694.80 43058.04 71286.93 70129.75 73096.77 71608.26 61215.06 69660.29 69973.01 66852.59 59505.66 67475.79 51205.33 67995.29 49173.17 68334.53 70327.71 91147.28 44978.74 36650.32 45715.64 53759.69 52264.10 64284.07 55062.48 69662.78 46100.06 69399.50 53280.10 58161.47 55870.77 75492.29 56293.48 74604.66 49421.72 54679.70 68310.55 73570.09 63742.89 97003.69 64317.70 60909.97 62738.48 76018.09 59924.87 58212.68 66851.66 70492.34 67372.91 57502.41 58752.10 59792.41 73227.19 64076.47 69763.79 80649.94 101221.80 66733.88 65066.97 63341.92 100425.20 77100.59 75584.27 71329.95 64114.61 67832.87 81199.85 L-1-Pyrroline-3-hydroxy-5-carboxylate 2457414.00 2776355.00 3157334.00 2459717.00 6690164.00 3097971.00 3652932.00 3354313.00 3644295.00 3169726.00 4514932.00 3551647.00 3298149.00 3609781.00 3860269.00 3732336.00 3251443.00 3971159.00 4272296.00 3233534.00 3443690.00 3208561.00 3450558.00 3717579.00 3059021.00 4869720.00 4140404.00 4237636.00 4024209.00 4452557.00 4387754.00 4313243.00 4048177.00 3941603.00 4585100.00 3347117.00 3050083.00 3227003.00 3093369.00 3460801.00 3957106.00 3139657.00 3696975.00 3921169.00 3175621.00 3037821.00 3734927.00 3414669.00 3480979.00 2677450.00 3391322.00 2189836.00 2346166.00 2530720.00 2540261.00 2145047.00 2711053.00 2630421.00 2762890.00 2155995.00 3322783.00 3011368.00 2918360.00 2597168.00 3314707.00 2843142.00 3212595.00 3433871.00 3137867.00 3111756.00 2529597.00 3267940.00 2773624.00 3651373.00 2802571.00 4970400.00 3014414.00 3166180.00 3544767.00 3847253.00 2936117.00 3528948.00 3420033.00 3387316.00 3482105.00 2723691.00 4152245.00 3000276.00 3172546.00 3991509.00 3473205.00 3360084.00 3474860.00 3174643.00 3735839.00 3280117.00 3227709.00 3786143.00 3-Sulfocatechol 46836.45 221064.80 27527.59 67806.90 11729.47 47681.18 115477.90 4582.72 209756.90 60816.36 70331.39 103172.40 174494.50 38755.43 4328.56 13802.78 88434.54 397508.80 47914.52 46908.51 124957.10 76227.12 9000.20 4595.91 71796.27 50424.62 3000.77 26785.01 30895.68 10966.85 14523.49 16606.56 14352.55 22270.73 10479.99 3521.28 10898.77 282317.00 26969.09 4911.03 6867.36 81040.88 50712.44 48723.83 110007.30 45856.89 5765.41 31486.18 77018.49 171606.60 58958.14 164146.00 101826.30 211945.30 858769.50 35538.12 50449.34 68836.17 79474.09 202238.10 72069.01 28162.89 188284.40 15483.65 33162.13 8117.50 101111.10 67174.50 85624.39 45433.42 18176.51 29812.35 155309.40 11799.54 138846.90 14733.33 72790.71 65779.44 126398.50 40296.55 340408.60 12404.96 27320.40 335417.40 31564.28 189080.50 176733.60 79651.02 104632.50 51422.19 171753.10 19974.93 85883.44 41303.61 151024.80 51454.32 41495.70 35761.46 Octanoic acid 44539.50 52074.59 37559.43 42364.48 37275.32 34130.76 34599.23 32823.61 42445.25 37380.44 38106.11 32433.69 39064.67 31605.73 34789.51 42058.71 32374.46 25702.88 23356.56 23401.02 32139.76 24994.21 31146.77 35644.20 21580.89 26408.01 28778.88 29932.54 27039.64 28239.71 26289.93 26047.38 28244.61 24644.84 32510.26 28482.26 25350.69 20149.54 28659.87 27818.42 32181.37 28309.46 26340.13 27204.06 33417.46 37321.80 22155.60 27240.73 18733.39 25744.44 35193.65 40001.52 44004.09 44229.28 54345.60 46025.79 51116.49 43408.42 43076.12 42754.66 44051.92 31293.10 38478.17 33523.13 38451.51 28269.40 40271.86 33982.93 36517.63 41941.70 40697.04 40850.62 42028.40 38131.98 40540.92 35735.20 35261.44 32039.92 37215.26 43223.96 34941.12 31611.59 35235.81 34126.91 40270.29 40869.74 27166.35 31422.90 38077.34 18757.63 34628.12 24476.15 30677.00 30588.23 31544.94 35984.33 27723.55 27749.01 MS_METABOLITE_DATA_END #METABOLITES METABOLITES_START metabolite_name KEGG ID quantitated m/z Rtmed Urate C00366 167.0195 1.193989 2',3'-Cyclic CMP C02354 304.0353 1.514019 Phosphate C00009 96.96776 1.218801 D-Glucose C00031 179.0547 1.163901 Pyruvate C00022 87.00687 1.212247 Lactate C00186 89.02254 1.210228 Mannitol C00392 181.0704 1.165073 D-Ribose C00121 149.044 1.191862 Citrate C00158 191.0182 1.195501 2-Oxoglutarate C00026 145.0129 1.198627 Succinate C00042 117.0176 1.216295 Fumarate C00122 115.0019 1.195005 Malate C00149 133.0126 1.194089 Oxaloacetate C00036 130.9999 1.173591 2-Hydroxyglutarate C02630 147.0283 1.194795 alpha-D-Ribose 1-phosphate C00620 229.0112 1.173049 Ascorbate C00072 175.0234 1.193072 Dehydroascorbate C05422 173.0078 1.195601 1-4-beta-D-Xylan C02352 131.0332 1.168919 L-1-Pyrroline-3-hydroxy-5-carboxylate C04281 128.0334 1.198224 3-Sulfocatechol C06336 188.9848 1.222893 Octanoic acid C06423 143.1057 1.848211 METABOLITES_END #END