#METABOLOMICS WORKBENCH torichristian_20240213_105231 DATATRACK_ID:4637 STUDY_ID:ST003102 ANALYSIS_ID:AN005076 PROJECT_ID:PR001925 VERSION 1 CREATED_ON 05-28-2024 #PROJECT PR:PROJECT_TITLE Cellular adaptation to cancer therapy along a resistance continuum PR:PROJECT_SUMMARY Recent research has shed light on the role of non-genetic plasticity in PR:PROJECT_SUMMARY transient drug tolerance and the acquisition of stable resistance. However, the PR:PROJECT_SUMMARY dynamics of cell state transitions occurring in the adaptation to cancer PR:PROJECT_SUMMARY therapies remain elusive and require a systems-level longitudinal framework. PR:PROJECT_SUMMARY Here we demonstrate that resistance develops through trajectories of cell state PR:PROJECT_SUMMARY transitions accompanied by a progressive increase in cell fitness, which we PR:PROJECT_SUMMARY denote the ‘resistance continuum’. This cellular adaptation involves a PR:PROJECT_SUMMARY step-wise assembly of gene expression programs and epigenetically reinforced PR:PROJECT_SUMMARY cell states underpinned by phenotypic plasticity stress adaptation and metabolic PR:PROJECT_SUMMARY reprogramming. Through systematic genetic perturbations, we identify an PR:PROJECT_SUMMARY acquisition of progressive metabolic dependencies, exposing a spectrum of PR:PROJECT_SUMMARY vulnerabilities that can be potentially exploited therapeutically. The concept PR:PROJECT_SUMMARY of the resistance continuum highlights the dynamic nature of cellular adaptation PR:PROJECT_SUMMARY and calls for complementary therapies directed at the mechanisms underlying PR:PROJECT_SUMMARY adaptive cell state transitions. PR:INSTITUTE NYU Langone Health PR:LAST_NAME Starvaggi Franca PR:FIRST_NAME Gustavo PR:ADDRESS 430 E 29th Street PR:EMAIL Gustavo.StarvaggiFranca@nyulangone.org PR:PHONE 646-501-4603 PR:FUNDING_SOURCE NIH grants: P50 CA225450 PR:DOI http://dx.doi.org/10.21228/M8WM7T #STUDY ST:STUDY_TITLE Cellular adaptation to cancer therapy along a resistance continuum ST:STUDY_SUMMARY Recent research has shed light on the role of non-genetic plasticity in ST:STUDY_SUMMARY transient drug tolerance and the acquisition of stable resistance. However, the ST:STUDY_SUMMARY dynamics of cell state transitions occurring in the adaptation to cancer ST:STUDY_SUMMARY therapies remain elusive and require a systems-level longitudinal framework. ST:STUDY_SUMMARY Here we demonstrate that resistance develops through trajectories of cell state ST:STUDY_SUMMARY transitions accompanied by a progressive increase in cell fitness, which we ST:STUDY_SUMMARY denote the ‘resistance continuum’. This cellular adaptation involves a ST:STUDY_SUMMARY step-wise assembly of gene expression programs and epigenetically reinforced ST:STUDY_SUMMARY cell states underpinned by phenotypic plasticity stress adaptation and metabolic ST:STUDY_SUMMARY reprogramming. Through systematic genetic perturbations, we identify an ST:STUDY_SUMMARY acquisition of progressive metabolic dependencies, exposing a spectrum of ST:STUDY_SUMMARY vulnerabilities that can be potentially exploited therapeutically. The concept ST:STUDY_SUMMARY of the resistance continuum highlights the dynamic nature of cellular adaptation ST:STUDY_SUMMARY and calls for complementary therapies directed at the mechanisms underlying ST:STUDY_SUMMARY adaptive cell state transitions. ST:INSTITUTE NYU Langone Health ST:LAST_NAME Starvaggi Franca ST:FIRST_NAME Gustavo ST:ADDRESS 430 East 29th Street, NY NY 10016 ST:EMAIL Gustavo.StarvaggiFranca@nyulangone.org ST:PHONE 6465015151 ST:SUBMIT_DATE 2024-02-13 #SUBJECT SU:SUBJECT_TYPE Cultured cells SU:SUBJECT_SPECIES Homo sapiens SU:TAXONOMY_ID 9606 #SUBJECT_SAMPLE_FACTORS: SUBJECT(optional)[tab]SAMPLE[tab]FACTORS(NAME:VALUE pairs separated by |)[tab]Additional sample data SUBJECT_SAMPLE_FACTORS C_1 S25059 Sample source:Ovarian cancer cells | Treatment:C RAW_FILE_NAME=SQ1169/S25059.mzXML SUBJECT_SAMPLE_FACTORS C_2 S25060 Sample source:Ovarian cancer cells | Treatment:C RAW_FILE_NAME=SQ1169/S25060.mzXML SUBJECT_SAMPLE_FACTORS C_3 S25061 Sample source:Ovarian cancer cells | Treatment:C RAW_FILE_NAME=SQ1169/S25061.mzXML SUBJECT_SAMPLE_FACTORS C_1_drug S25062 Sample source:Ovarian cancer cells | Treatment:C_drug RAW_FILE_NAME=SQ1169/S25062.mzXML SUBJECT_SAMPLE_FACTORS C_2_drug S25063 Sample source:Ovarian cancer cells | Treatment:C_drug RAW_FILE_NAME=SQ1169/S25063.mzXML SUBJECT_SAMPLE_FACTORS C_3_drug S25064 Sample source:Ovarian cancer cells | Treatment:C_drug RAW_FILE_NAME=SQ1169/S25064.mzXML SUBJECT_SAMPLE_FACTORS T320_1 S25065 Sample source:Ovarian cancer cells | Treatment:T320 RAW_FILE_NAME=SQ1169/S25065.mzXML SUBJECT_SAMPLE_FACTORS T320_2 S25066 Sample source:Ovarian cancer cells | Treatment:T320 RAW_FILE_NAME=SQ1169/S25066.mzXML SUBJECT_SAMPLE_FACTORS T320_3 S25067 Sample source:Ovarian cancer cells | Treatment:T320 RAW_FILE_NAME=SQ1169/S25067.mzXML SUBJECT_SAMPLE_FACTORS T320_1_drug S25068 Sample source:Ovarian cancer cells | Treatment:T320_drug RAW_FILE_NAME=SQ1169/S25068.mzXML SUBJECT_SAMPLE_FACTORS T320_2_drug S25069 Sample source:Ovarian cancer cells | Treatment:T320_drug RAW_FILE_NAME=SQ1169/S25069.mzXML SUBJECT_SAMPLE_FACTORS T320_3_drug S25070 Sample source:Ovarian cancer cells | Treatment:T320_drug RAW_FILE_NAME=SQ1169/S25070.mzXML #COLLECTION CO:COLLECTION_SUMMARY To generate drug-induced PARPi resistant populations, 1×106 Kuramochi CO:COLLECTION_SUMMARY drug-naïve cells (C) were initially seeded in 150 mm plates. CO:SAMPLE_TYPE Ovarian cancer cells #TREATMENT TR:TREATMENT_SUMMARY Twenty four hours after seeding, 1 uM of olaparib (Selleckchem, S1060) was added TR:TREATMENT_SUMMARY and cells were maintained under treatment until reaching confluency (> 70%), TR:TREATMENT_SUMMARY thus characterizing resistance at this dose. Cells were harvested (0.25% TR:TREATMENT_SUMMARY Trypsin/EDTA for 5 min at 37°C) and a fraction of the surviving population TR:TREATMENT_SUMMARY (1×106 cells) was seeded again and treated with 2.5 uM until cells reached TR:TREATMENT_SUMMARY confluency. This process was repeated sequentially by doubling the drug TR:TREATMENT_SUMMARY concentrations until the cell populations were able to achieve confluency at 320 TR:TREATMENT_SUMMARY uM of olaparib (T320). The initial dose was determined by cell viability assays, TR:TREATMENT_SUMMARY indicating a low starting dose (< IC30). At each step, aliquots of the TR:TREATMENT_SUMMARY adapted populations were frozen (10% DMSO, 50% FBS, 40% media) for further TR:TREATMENT_SUMMARY experiments #SAMPLEPREP SP:SAMPLEPREP_SUMMARY Kuramochi cells (C and T320) were cultured until ~80% confluence either on 320 SP:SAMPLEPREP_SUMMARY uM of olaparib for 24h or off treatment in triplicates per condition. Cell SP:SAMPLEPREP_SUMMARY pellets were collected and frozen with liquid nitrogen for submission to the NYU SP:SAMPLEPREP_SUMMARY Metabolomics Core Resource Laboratory. Samples were subjected to an LCMS SP:SAMPLEPREP_SUMMARY analysis to detect and quantify known peaks. A metabolite extraction was carried SP:SAMPLEPREP_SUMMARY out on each sample based on a previously described method116. #CHROMATOGRAPHY CH:METHODS_FILENAME L12 CH:CHROMATOGRAPHY_COMMENTS The LC column was a MilliporeTM ZIC-pHILIC (2.1 x150 mm, 5 μm) coupled to a CH:CHROMATOGRAPHY_COMMENTS Dionex Ultimate 3000TM system and the column oven temperature was set to 25oC CH:CHROMATOGRAPHY_COMMENTS for the gradient elution. A flow rate of 100 μL/min was used with the following CH:CHROMATOGRAPHY_COMMENTS buffers; A) 10 mM ammonium carbonate in water, pH 9.0, and B) neat acetonitrile. CH:CHROMATOGRAPHY_COMMENTS The gradient profile was as follows; 80-20%B (0-30 min), 20-80%B (30-31 min), CH:CHROMATOGRAPHY_COMMENTS 80-80%B (31-42 min). Injection volume was set to 2 μL for all analyses (42 min CH:CHROMATOGRAPHY_COMMENTS total run time per injection). CH:INSTRUMENT_NAME Ulitmate 3000 CH:COLUMN_NAME SeQuant ZIC-pHILIC (150 x 4.6mm,5um) CH:COLUMN_PRESSURE 1800 CH:COLUMN_TEMPERATURE 25 CH:FLOW_GRADIENT 80-20%B (0-30 min), 20-80%B (30-31 min), 80-80%B (31-42 min) CH:FLOW_RATE 0.1mL/min CH:INJECTION_TEMPERATURE 4 CH:INTERNAL_STANDARD ISTD (500nM amino acid cocktail) CH:SAMPLE_INJECTION 2uL CH:SOLVENT_A 100% water; 10 mM ammonium carbonate, pH 9.0 CH:SOLVENT_B 100% acetonitrile CH:ANALYTICAL_TIME 30m CH:OVEN_TEMPERATURE 28 CH:CHROMATOGRAPHY_TYPE HILIC #ANALYSIS AN:ANALYSIS_TYPE MS #MS MS:INSTRUMENT_NAME Thermo Q Exactive Orbitrap MS:INSTRUMENT_TYPE Triple quadrupole MS:MS_TYPE ESI MS:MS_COMMENTS M.13 Polar metabolites (pHILIC Hybrid). MS analyses were carried out by coupling MS:MS_COMMENTS the LC system to a Thermo Q Exactive HFTM mass spectrometer operating in heated MS:MS_COMMENTS electrospray ionization mode (HESI). Method duration was 30 min with a polarity MS:MS_COMMENTS switching data-dependent Top 5 method for both positive and negative modes. MS:MS_COMMENTS Spray voltage for both positive and negative modes was 3.5kV and capillary MS:MS_COMMENTS temperature was set to 320oC with a sheath gas rate of 35, aux gas of 10, and MS:MS_COMMENTS max spray current of 100 μA. The full MS scan for both polarities utilized MS:MS_COMMENTS 120,000 resolution with an AGC target of 3e6 and a maximum IT of 100 ms, and the MS:MS_COMMENTS scan range was from 67-1000 m/z. Tandem MS spectra for both positive and MS:MS_COMMENTS negative mode used a resolution of 15,000, AGC target of 1e5, maximum IT of 50 MS:MS_COMMENTS ms, isolation window of 0.4 m/z, isolation offset of 0.1 m/z, fixed first mass MS:MS_COMMENTS of 50 m/z, and 3-way multiplexed normalized collision energies (nCE) of 10, 35, MS:MS_COMMENTS 80. The minimum AGC target was 1e4 with an intensity threshold of 2e5. All data MS:MS_COMMENTS were acquired in profile mode. MS:ION_MODE UNSPECIFIED #MS_METABOLITE_DATA MS_METABOLITE_DATA:UNITS Arbitrary units MS_METABOLITE_DATA_START Samples S25059 S25060 S25061 S25062 S25063 S25064 S25065 S25066 S25067 S25068 S25069 S25070 Factors Sample source:Ovarian cancer cells | Treatment:C Sample source:Ovarian cancer cells | Treatment:C Sample source:Ovarian cancer cells | Treatment:C Sample source:Ovarian cancer cells | Treatment:C_drug Sample source:Ovarian cancer cells | Treatment:C_drug Sample source:Ovarian cancer cells | Treatment:C_drug Sample source:Ovarian cancer cells | Treatment:T320 Sample source:Ovarian cancer cells | Treatment:T320 Sample source:Ovarian cancer cells | Treatment:T320 Sample source:Ovarian cancer cells | Treatment:T320_drug Sample source:Ovarian cancer cells | Treatment:T320_drug Sample source:Ovarian cancer cells | Treatment:T320_drug 1-Methylnicotinamide 2114374.0000 1408726.0000 1615903.0000 2248666.0000 1732336.0000 2210414.0000 1893117.0000 1177037.0000 1419642.0000 3783231.0000 2423506.0000 1938106.0000 2_3-Diphosphoglyceric acid 3-Hydroxybutyric acid 3-Phosphoglyceric acid 170759.0000 149343.0000 108346.0000 139224.0000 4_5-Dihydroorotic acid 20243.0000 4-Hydroxyproline 27546688.0000 23484414.0000 26696800.0000 31338912.0000 45674308.0000 39104164.0000 21991280.0000 18709018.0000 23925228.0000 30516400.0000 30468482.0000 37582408.0000 5^-Methylthioadenosine 53957.0000 440542.0000 272713.0000 145795.0000 200723.0000 588198.0000 1027254.0000 989013.0000 946375.0000 1589365.0000 1489255.0000 1477892.0000 5-Phosphoribosylamine 6-Phosphogluconic acid Acetoacetic acid 64051.0000 Acetyl-CoA 13079.0000 18706.0000 Acetylcysteine 16547.0000 11961.0000 11099.0000 11823.0000 14427.0000 26996.0000 15729.0000 12668.0000 Adenine 12754629.0000 11876483.0000 20095038.0000 13587236.0000 31531946.0000 21643836.0000 18094284.0000 9381936.0000 16966136.0000 15707853.0000 8494545.0000 8234120.0000 Adenosine 2718504.0000 12232565.0000 22841608.0000 13519219.0000 38184288.0000 36275036.0000 145094032.0000 111367736.0000 134419792.0000 194129072.0000 92453864.0000 120906056.0000 Adenosine diphosphate ribose 17452.0000 12323.0000 Adenosine monophosphate 12915472.0000 14613828.0000 25499208.0000 31207134.0000 15806046.0000 29523582.0000 9101147.0000 9102435.0000 8716667.0000 13496443.0000 21271224.0000 13214177.0000 Adenosine triphosphate 2308190.0000 665913.0000 302638.0000 388467.0000 Adenylsuccinic acid ADP 3171900.0000 2520935.0000 2093419.0000 Allantoin 151777.0000 70249.0000 77923.0000 119226.0000 115284.0000 107855.0000 47249.0000 37355.0000 36982.0000 122653.0000 92270.0000 80864.0000 Aminoadipic acid 806428.0000 507501.0000 514690.0000 541170.0000 479036.0000 659234.0000 513881.0000 336770.0000 373138.0000 629196.0000 353145.0000 336641.0000 Argininosuccinic acid 62561.0000 40067.0000 35473.0000 101738.0000 74356.0000 74977.0000 37315.0000 26606.0000 30085.0000 54378.0000 33729.0000 45609.0000 Beta-Alanine 82503.0000 105283.0000 445887.0000 87783.0000 247487.0000 101004.0000 148333.0000 254548.0000 137895.0000 109148.0000 Betaine 88361536.0000 52707804.0000 55134964.0000 67980240.0000 61060900.0000 68629416.0000 46893692.0000 39361348.0000 44916284.0000 45625516.0000 39537860.0000 24891990.0000 Butyrylcarnitine 1798384.0000 1101606.0000 1004029.0000 405564.0000 348414.0000 417572.0000 383887.0000 297983.0000 286018.0000 102157.0000 70902.0000 50220.0000 Carbamoyl phosphate Carnosine 1676182.0000 1577910.0000 1800014.0000 1800111.0000 1449416.0000 1424258.0000 275128.0000 459943.0000 395536.0000 480173.0000 531598.0000 729053.0000 CDP 159213.0000 108902.0000 Choline 78426808.0000 42616200.0000 61627136.0000 73404808.0000 67817264.0000 83447560.0000 82100328.0000 62639256.0000 75769616.0000 79341920.0000 67364088.0000 57035196.0000 cis-Aconitic acid 947891.0000 853014.0000 869566.0000 1884434.0000 821602.0000 1512535.0000 279374.0000 526420.0000 408472.0000 410514.0000 Citric acid 8124778.0000 2806016.0000 1675549.0000 6409892.0000 2457471.0000 2151366.0000 1369532.0000 1450879.0000 1561857.0000 Citrulline 458848.0000 395705.0000 1383332.0000 996755.0000 423878.0000 Creatine 455743360.0000 309733920.0000 376360800.0000 492448672.0000 400311840.0000 552962560.0000 528107328.0000 397231232.0000 438507200.0000 569403136.0000 376101184.0000 340401344.0000 Creatinine 12486196.0000 7149024.0000 6668872.0000 12002201.0000 13863826.0000 10854827.0000 6739481.0000 4530906.0000 5252085.0000 12818453.0000 8538121.0000 5989057.0000 Cyclic AMP 38492.0000 48330.0000 55193.0000 44252.0000 64605.0000 65827.0000 40004.0000 38672.0000 37620.0000 46027.0000 40023.0000 25712.0000 Cytidine 465758.0000 523035.0000 822467.0000 2451325.0000 2781189.0000 4428615.0000 1499353.0000 1728710.0000 1882498.0000 3400592.0000 2326274.0000 2737227.0000 Cytidine monophosphate 126015.0000 125978.0000 267170.0000 399133.0000 168888.0000 389422.0000 313706.0000 151176.0000 186218.0000 439542.0000 417155.0000 270123.0000 Cytidine triphosphate 35577.0000 Cytosine 89443.0000 91591.0000 D-2-Hydroxyglutaric acid 9832902.0000 6928304.0000 6833070.0000 8467581.0000 6931932.0000 7386606.0000 4966380.0000 3460945.0000 3187388.0000 7603922.0000 4483318.0000 3436508.0000 D-Glucose 127606.0000 259947.0000 386343.0000 D-Glyceraldehyde 3-phosphate 494872.0000 199195.0000 337256.0000 760340.0000 475630.0000 528113.0000 297914.0000 1536611.0000 733426.0000 543612.0000 Dihydrofolic acid Dihydroxyacetone phosphate 39590.0000 27877.0000 31754.0000 52645.0000 19034.0000 22056.0000 35454.0000 31514.0000 21382.0000 43829.0000 23225.0000 25630.0000 D-Ribose 5-phosphate 138373.0000 102188.0000 151290.0000 204226.0000 112063.0000 166363.0000 260981.0000 267228.0000 113636.0000 462212.0000 358201.0000 324318.0000 D-Sedoheptulose 7-phosphate 185835.0000 194839.0000 210715.0000 492804.0000 238073.0000 691426.0000 421969.0000 225308.0000 142345.0000 542340.0000 305526.0000 263424.0000 dTDP 35510.0000 49283.0000 35604.0000 44573.0000 FAD 43835.0000 38092.0000 38039.0000 53193.0000 32828.0000 49710.0000 19215.0000 20032.0000 16572.0000 36513.0000 33897.0000 29892.0000 Folic acid Fructose 1_6-bisphosphate Fructose 6-phosphate 258742.0000 291358.0000 191656.0000 374899.0000 106900.0000 258627.0000 127460.0000 213082.0000 95026.0000 298669.0000 244124.0000 430691.0000 Fumaric acid 3904827.0000 3124032.0000 3014572.0000 3738980.0000 3113585.0000 3637065.0000 3163203.0000 2458501.0000 2641429.0000 3948623.0000 2697427.0000 2586967.0000 Glucose 6-phosphate 785180.0000 1028874.0000 680627.0000 831045.0000 197768.0000 524428.0000 268375.0000 402437.0000 225867.0000 441227.0000 435965.0000 599575.0000 Glutathione 52620132.0000 37125696.0000 29882926.0000 35451956.0000 25834686.0000 43729736.0000 10793513.0000 19826476.0000 16631507.0000 31351286.0000 23470454.0000 29373200.0000 Glycerol 3-phosphate 343642.0000 184027.0000 185630.0000 801687.0000 593899.0000 736808.0000 532259.0000 404636.0000 258906.0000 1046306.0000 555235.0000 860610.0000 Glycine 2810433.0000 1918287.0000 1909939.0000 2628048.0000 2599744.0000 2009912.0000 3179273.0000 2378640.0000 3214026.0000 4486654.0000 3180984.0000 3052528.0000 Guanidoacetic acid Guanine 654745.0000 625762.0000 1140162.0000 1367874.0000 2978411.0000 1811671.0000 4049997.0000 3947371.0000 3979727.0000 9047868.0000 7954330.0000 6340194.0000 Guanosine 137620.0000 141301.0000 271547.0000 213822.0000 401587.0000 561966.0000 1323751.0000 1476952.0000 937952.0000 2763993.0000 1255783.0000 2435139.0000 Guanosine diphosphate Guanosine monophosphate 168965.0000 151796.0000 298272.0000 526226.0000 120453.0000 365564.0000 176946.0000 201082.0000 159969.0000 323032.0000 449175.0000 242437.0000 Guanosine triphosphate Homocysteine Hypotaurine 312333.0000 210878.0000 204146.0000 267917.0000 215443.0000 283727.0000 2224543.0000 2386757.0000 2810693.0000 1732345.0000 1084552.0000 1288653.0000 Hypoxanthine 12929929.0000 12283001.0000 18993024.0000 33419862.0000 26504994.0000 46526708.0000 74784720.0000 86057128.0000 75603984.0000 150879056.0000 139521792.0000 115301472.0000 Inosine 1647334.0000 1101056.0000 1501680.0000 2284185.0000 2608747.0000 5895953.0000 6073799.0000 7602577.0000 4489106.0000 12548218.0000 8946998.0000 12439654.0000 Inosinic acid 54345.0000 52645.0000 56128.0000 94246.0000 136618.0000 47336.0000 44209.0000 60200.0000 L-Acetylcarnitine 6846546.0000 3940116.0000 3539773.0000 3747928.0000 3909563.0000 4608620.0000 1033366.0000 811558.0000 1087760.0000 1617760.0000 1264800.0000 1201407.0000 L-Alanine 17005358.0000 12052503.0000 13186808.0000 15251723.0000 13826124.0000 16555750.0000 10896866.0000 8833393.0000 10440218.0000 15104625.0000 11848752.0000 9943576.0000 L-Arginine L-Asparagine 18566394.0000 13540842.0000 14209072.0000 22333840.0000 21086912.0000 21839276.0000 13301042.0000 10082846.0000 11602760.0000 26964530.0000 21101684.0000 19669158.0000 L-Aspartic acid 65476028.0000 53073676.0000 49898676.0000 35721112.0000 31390280.0000 33657964.0000 29714026.0000 31041448.0000 30334876.0000 25158530.0000 21886326.0000 21984880.0000 L-Carnitine 54264724.0000 31123530.0000 29000808.0000 18128362.0000 15385179.0000 17695046.0000 23289908.0000 16527756.0000 16006474.0000 12440643.0000 9202021.0000 6750878.0000 L-Cystathionine 497209.0000 229405.0000 270475.0000 102001.0000 56230.0000 89610.0000 223113.0000 163808.0000 161145.0000 142195.0000 111712.0000 133725.0000 L-Cysteine L-Cystine L-Glutamic acid 253509024.0000 212792384.0000 203460832.0000 301381632.0000 290768192.0000 300588192.0000 203757072.0000 157135904.0000 168793376.0000 296404224.0000 221843232.0000 193731424.0000 L-Glutamine 276856800.0000 197414640.0000 202074512.0000 280831776.0000 253195952.0000 270837952.0000 135612352.0000 115406912.0000 102174656.0000 306161856.0000 232731792.0000 193359792.0000 L-Histidine 11129495.0000 7611391.0000 9158971.0000 12532447.0000 11663807.0000 14401580.0000 8197110.0000 6734412.0000 7046352.0000 16538709.0000 13686776.0000 12645301.0000 L-Isoleucine 13178723.0000 10128688.0000 10139029.0000 17687634.0000 17569698.0000 20825838.0000 10716648.0000 9790375.0000 10608295.0000 28754472.0000 22938424.0000 17443590.0000 L-Kynurenine 43847.0000 29059.0000 34365.0000 55185.0000 48076.0000 58359.0000 32707.0000 17259.0000 25217.0000 61445.0000 51132.0000 39204.0000 L-Lactic acid 4846457.0000 3602150.0000 4666296.0000 8124404.0000 7037520.0000 10231948.0000 9054548.0000 11391582.0000 13112671.0000 23404406.0000 21885868.0000 16824348.0000 L-Leucine 9028232.0000 7536089.0000 7541747.0000 12841553.0000 13643864.0000 16565554.0000 7777373.0000 7096500.0000 8133123.0000 17758058.0000 16885026.0000 13104040.0000 L-Lysine 2795203.0000 3011852.0000 2122288.0000 2027438.0000 2452781.0000 2564040.0000 L-Malic acid 48784440.0000 39072792.0000 36280720.0000 44760220.0000 37871152.0000 44292900.0000 36351044.0000 30381232.0000 32522886.0000 46606180.0000 32869224.0000 31159182.0000 L-Methionine 13885816.0000 9276050.0000 10215711.0000 16225653.0000 15609773.0000 20250830.0000 8095773.0000 6908666.0000 7670687.0000 20395892.0000 14925037.0000 12905367.0000 L-Phenylalanine 12636862.0000 9459003.0000 10170182.0000 16360255.0000 14952344.0000 19325760.0000 9454130.0000 8732441.0000 9201637.0000 26883434.0000 18438626.0000 14288641.0000 L-Proline 212620704.0000 164172624.0000 174754080.0000 286926688.0000 256647408.0000 298978880.0000 227969456.0000 191865760.0000 220018208.0000 401239872.0000 332688928.0000 276524576.0000 L-Serine 3568942.0000 2889386.0000 2835909.0000 6816564.0000 7444380.0000 6872162.0000 2811942.0000 1984207.0000 2515021.0000 6799933.0000 5407826.0000 4441574.0000 L-Threonine 5469120.0000 4980916.0000 3102842.0000 6087730.0000 7639550.0000 7327574.0000 2750377.0000 1934943.0000 2123756.0000 7329418.0000 5497102.0000 4678581.0000 L-Tryptophan 2857821.0000 1879309.0000 2146953.0000 3168217.0000 2806079.0000 3806780.0000 1920514.0000 1685713.0000 1714515.0000 6307342.0000 4020774.0000 2868954.0000 L-Tyrosine 6602682.0000 4705958.0000 5410405.0000 7442766.0000 7299072.0000 9598483.0000 5120105.0000 4221701.0000 4797982.0000 10866463.0000 8801893.0000 7517255.0000 L-Valine 3887265.0000 3176424.0000 3537432.0000 5337976.0000 5749784.0000 7372222.0000 3670175.0000 3393749.0000 4050674.0000 7248268.0000 6730770.0000 5057248.0000 N6-Acetyl-L-lysine N-Acetylglutamic acid 437506.0000 455718.0000 388091.0000 694470.0000 538071.0000 828750.0000 655369.0000 440070.0000 449707.0000 2757565.0000 2290190.0000 1916381.0000 N-Acetylglutamine 85807.0000 35594.0000 42101.0000 119016.0000 109172.0000 130557.0000 34636.0000 148057.0000 59946.0000 54172.0000 N-Acetyl-L-alanine 427204.0000 290222.0000 297521.0000 673519.0000 537957.0000 738934.0000 220137.0000 167928.0000 191910.0000 505876.0000 324494.0000 253040.0000 N-Acetyl-L-methionine 69612.0000 58148.0000 91912.0000 97659.0000 93223.0000 176194.0000 56340.0000 48033.0000 50011.0000 108517.0000 86953.0000 62320.0000 N-Acetyl-L-phenylalanine N-Acetylornithine 374046.0000 218229.0000 240670.0000 490568.0000 423074.0000 519890.0000 183452.0000 133765.0000 144227.0000 605606.0000 450635.0000 340903.0000 N-Acetylserine 4732952.0000 2860668.0000 2789370.0000 5338540.0000 3784712.0000 4668273.0000 1464423.0000 1185714.0000 1169262.0000 3401320.0000 2588735.0000 2288930.0000 NAD 2533599.0000 1896145.0000 1919304.0000 3267393.0000 2551903.0000 3144706.0000 2580686.0000 1900034.0000 1666175.0000 4960302.0000 3074281.0000 2911780.0000 NADH 15579.0000 28131.0000 27216.0000 14330.0000 20065.0000 30144.0000 49607.0000 60028.0000 18534.0000 NADP 61583.0000 31539.0000 29760.0000 39972.0000 NADPH Niacinamide 5869116.0000 5189126.0000 7630274.0000 6654328.0000 8837329.0000 9742746.0000 16595818.0000 17635556.0000 20533556.0000 13661126.0000 10544257.0000 10313584.0000 Nicotinic acid O-Phosphoethanolamine 4801974.0000 2785894.0000 2294260.0000 3367765.0000 1996008.0000 902265.0000 2099551.0000 1536083.0000 1935993.0000 1820756.0000 Ornithine 1517996.0000 1165817.0000 1049842.0000 1470390.0000 1038674.0000 1020994.0000 1173615.0000 1143883.0000 1212533.0000 Orotic acid 59195.0000 25119.0000 23863.0000 Orotidylic acid Oxidized glutathione 3079817.0000 3030681.0000 3757673.0000 4892279.0000 5072525.0000 6289784.0000 3950700.0000 2173352.0000 2248925.0000 6077050.0000 4375543.0000 3896310.0000 Oxoadipic acid 25097.0000 Oxoglutaric acid 6880711.0000 3196041.0000 2341803.0000 5402663.0000 4567458.0000 4975962.0000 2913470.0000 1433569.0000 985727.0000 4467549.0000 1897744.0000 1301978.0000 Palmitic acid 14556558.0000 17228542.0000 13708993.0000 22179464.0000 11970822.0000 34205888.0000 21119342.0000 12307041.0000 10907361.0000 23753020.0000 19121690.0000 19514822.0000 Pantothenic acid 209534336.0000 145566064.0000 143656656.0000 206778032.0000 187038832.0000 217087968.0000 27307240.0000 20111782.0000 19381716.0000 69964536.0000 46718812.0000 37172492.0000 Phenol Phosphocreatine 436748.0000 286412.0000 189162.0000 262313.0000 370011.0000 107944.0000 123003.0000 87539.0000 47179.0000 103746.0000 76859.0000 Phosphoenolpyruvic acid 289097.0000 152739.0000 79329.0000 282647.0000 54135.0000 163533.0000 106211.0000 129373.0000 242479.0000 Phosphoribosyl pyrophosphate Phosphorylcholine 673457024.0000 489061888.0000 482739712.0000 424370496.0000 266840800.0000 433779296.0000 327012448.0000 304131776.0000 230738112.0000 333570656.0000 280216032.0000 271512896.0000 Phosphoserine 46738.0000 47905.0000 34970.0000 65848.0000 56660.0000 71187.0000 71747.0000 61562.0000 63548.0000 51357.0000 Pipecolic acid 138153.0000 71802.0000 93739.0000 141521.0000 164674.0000 143230.0000 85479.0000 115908.0000 69509.0000 188904.0000 192831.0000 149633.0000 Propionylcarnitine 1642776.0000 1010658.0000 985026.0000 683018.0000 742547.0000 994730.0000 1087116.0000 704475.0000 1073099.0000 572786.0000 381385.0000 467678.0000 Pyruvic acid 267907.0000 295622.0000 179844.0000 108064.0000 115342.0000 148865.0000 251081.0000 170506.0000 139110.0000 381668.0000 145988.0000 110256.0000 Ribose 1-phosphate 126579.0000 165453.0000 92561.0000 329455.0000 476211.0000 132206.0000 727042.0000 763124.0000 621438.0000 Saccharopine 17805.0000 11872.0000 S-Adenosylhomocysteine 51106.0000 37028.0000 43673.0000 41036.0000 26697.0000 56410.0000 64326.0000 65125.0000 49298.0000 94842.0000 71409.0000 59398.0000 S-Adenosylmethionine 578064.0000 544771.0000 369511.0000 447068.0000 180378.0000 574530.0000 267361.0000 382906.0000 231041.0000 435587.0000 506756.0000 458114.0000 Sarcosine 9743612.0000 6870772.0000 7225253.0000 9967180.0000 6718418.0000 10012651.0000 6001293.0000 4371680.0000 6222441.0000 9202004.0000 6162220.0000 5641224.0000 Succinic acid 1003028.0000 1324160.0000 1496689.0000 1500859.0000 1231287.0000 998356.0000 1444472.0000 1863140.0000 1430643.0000 1319019.0000 Taurine 6196021.0000 3765482.0000 4011156.0000 7110366.0000 7178212.0000 7201448.0000 29583500.0000 22754908.0000 24874688.0000 28632508.0000 18221562.0000 19427088.0000 Thymidine 104415.0000 Uracil 30202.0000 34601.0000 61444.0000 69502.0000 120421.0000 252771.0000 512980.0000 524190.0000 494080.0000 885843.0000 368586.0000 809055.0000 Ureidopropionic acid 5261248.0000 3907711.0000 3936868.0000 6074508.0000 5874294.0000 6360919.0000 3141551.0000 2668618.0000 2958149.0000 7400816.0000 5356586.0000 5442468.0000 Ureidosuccinic acid 48159.0000 21809.0000 19930.0000 41728.0000 44665.0000 18300.0000 57090.0000 16715.0000 23669.0000 207625.0000 49730.0000 27302.0000 Uric acid Uridine 143938.0000 147888.0000 381725.0000 315088.0000 471512.0000 778838.0000 1286664.0000 1452525.0000 1955792.0000 1985880.0000 1371515.0000 1915616.0000 Uridine 5^-diphosphate 943851.0000 685258.0000 665436.0000 676780.0000 587930.0000 775166.0000 337912.0000 367400.0000 237990.0000 439968.0000 297136.0000 310839.0000 Uridine 5^-monophosphate 1386795.0000 1624698.0000 2720576.0000 3255393.0000 2057009.0000 3255484.0000 2317457.0000 2275336.0000 2138432.0000 2596398.0000 3271485.0000 2238598.0000 Uridine diphosphate glucose 7198456.0000 5317482.0000 5132685.0000 4814032.0000 2593706.0000 5843933.0000 2815648.0000 2527809.0000 1648551.0000 3829184.0000 2577153.0000 2157706.0000 Uridine diphosphate-N-acetylglucosamine 1149853.0000 1027650.0000 949548.0000 1124581.0000 1143384.0000 1340530.0000 1335075.0000 1183256.0000 1165734.0000 2027478.0000 1302075.0000 1183150.0000 Uridine triphosphate 273523.0000 102121.0000 Valerylcarnitine 16817308.0000 10939431.0000 11551312.0000 1117243.0000 1067898.0000 1527041.0000 3015890.0000 2303170.0000 2329298.0000 516413.0000 460126.0000 390392.0000 Xanthine 1377041.0000 1062218.0000 1230535.0000 5240842.0000 4612652.0000 6986999.0000 532931.0000 413088.0000 438820.0000 920099.0000 663628.0000 542279.0000 Xanthosine Xanthylic acid MS_METABOLITE_DATA_END #METABOLITES METABOLITES_START metabolite_name pubchem_id inchi_key kegg_id other_id other_id_type ri ri_type moverz_quant 1-Methylnicotinamide 2,3-Diphosphoglyceric acid 3-Hydroxybutyric acid 3-Phosphoglyceric acid 4,5-Dihydroorotic acid 4-Hydroxyproline 5'-Methylthioadenosine 5-Phosphoribosylamine 6-Phosphogluconic acid Acetoacetic acid Acetyl-CoA Acetylcysteine Adenine Adenosine Adenosine diphosphate ribose Adenosine monophosphate Adenosine triphosphate Adenylsuccinic acid ADP Allantoin Aminoadipic acid Argininosuccinic acid Beta-Alanine Betaine Butyrylcarnitine Carbamoyl phosphate Carnosine CDP Choline cis-Aconitic acid Citric acid Citrulline Creatine Creatinine Cyclic AMP Cytidine Cytidine monophosphate Cytidine triphosphate Cytosine D-2-Hydroxyglutaric acid D-Glucose D-Glyceraldehyde 3-phosphate Dihydrofolic acid Dihydroxyacetone phosphate D-Ribose 5-phosphate D-Sedoheptulose 7-phosphate dTDP FAD Folic acid Fructose 1,6-bisphosphate Fructose 6-phosphate Fumaric acid Glucose 6-phosphate Glutathione Glycerol 3-phosphate Glycine Guanidoacetic acid Guanine Guanosine Guanosine diphosphate Guanosine monophosphate Guanosine triphosphate Homocysteine Hypotaurine Hypoxanthine Inosine Inosinic acid L-Acetylcarnitine L-Alanine L-Arginine L-Asparagine L-Aspartic acid L-Carnitine L-Cystathionine L-Cysteine L-Cystine L-Glutamic acid L-Glutamine L-Histidine L-Isoleucine L-Kynurenine L-Lactic acid L-Leucine L-Lysine L-Malic acid L-Methionine L-Phenylalanine L-Proline L-Serine L-Threonine L-Tryptophan L-Tyrosine L-Valine N6-Acetyl-L-lysine N-Acetylglutamic acid N-Acetylglutamine N-Acetyl-L-alanine N-Acetyl-L-methionine N-Acetyl-L-phenylalanine N-Acetylornithine N-Acetylserine NAD NADH NADP NADPH Niacinamide Nicotinic acid O-Phosphoethanolamine Ornithine Orotic acid Orotidylic acid Oxidized glutathione Oxoadipic acid Oxoglutaric acid Palmitic acid Pantothenic acid Phenol Phosphocreatine Phosphoenolpyruvic acid Phosphoribosyl pyrophosphate Phosphorylcholine Phosphoserine Pipecolic acid Propionylcarnitine Pyruvic acid Ribose 1-phosphate Saccharopine S-Adenosylhomocysteine S-Adenosylmethionine Sarcosine Succinic acid Taurine Thymidine Uracil Ureidopropionic acid Ureidosuccinic acid Uric acid Uridine Uridine 5'-diphosphate Uridine 5'-monophosphate Uridine diphosphate glucose Uridine diphosphate-N-acetylglucosamine Uridine triphosphate Valerylcarnitine Xanthine Xanthosine Xanthylic acid METABOLITES_END #END