#METABOLOMICS WORKBENCH BPnorman_20220926_051418 DATATRACK_ID:3476 STUDY_ID:ST002296 ANALYSIS_ID:AN003750 PROJECT_ID:PR001471 VERSION 1 CREATED_ON September 30, 2022, 8:18 am #PROJECT PR:PROJECT_TITLE Metabolomic analysis in SONIA 2, a phase 3 international randomised-controlled PR:PROJECT_TITLE trial of nitisinone in alkaptonuria (AKU) PR:PROJECT_SUMMARY Abstract from main SONIA 2 publication: Background Alkaptonuria is a rare, PR:PROJECT_SUMMARY genetic, multisystem disease characterised by the accumulation of homogentisic PR:PROJECT_SUMMARY acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA PR:PROJECT_SUMMARY 2 was to investigate the efficacy and safety of once-daily nitisinone for PR:PROJECT_SUMMARY reducing HGA excretion in patients with alkaptonuria and to evaluate whether PR:PROJECT_SUMMARY nitisinone has a clinical benefit. Methods SONIA 2 was a 4-year, open-label, PR:PROJECT_SUMMARY evaluator-blind, randomised, no treatment controlled, parallel-group study done PR:PROJECT_SUMMARY at three sites in the UK, France, and Slovakia. Patients aged 25 years or older PR:PROJECT_SUMMARY with confirmed alkaptonuria and any clinical disease manifestations were PR:PROJECT_SUMMARY randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no PR:PROJECT_SUMMARY treatment. Patients could not be masked to treatment due to colour changes in PR:PROJECT_SUMMARY the urine, but the study was evaluator-blinded as far as possible. The primary PR:PROJECT_SUMMARY endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical PR:PROJECT_SUMMARY evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, PR:PROJECT_SUMMARY 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned PR:PROJECT_SUMMARY patients with a valid u-HGA24 measurement at baseline. Safety variables were PR:PROJECT_SUMMARY analysed in all randomly assigned patients. The study was registered at PR:PROJECT_SUMMARY ClinicalTrials.gov (NCT01916382). Findings Between May 7, 2014, and Feb 16, PR:PROJECT_SUMMARY 2015, 139 patients were screened, of whom 138 were included in the study, with PR:PROJECT_SUMMARY 69 patients randomly assigned to each group. 55 patients in the nitisinone group PR:PROJECT_SUMMARY and 53 in the control group completed the study. u-HGA24 at 12 months was PR:PROJECT_SUMMARY significantly decreased by 99·7% in the nitisinone group compared with the PR:PROJECT_SUMMARY control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% PR:PROJECT_SUMMARY CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score PR:PROJECT_SUMMARY from baseline was significantly lower in the nitisinone group compared with the PR:PROJECT_SUMMARY control group (adjusted mean difference –8·6 points [–16·0 to –1·2], PR:PROJECT_SUMMARY p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone PR:PROJECT_SUMMARY group and 284 events occurred in 57 (83%) patients in the control group. No PR:PROJECT_SUMMARY treatment-related deaths occurred. Interpretation Nitisinone 10 mg daily was PR:PROJECT_SUMMARY well tolerated and effective in reducing urinary excretion of HGA. Nitisinone PR:PROJECT_SUMMARY decreased ochronosis and improved clinical signs, indicating a slower disease PR:PROJECT_SUMMARY progression. PR:INSTITUTE University of Liverpool Institute of Life Course & Medical Sciences PR:DEPARTMENT Department of Musculoskeletal & Ageing Science PR:LAST_NAME Brendan PR:FIRST_NAME Norman PR:ADDRESS William Henry Duncan Building, 6 West Derby Street, Liverpool, UK. L7 8TX PR:EMAIL bnorman@liverpool.ac.uk PR:PHONE +447809606497 PR:FUNDING_SOURCE European Commission for the Framework 7 grant award (DevelopAKUre, project PR:FUNDING_SOURCE number: 304985), Alkaptonuria Society (BPN is funded by the Alkaptonuria Society PR:FUNDING_SOURCE through a Sireau Fellowship Award). #STUDY ST:STUDY_TITLE Comprehensive biotransformation analysis of phenylalanine-tyrosine metabolism ST:STUDY_TITLE reveals alternative routes of metabolite clearance in nitisinone-treated ST:STUDY_TITLE alkaptonuria (Serum metabolomic analysis) ST:STUDY_SUMMARY Background: Metabolomic analyses in alkaptonuria (AKU) have recently revealed ST:STUDY_SUMMARY alternative pathways in phenylalanine-tyrosine (phe-tyr) metabolism from ST:STUDY_SUMMARY biotransformation of homo-gentisic acid (HGA), the active molecule in this ST:STUDY_SUMMARY disease. The aim of this research was to study the phe-tyr metabolic pathway and ST:STUDY_SUMMARY whether the metabolites upstream of HGA, increased in nitisinone-treated ST:STUDY_SUMMARY patients, also undergo phase 1 and 2 biotransformation reactions. Methods: ST:STUDY_SUMMARY Metabolomic analyses were performed on serum and urine from patients partaking ST:STUDY_SUMMARY in the SONIA 2 phase 3 international randomised-controlled trial of nitisinone ST:STUDY_SUMMARY in AKU (EudraCT no. 2013-001633-41). Serum and urine samples were taken from the ST:STUDY_SUMMARY same patients at baseline (pre-nitisinone) then at 24 and 48 months on ST:STUDY_SUMMARY nitisinone treatment (patients N = 47 serum; 53 urine) or no treatment (patients ST:STUDY_SUMMARY N = 45 serum; 50 urine). Targeted feature extraction was per-formed to ST:STUDY_SUMMARY specifically mine data for the entire complement of theoretically predicted ST:STUDY_SUMMARY phase 1 and 2 biotransformation products derived from phenylalanine, tyrosine, ST:STUDY_SUMMARY 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid, in addition to ST:STUDY_SUMMARY phenylalanine-derived metabolites with known increases in phenylketonuria. ST:STUDY_SUMMARY Results: In total, we ob-served 13 phase 1 and 2 biotransformation products from ST:STUDY_SUMMARY phenylalanine through to HGA. Each of these products were observed in urine and ST:STUDY_SUMMARY two were detected in serum. The derivatives of the metabolites upstream of HGA ST:STUDY_SUMMARY were markedly increased in urine of nitisinone-treated patients (fold change ST:STUDY_SUMMARY 1.2-16.2) and increases in 12 of these compounds were directly proportional to ST:STUDY_SUMMARY the degree of nitisinone-induced hypertyrosinaemia (correlation coefficient with ST:STUDY_SUMMARY serum tyrosine = 0.2-0.7). Increases in the urinary phenylalanine metabolites ST:STUDY_SUMMARY were also observed across consecutive visits in the treated group. Conclusions: ST:STUDY_SUMMARY Nitisinone treatment results in marked increases in a wider network of phe-tyr ST:STUDY_SUMMARY metabolites than shown before. This network comprises alternative ST:STUDY_SUMMARY biotransformation products from the major metabolites of this pathway, produced ST:STUDY_SUMMARY by reactions including hydration (phase 1) and bioconjugation (phase 2) of ST:STUDY_SUMMARY acetyl, methyl, acetylcysteine, glucuronide, glycine and sulfate groups. We ST:STUDY_SUMMARY propose that these alternative routes of phe-tyr metabolism, predominantly in ST:STUDY_SUMMARY urine, minimise tyrosinaemia as well as phenylalanaemia. ST:INSTITUTE University of Liverpool Institute of Life Course & Medical Sciences ST:DEPARTMENT Department of Musculoskeletal & Ageing Science ST:LAST_NAME Brendan ST:FIRST_NAME Norman ST:ADDRESS William Henry Duncan Building, 6 West Derby Street, Liverpool, UK. 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RAW_FILE_NAME=P13_V6.d SUBJECT_SAMPLE_FACTORS P15 P15_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P15_V1.d SUBJECT_SAMPLE_FACTORS P15 P15_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P15_V4.d SUBJECT_SAMPLE_FACTORS P15 P15_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P15_V6.d SUBJECT_SAMPLE_FACTORS P16 P16_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P16_V1.d SUBJECT_SAMPLE_FACTORS P16 P16_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P16_V4.d SUBJECT_SAMPLE_FACTORS P16 P16_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P16_V6.d SUBJECT_SAMPLE_FACTORS P17 P17_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P17_V1.d SUBJECT_SAMPLE_FACTORS P17 P17_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P17_V4.d SUBJECT_SAMPLE_FACTORS P17 P17_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P17_V6.d SUBJECT_SAMPLE_FACTORS P18 P18_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P18_V1.d SUBJECT_SAMPLE_FACTORS P18 P18_V4 Trial arm:Treated Time point=24 months; 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RAW_FILE_NAME=P22_V1.d SUBJECT_SAMPLE_FACTORS P22 P22_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P22_V4.d SUBJECT_SAMPLE_FACTORS P22 P22_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P22_V6.d SUBJECT_SAMPLE_FACTORS P23 P23_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P23_V1.d SUBJECT_SAMPLE_FACTORS P23 P23_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P23_V4.d SUBJECT_SAMPLE_FACTORS P23 P23_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P23_V6.d SUBJECT_SAMPLE_FACTORS P24 P24_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P24_V1.d SUBJECT_SAMPLE_FACTORS P24 P24_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P24_V4.d SUBJECT_SAMPLE_FACTORS P24 P24_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P24_V6.d SUBJECT_SAMPLE_FACTORS P25 P25_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P25_V1.d SUBJECT_SAMPLE_FACTORS P25 P25_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P25_V4.d SUBJECT_SAMPLE_FACTORS P25 P25_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P25_V6.d SUBJECT_SAMPLE_FACTORS P26 P26_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P26_V1.d SUBJECT_SAMPLE_FACTORS P26 P26_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P26_V4.d SUBJECT_SAMPLE_FACTORS P26 P26_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P26_V6.d SUBJECT_SAMPLE_FACTORS P28 P28_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P28_V1.d SUBJECT_SAMPLE_FACTORS P28 P28_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P28_V4.d SUBJECT_SAMPLE_FACTORS P28 P28_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P28_V6.d SUBJECT_SAMPLE_FACTORS P29 P29_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P29_V1.d SUBJECT_SAMPLE_FACTORS P29 P29_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P29_V4.d SUBJECT_SAMPLE_FACTORS P29 P29_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P29_V6.d SUBJECT_SAMPLE_FACTORS P3 P3_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P3_V1.d SUBJECT_SAMPLE_FACTORS P3 P3_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P3_V4.d SUBJECT_SAMPLE_FACTORS P3 P3_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P3_V6.d SUBJECT_SAMPLE_FACTORS P30 P30_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P30_V1.d SUBJECT_SAMPLE_FACTORS P30 P30_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P30_V4.d SUBJECT_SAMPLE_FACTORS P30 P30_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P30_V6.d SUBJECT_SAMPLE_FACTORS P31 P31_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P31_V1.d SUBJECT_SAMPLE_FACTORS P31 P31_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P31_V4.d SUBJECT_SAMPLE_FACTORS P31 P31_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P31_V6.d SUBJECT_SAMPLE_FACTORS P32 P32_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P32_V1.d SUBJECT_SAMPLE_FACTORS P32 P32_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P32_V4.d SUBJECT_SAMPLE_FACTORS P32 P32_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P32_V6.d SUBJECT_SAMPLE_FACTORS P33 P33_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P33_V1.d SUBJECT_SAMPLE_FACTORS P33 P33_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P33_V4.d SUBJECT_SAMPLE_FACTORS P33 P33_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P33_V6.d SUBJECT_SAMPLE_FACTORS P34 P34_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P34_V1.d SUBJECT_SAMPLE_FACTORS P34 P34_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P34_V4.d SUBJECT_SAMPLE_FACTORS P34 P34_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P34_V6.d SUBJECT_SAMPLE_FACTORS P35 P35_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P35_V1.d SUBJECT_SAMPLE_FACTORS P35 P35_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P35_V4.d SUBJECT_SAMPLE_FACTORS P35 P35_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P35_V6.d SUBJECT_SAMPLE_FACTORS P36 P36_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P36_V1.d SUBJECT_SAMPLE_FACTORS P36 P36_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P36_V4.d SUBJECT_SAMPLE_FACTORS P36 P36_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P36_V6.d SUBJECT_SAMPLE_FACTORS P37 P37_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P37_V1.d SUBJECT_SAMPLE_FACTORS P37 P37_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P37_V4.d SUBJECT_SAMPLE_FACTORS P37 P37_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P37_V6.d SUBJECT_SAMPLE_FACTORS P39 P39_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P39_V1.d SUBJECT_SAMPLE_FACTORS P39 P39_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P39_V4.d SUBJECT_SAMPLE_FACTORS P39 P39_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P39_V6.d SUBJECT_SAMPLE_FACTORS P40 P40_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P40_V1.d SUBJECT_SAMPLE_FACTORS P40 P40_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P40_V4.d SUBJECT_SAMPLE_FACTORS P40 P40_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P40_V6.d SUBJECT_SAMPLE_FACTORS P41 P41_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P41_V1.d SUBJECT_SAMPLE_FACTORS P41 P41_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P41_V4.d SUBJECT_SAMPLE_FACTORS P41 P41_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P41_V6.d SUBJECT_SAMPLE_FACTORS P42 P42_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P42_V1.d SUBJECT_SAMPLE_FACTORS P42 P42_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P42_V4.d SUBJECT_SAMPLE_FACTORS P42 P42_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P42_V6.d SUBJECT_SAMPLE_FACTORS P43 P43_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P43_V1.d SUBJECT_SAMPLE_FACTORS P43 P43_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P43_V4.d SUBJECT_SAMPLE_FACTORS P43 P43_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P43_V6.d SUBJECT_SAMPLE_FACTORS P44 P44_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P44_V1.d SUBJECT_SAMPLE_FACTORS P44 P44_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P44_V4.d SUBJECT_SAMPLE_FACTORS P44 P44_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P44_V6.d SUBJECT_SAMPLE_FACTORS P46 P46_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P46_V1.d SUBJECT_SAMPLE_FACTORS P46 P46_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P46_V4.d SUBJECT_SAMPLE_FACTORS P46 P46_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P46_V6.d SUBJECT_SAMPLE_FACTORS P47 P47_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P47_V1.d SUBJECT_SAMPLE_FACTORS P47 P47_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P47_V4.d SUBJECT_SAMPLE_FACTORS P47 P47_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P47_V6.d SUBJECT_SAMPLE_FACTORS P48 P48_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P48_V1.d SUBJECT_SAMPLE_FACTORS P48 P48_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P48_V4.d SUBJECT_SAMPLE_FACTORS P48 P48_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P48_V6.d SUBJECT_SAMPLE_FACTORS P49 P49_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P49_V1.d SUBJECT_SAMPLE_FACTORS P49 P49_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P49_V4.d SUBJECT_SAMPLE_FACTORS P49 P49_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P49_V6.d SUBJECT_SAMPLE_FACTORS P5 P5_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P5_V1.d SUBJECT_SAMPLE_FACTORS P5 P5_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P5_V4.d SUBJECT_SAMPLE_FACTORS P5 P5_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P5_V6.d SUBJECT_SAMPLE_FACTORS P50 P50_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P50_V1.d SUBJECT_SAMPLE_FACTORS P50 P50_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P50_V4.d SUBJECT_SAMPLE_FACTORS P50 P50_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P50_V6.d SUBJECT_SAMPLE_FACTORS P52 P52_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P52_V1.d SUBJECT_SAMPLE_FACTORS P52 P52_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P52_V4.d SUBJECT_SAMPLE_FACTORS P52 P52_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P52_V6.d SUBJECT_SAMPLE_FACTORS P55 P55_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P55_V1.d SUBJECT_SAMPLE_FACTORS P55 P55_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P55_V4.d SUBJECT_SAMPLE_FACTORS P55 P55_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P55_V6.d SUBJECT_SAMPLE_FACTORS P6 P6_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P6_V1.d SUBJECT_SAMPLE_FACTORS P6 P6_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P6_V4.d SUBJECT_SAMPLE_FACTORS P6 P6_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P6_V6.d SUBJECT_SAMPLE_FACTORS P60 P60_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P60_V1.d SUBJECT_SAMPLE_FACTORS P60 P60_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P60_V4.d SUBJECT_SAMPLE_FACTORS P60 P60_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P60_V6.d SUBJECT_SAMPLE_FACTORS P61 P61_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P61_V1.d SUBJECT_SAMPLE_FACTORS P61 P61_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P61_V4.d SUBJECT_SAMPLE_FACTORS P61 P61_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P61_V6.d SUBJECT_SAMPLE_FACTORS P7 P7_V1 Trial arm:Treated Time point=Baseline; RAW_FILE_NAME=P7_V1.d SUBJECT_SAMPLE_FACTORS P7 P7_V4 Trial arm:Treated Time point=24 months; RAW_FILE_NAME=P7_V4.d SUBJECT_SAMPLE_FACTORS P7 P7_V6 Trial arm:Treated Time point=48 months; RAW_FILE_NAME=P7_V6.d SUBJECT_SAMPLE_FACTORS P9 P9_V1 Trial arm:Untreated Time point=Baseline; RAW_FILE_NAME=P9_V1.d SUBJECT_SAMPLE_FACTORS P9 P9_V4 Trial arm:Untreated Time point=24 months; RAW_FILE_NAME=P9_V4.d SUBJECT_SAMPLE_FACTORS P9 P9_V6 Trial arm:Untreated Time point=48 months; RAW_FILE_NAME=P9_V6.d #COLLECTION CO:COLLECTION_SUMMARY Serum and urine samples were collected at the three study sites; Liverpool, CO:COLLECTION_SUMMARY Paris and Piešťany. Samples collected at Paris and Piešťany were transported CO:COLLECTION_SUMMARY frozen to the Royal Liverpool University Hospital for metabolite analysis and CO:COLLECTION_SUMMARY storage at -80 °C. Serum samples (S-monovette, Sarstedt, Germany) were CO:COLLECTION_SUMMARY collected from patients after an overnight fast (≥8 h). Samples were CO:COLLECTION_SUMMARY centrifuged at 1500 ×g for 10 min at 4 °C; and the supernatant was stored at CO:COLLECTION_SUMMARY -20 °C until analysis. CO:SAMPLE_TYPE Blood (serum) CO:STORAGE_CONDITIONS -20℃ #TREATMENT TR:TREATMENT_SUMMARY Samples studied were from patients partaking in the SONIA 2 clinical trial of TR:TREATMENT_SUMMARY nitisinone in AKU. SONIA 2 was a 4-year, open-label, evaluator-blind, TR:TREATMENT_SUMMARY randomised, no treatment controlled, parallel-group study undertaken at three TR:TREATMENT_SUMMARY study sites; Liverpool (UK), Paris (France) and Piešťany (Slovakia). The TR:TREATMENT_SUMMARY details and outcomes of the trial are published (1). Serum and urine samples TR:TREATMENT_SUMMARY were collected from participants at baseline (pre-treatment) then at 3 months TR:TREATMENT_SUMMARY and 1, 2, 3 and 4 years on 10 mg oral daily nitisinone (Orfadin®) treatment or TR:TREATMENT_SUMMARY no treatment. The serum and urine samples from visit 1 (baseline; TR:TREATMENT_SUMMARY pre-treatment), visit 4 (2 years), visit 6 (4 years) underwent metabolomic TR:TREATMENT_SUMMARY analysis. In this study, only the data from patients with samples available for TR:TREATMENT_SUMMARY these three time points were included; 53 and 50 patients in treated and TR:TREATMENT_SUMMARY untreated groups respectively for urine, and 47 and 45 patients in treated and TR:TREATMENT_SUMMARY untreated groups respectively for serum. Reference: (1) Ranganath, L.R.; TR:TREATMENT_SUMMARY Psarelli, E.E.; Arnoux, J.B.; Braconi, D.; Briggs, M.; Bröijersén, A.; Loftus, TR:TREATMENT_SUMMARY N.; Bygott, H.; Cox, T.F.; Davison, A.S.; et al. Efficacy and Safety of TR:TREATMENT_SUMMARY Once-Daily Nitisinone for Patients with Alkaptonuria (SONIA 2): An TR:TREATMENT_SUMMARY International, Multicentre, Open-Label, Randomised Controlled Trial. Lancet TR:TREATMENT_SUMMARY Diabetes Endocrinol. 2020, 8, 762–772, doi:10.1016/S2213-8587(20)30228-X. TR:TREATMENT_PROTOCOL_ID Clinical trial ID: EudraCT no. 2013-001633-41 TR:TREATMENT_COMPOUND Nitisinone (NTBC) TR:TREATMENT_DOSE 10 mg daily TR:TREATMENT_DOSEDURATION 48 months total #SAMPLEPREP SP:SAMPLEPREP_SUMMARY Serum samples were prepared using the Agilent Bravo metabolomics platform. This SP:SAMPLEPREP_SUMMARY automated platform was programmed to pipette 100 µL of serum into a 96-well SP:SAMPLEPREP_SUMMARY plate from a 96-well plate that contained 200 µL of serum. Following this, 450 SP:SAMPLEPREP_SUMMARY μL of a 1:1 mixture of methanol:ethanol was added to the plate to precipitate SP:SAMPLEPREP_SUMMARY proteins. The supernatant was then applied to a Captiva EMR-lipid 96-well plate SP:SAMPLEPREP_SUMMARY and left to stand for 5 min and a vacuum was applied to the plate (2-5 Hg) to SP:SAMPLEPREP_SUMMARY initiate flow. Eluents were collected into 1 mL 96-well plates and subsequently SP:SAMPLEPREP_SUMMARY dried under a stream of nitrogen. Prior to analysis, samples were reconstituted SP:SAMPLEPREP_SUMMARY with 100 µL of 10 % methanol and were agitated on a plate shaker (MTS 2/4m IKA) SP:SAMPLEPREP_SUMMARY at 600 rpm for 10 min. #CHROMATOGRAPHY CH:CHROMATOGRAPHY_SUMMARY Analysis of serum and urine samples was performed using a published LC-QTOF-MS CH:CHROMATOGRAPHY_SUMMARY acquisition method, which employed a 1290 Infinity II HPLC coupled to a 6550 CH:CHROMATOGRAPHY_SUMMARY QTOF-MS equipped with dual AJS electrospray ionisation source (Agilent, Cheadle, CH:CHROMATOGRAPHY_SUMMARY UK). Data acquisition parameters are detailed in brief below and in full in CH:CHROMATOGRAPHY_SUMMARY Supplementary Materials. Reversed-phase LC was performed on an Atlantis dC18 CH:CHROMATOGRAPHY_SUMMARY column (3×100 mm, 3 μm, Waters, Manchester, UK) maintained at 60 °C. Mobile CH:CHROMATOGRAPHY_SUMMARY phase composition was (A) water and (B) methanol, both with 5 mmol/L ammonium CH:CHROMATOGRAPHY_SUMMARY formate and 0.1 % formic acid. The elution gradient began at 5 % B 0–1 min and CH:CHROMATOGRAPHY_SUMMARY increased linearly to 100 % B by 12 min, held at 100 % B until 14 min, then at 5 CH:CHROMATOGRAPHY_SUMMARY % B for a further 5 min. MS data acquisition was performed in positive and CH:CHROMATOGRAPHY_SUMMARY negative ionisation polarity with mass range 50–1700 in 2 GHz mode with CH:CHROMATOGRAPHY_SUMMARY acquisition rate at 3 spectra/second. Sample injection volume was 1 and 2 µL in CH:CHROMATOGRAPHY_SUMMARY negative and positive polarities, respectively. CH:CHROMATOGRAPHY_TYPE Reversed phase CH:INSTRUMENT_NAME Agilent 1290 Infinity II CH:COLUMN_NAME Waters Atlantis dC18 (3x100 mm, 3 µm) #ANALYSIS AN:ANALYSIS_TYPE MS #MS MS:INSTRUMENT_NAME Agilent 6550 QTOF MS:INSTRUMENT_TYPE QTOF MS:MS_TYPE ESI MS:ION_MODE NEGATIVE MS:MS_COMMENTS MS acquisition conditions detailed in attached Supplementary Materials. Raw data MS:MS_COMMENTS were mined using the targeted feature extraction function in Masshunter MS:MS_COMMENTS Profinder (build 10.00, Agilent) with mass targets based on chemical formulae of MS:MS_COMMENTS known/predicted phe-tyr pathway metabolites from the customised compound MS:MS_COMMENTS databases described below. A combined compound database was compiled using PCDL MS:MS_COMMENTS Manager (Agilent, build 08.00). Accurate mass retention time (AMRT) matched MS:MS_COMMENTS metabolites were present in our published AMRT database, which was generated MS:MS_COMMENTS from chemical standards using the same LC-QTOF-MS methodology employed here: MS:MS_COMMENTS phenylalanine, phenylethylamine, tyrosine, N-acetyl-tyrosine, tyramine, HPPA, MS:MS_COMMENTS HPLA and HGA. Other established phenylalanine metabolites added to the database MS:MS_COMMENTS for mining by accurate mass alone were hydroxyphenylacetic acid, MS:MS_COMMENTS phenylacetaldehyde, phenylacetamide, phenylacetic acid, phenylacetylglutamine, MS:MS_COMMENTS phenylethylamine, phenyllactic acid and phenylpyruvic acid. The remaining MS:MS_COMMENTS formulae were from non-established but theoretically possible phase 1 and 2 MS:MS_COMMENTS biotransformation products derived from phenylalanine (n=74), tyrosine (n=74), MS:MS_COMMENTS HPPA (n=67) and HPLA (n=67) predicted using the Biotransformation Mass Defects MS:MS_COMMENTS tool (Agilent), in addition to the HGA biotransformation products (n=7) MS:MS_COMMENTS previously established by our group. Feature extraction parameters were accurate MS:MS_COMMENTS mass match window ±5 ppm with addition of matched retention time (RT; window MS:MS_COMMENTS ±0.3 min) for AMRT database metabolites. Allowed ion species were: H+, Na+, and MS:MS_COMMENTS NH4+ in positive polarity, and H− and CHO2- in negative polarity. Charge state MS:MS_COMMENTS range was 1–2, and dimers were allowed. ‘Find by formula’ filters were: MS:MS_COMMENTS score >60 in at least 60 % of samples in at least one sample group. Where MS:MS_COMMENTS compounds were detected in both positive and negative ionisation, the polarity MS:MS_COMMENTS with the clearest signal was selected for further analysis. Extracted peak area MS:MS_COMMENTS intensity data were exported in .csv file format and imported into Mass Profiler MS:MS_COMMENTS Professional (MPP; build 15.1, Agilent), in which all statistical analyses were MS:MS_COMMENTS performed unless stated otherwise. In MPP, all data were log2 transformed and MS:MS_COMMENTS pareto scaled. Urine data were normalised to 24-h creatinine values. QC was MS:MS_COMMENTS performed based on compound signal intensity data from the pooled samples MS:MS_COMMENTS interspersed throughout each analytical sequence. Compounds were retained for MS:MS_COMMENTS subsequent statistical analyses if a) observed in 100 % of replicate injections MS:MS_COMMENTS for at least one sample group pool, and b) peak area coefficient of variation MS:MS_COMMENTS (CV) remained <30% across replicate injections for each sample group pool across MS:MS_COMMENTS batches 1 and 2 combined. #MS_METABOLITE_DATA MS_METABOLITE_DATA:UNITS peak area (pareto-scaled, log2-transformed) MS_METABOLITE_DATA_START Samples F1_V1 F1_V4 F1_V6 F10_V1 F10_V4 F10_V6 F12_V1 F12_V4 F12_V6 F14_V1 F14_V4 F14_V6 F15_V1 F15_V4 F15_V6 F16_V1 F16_V4 F16_V6 F2_V1 F2_V4 F2_V6 F20_V1 F20_V4 F20_V6 F23_V1 F23_V4 F23_V6 F24_V1 F24_V4 F24_V6 F26_V1 F26_V4 F26_V6 F29_V1 F29_V4 F29_V6 F3_V1 F3_V4 F3_V6 F31_V1 F31_V4 F31_V6 F4_V1 F4_V4 F4_V6 F5_V1 F5_V4 F5_V6 F6_V1 F6_V4 F6_V6 F7_V1 F7_V4 F7_V6 F9_V1 F9_V4 F9_V6 L10_V1 L10_V4 L10_V6 L11_V1 L11_V4 L11_V6 L12_V1 L12_V4 L12_V6 L14_V1 L14_V4 L14_V6 L15_V1 L15_V4 L15_V6 L17_V1 L17_V4 L17_V6 L18_V1 L18_V4 L18_V6 L19_V1 L19_V4 L19_V6 L21_V1 L21_V4 L21_V6 L23_V1 L23_V4 L23_V6 L24_V1 L24_V4 L24_V6 L28_V1 L28_V4 L28_V6 L29_V1 L29_V4 L29_V6 L3_V1 L3_V4 L3_V6 L30_V1 L30_V4 L30_V6 L31_V1 L31_V4 L31_V6 L33_V1 L33_V4 L33_V6 L35_V1 L35_V4 L35_V6 L36_V1 L36_V4 L36_V6 L37_V1 L37_V4 L37_V6 L38_V1 L38_V4 L38_V6 L4_V1 L4_V4 L4_V6 L40_V1 L40_V4 L40_V6 L6_V1 L6_V4 L6_V6 L7_V1 L7_V4 L7_V6 L8_V1 L8_V4 L8_V6 L9_V1 L9_V4 L9_V6 P1_V1 P1_V4 P1_V6 P11_V1 P11_V4 P11_V6 P12_V1 P12_V4 P12_V6 P13_V1 P13_V4 P13_V6 P15_V1 P15_V4 P15_V6 P16_V1 P16_V4 P16_V6 P17_V1 P17_V4 P17_V6 P18_V1 P18_V4 P18_V6 P2_V1 P2_V4 P2_V6 P20_V1 P20_V4 P20_V6 P21_V1 P21_V4 P21_V6 P22_V1 P22_V4 P22_V6 P23_V1 P23_V4 P23_V6 P24_V1 P24_V4 P24_V6 P25_V1 P25_V4 P25_V6 P26_V1 P26_V4 P26_V6 P28_V1 P28_V4 P28_V6 P29_V1 P29_V4 P29_V6 P3_V1 P3_V4 P3_V6 P30_V1 P30_V4 P30_V6 P31_V1 P31_V4 P31_V6 P32_V1 P32_V4 P32_V6 P33_V1 P33_V4 P33_V6 P34_V1 P34_V4 P34_V6 P35_V1 P35_V4 P35_V6 P36_V1 P36_V4 P36_V6 P37_V1 P37_V4 P37_V6 P39_V1 P39_V4 P39_V6 P40_V1 P40_V4 P40_V6 P41_V1 P41_V4 P41_V6 P42_V1 P42_V4 P42_V6 P43_V1 P43_V4 P43_V6 P44_V1 P44_V4 P44_V6 P46_V1 P46_V4 P46_V6 P47_V1 P47_V4 P47_V6 P48_V1 P48_V4 P48_V6 P49_V1 P49_V4 P49_V6 P5_V1 P5_V4 P5_V6 P50_V1 P50_V4 P50_V6 P52_V1 P52_V4 P52_V6 P55_V1 P55_V4 P55_V6 P6_V1 P6_V4 P6_V6 P60_V1 P60_V4 P60_V6 P61_V1 P61_V4 P61_V6 P7_V1 P7_V4 P7_V6 P9_V1 P9_V4 P9_V6 Factors Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated Trial arm:Treated Trial arm:Treated Trial arm:Treated Trial arm:Untreated Trial arm:Untreated Trial arm:Untreated HPPA -1.3971331 2.8457863 2.4980693 -2.1469307 -1.1691493 -1.4584287 -2.155641 -1.2148578 -1.301937 -1.7536641 -0.86793715 -1.5842042 -1.238412 2.7553978 3.5240147 -1.9062439 -0.70892954 3.0236723 -1.1745858 -0.87793475 0.6131775 -1.0794888 2.4782186 2.9057345 -1.3860476 -1.4417288 -1.0796133 -0.81023294 2.796874 3.0506737 -1.8944703 3.1559935 3.1205285 -1.2041315 3.2631211 2.9113119 -0.99259716 -1.1927136 -1.2585303 -1.0598472 2.7566264 2.769345 -0.94679666 2.2558713 -0.8079479 -0.9298228 2.8620915 3.0965567 -1.3653257 -1.4155475 -1.4072115 -1.298469 -1.5285087 -0.8550589 -0.7299675 2.5385842 2.3059728 -1.8913168 1.9485707 2.7104235 -1.2945156 -1.046441 -1.5263394 -2.2809002 2.0851216 2.9864714 -1.2220643 1.6180177 2.3674302 -2.0508108 -0.93364906 -0.95391005 -1.905815 -0.096967 -0.44278044 -1.8924489 2.3231285 2.9450715 -1.7851596 2.144829 2.694841 -2.2021232 -0.51168907 -0.9972151 -1.9399456 -0.5151002 -0.8448966 -1.2702855 -0.5052032 -0.9655927 -2.4549081 3.3259597 4.2154737 -1.0080669 -0.40938357 -0.8777056 -1.0215601 -0.7578968 -0.27600035 -1.5992258 2.4497292 2.782022 -1.338933 -1.4953207 -0.57947063 -1.7856276 3.133539 2.597566 -1.3072953 -0.8495659 -0.6310482 -1.9294373 -1.0103698 -1.1871221 -3.885317 -1.236468 -1.0401096 -1.4680982 -1.1437881 -0.7669371 -1.3567457 -1.2375314 -0.9911048 -1.0077991 2.2310743 2.2284746 -2.3126564 3.0842078 2.3121781 -1.9687485 2.3876185 2.475644 -1.6570153 2.4452932 1.7331456 -1.4515634 -0.9175568 -1.0256866 -2.5322187 -1.4266168 -1.7223802 -1.5793586 2.1903825 2.8487082 -2.17988 -1.0675877 -0.90103066 -1.6245061 -0.5656823 -0.51726437 -1.6170737 2.5222242 2.3338401 -1.1079847 -1.2007539 -1.1864905 -0.5510398 -0.4233513 -0.7543596 -1.3844556 2.2836766 2.689053 -1.0640038 2.806491 3.0881033 -2.151192 -1.2350167 -1.0764878 -1.35504 -1.1246405 -0.5001106 -1.2364197 2.9511793 3.0431461 -2.2573211 2.9024723 2.835278 -1.3766917 -0.67061996 -1.2107205 -1.523184 -0.4816586 -0.9846397 -2.0634048 2.7716997 2.7239926 -1.5404251 -0.7610741 -0.97668433 -1.4319588 -1.1360811 -1.3127714 -1.8454984 2.3342335 2.3341165 -1.6086258 2.7252753 0.84886724 -1.2691529 2.6685925 2.9753463 -0.78437686 -0.9026435 -0.8313573 -2.1285799 -0.7737573 -0.7817579 -1.6832063 2.5668743 2.2503042 -0.9997833 -1.0071558 -1.0764288 -1.8895937 2.4790416 2.7624974 -1.3648323 -1.0584178 -0.9684657 -1.9351763 2.5748227 2.4670923 -1.3490582 0.20323546 -0.7505867 -1.317769 -0.8581819 -0.33130154 -1.0467805 -1.0609747 -0.7330752 -1.2950776 2.5718837 2.6154563 -1.133667 2.7366424 2.7035046 -0.8732792 2.76123 2.8559592 -1.4302438 2.1990554 2.50798 -1.4897474 1.4197148 2.3685753 -1.0755706 -1.0255505 -0.7199688 -1.3283306 -0.8839491 -0.6664756 -2.0623033 -0.91025233 -1.2626055 -1.320049 2.4922767 2.137023 -1.5175664 3.057682 2.915937 -0.69952184 -2.1842494 -0.98277843 -1.1591156 3.099014 2.869991 -1.471493 -1.2606025 -0.9379256 -2.2795815 2.8998635 2.498539 -1.1436133 -1.2659445 -1.3949023 HPLA -1.2043579 2.5980015 2.7057052 -1.8654467 -1.5202448 -1.7173547 -2.3604672 -1.5500835 -1.684626 -1.4129634 -1.301867 -1.6113932 -1.3340558 3.0937464 3.2439227 -1.5103893 -1.1868527 3.1657054 -0.744242 -1.0192164 -0.37581348 -1.235664 2.8391087 2.880188 -0.9040885 -0.64269876 -1.2517765 -0.9907875 2.8104336 3.0362787 -1.7682644 3.1086931 3.3727498 -1.560053 2.497952 2.7529743 -1.0740693 -1.3788155 -1.1348782 -1.4213042 2.6471238 2.7649808 -0.8101502 2.2420506 -1.1944852 -1.0417907 2.880188 2.846111 -1.1124938 -1.3906248 -1.0940765 -1.0588669 -1.6166371 -0.9894726 -0.81115466 2.86674 3.047056 -1.9530582 1.8680252 3.1329694 -1.7415968 -1.7155807 -1.9597416 -1.5018065 2.506272 3.0142555 -1.1676419 2.111293 2.5736167 -1.5768154 -0.92705405 -1.3463787 -1.643389 -0.37136763 -1.017561 -1.750501 3.0086474 2.9857955 -1.7665774 2.5323405 2.7799797 -1.855453 -0.9212692 -1.2598982 -1.365262 -1.096766 -1.0737684 -1.0395924 -0.89054304 -1.3755946 -1.8085778 3.1329694 3.5816784 -1.0883199 -0.810324 -1.4994545 -1.0105095 -1.2558185 -1.1603389 -1.0067829 2.4925005 3.0198224 -1.1335458 -1.470322 -0.7671201 -1.5579627 3.0198224 2.8999221 -1.2499729 -1.3380636 -1.0909406 -1.6381868 -1.1399734 -1.1501157 -3.226761 -1.4388912 -1.4628537 -1.6106669 -1.4987342 -1.1643145 -1.1615638 -1.3239291 -1.0908376 -0.94740385 3.1424677 3.1471717 -1.9345616 3.103745 2.9973078 -1.805704 2.7426713 2.880188 -1.4716152 2.7451563 2.0268793 -1.4603549 -1.1665993 -1.15E+00 -1.9528372 -1.3423373 -1.6821927 -1.585701 1.9424142 3.24E+00 -1.56E+00 -1.31E+00 -1.3509406 -1.4157348 -1.2991389 -1.35E+00 -1.34E+00 2.5386777 2.3727088 -0.8829964 -1.19E+00 -1.1770006 -6.70E-01 -1.3168615 -1.09E+00 -1.2967045 2.70E+00 2.37E+00 -0.73485816 2.7502823 2.7191875 -1.3028128 -1.2834674 -1.34E+00 -1.40E+00 -1.16E+00 -1.0439347 -1.1566167 2.90E+00 2.4790194 -1.411751 3.1184988 3.0362787 -1.088801 -1.18E+00 -1.35E+00 -1.143926 -1.1476251 -1.0770953 -1.4748577 3.0523887 3.128176 -1.18E+00 -1.0924714 -0.45502406 -1.0914433 -1.4089832 -1.3377075 -1.6873336 2.5090706 2.3861961 -1.5685002 2.6136231 -0.14180094 -0.94998336 2.846111 3.1882513 -1.2344451 -1.1919951 -1.2046949 -1.8586503 -1.2222693 -1.3214957 -1.4196317 2.6498199 2.4878097 -0.8208118 -1.1921161 -1.2218724 -1.2049214 2.2646365 2.5050316 -0.95369494 -1.1548785 -0.94020975 -1.4595851 2.4803042 2.2256634 -1.2851474 -0.56193024 -1.0704732 -1.1219118 -1.1890168 -0.82590955 -0.7924361 -1.14E+00 -1.02E+00 -0.7019523 3.06E+00 2.44E+00 -1.08E+00 2.846111 2.880188 -0.8924626 2.58E+00 2.63E+00 -7.03E-01 2.72E+00 2.968194 -1.20E+00 0.859842 2.03E+00 -7.60E-01 -9.82E-01 -0.6468533 -9.98E-01 -0.95876354 -0.8087088 -1.81E+00 -1.24E+00 -1.30E+00 -1.2548422 2.76E+00 2.342953 -1.4720582 2.7378047 2.85E+00 -0.76566964 -2.75E+00 -1.2532114 -1.29E+00 2.5634713 2.7145488 -1.363491 -0.98323077 -0.9692966 -1.92E+00 2.919159 2.8104336 -1.23E+00 -1.3305541 -1.70E+00 HGA 1.4957378 -2.6906478 -2.825116 0.4926706 0.70240873 0.80839694 0.28657162 1.9972298 0.37087855 0.3022636 1.3631636 1.4749205 2.4407172 -2.604559 -2.6169484 0.96084005 -0.11841314 -2.685636 0.96517754 1.2888703 1.6632975 2.0466 -2.77105 -2.612381 1.0335201 2.4723492 2.741513 1.5687157 -3.3660564 -2.7399957 0.9047547 -2.6095836 -2.5721416 1.3111545 -2.4852178 -2.7292125 1.1971846 1.6479706 1.9434041 1.3205217 -2.582491 -2.5102286 1.9186367 -1.618494 1.4850186 2.453631 -2.6302693 -3.0962024 1.792009 2.0636826 1.4081923 1.6616234 1.236229 2.1232882 2.0628705 -2.7145894 -2.6263537 0.83835274 -2.6605575 -2.302729 1.6294445 -0.16066572 0.46019387 0.30891874 -2.947154 -2.34879 1.284169 -2.46695 -1.6309073 0.9750723 0.8846419 1.148107 0.526972 2.256393 2.2649236 1.2106361 -2.5515192 -2.1663373 0.18701081 -2.958099 -2.5580416 1.0827185 1.1792877 1.5031167 0.62078846 0.4734716 1.3533105 1.2120297 0.81507343 1.487993 1.2549562 -2.6075115 -1.6537484 1.2799301 1.016959 1.2594717 0.69889665 1.1650982 2.948787 2.2607305 -1.9302093 -2.5387983 2.3467066 1.1597472 2.465564 1.2891753 -2.422614 -2.6814616 1.8060238 1.4034553 2.138483 1.0981421 2.0833857 2.0486097 -1.7120625 1.3151717 1.6692574 -0.001330622 1.568669 1.2109869 2.1926615 1.2359179 1.6700991 1.9913818 -2.781941 -3.186385 0.53621215 -2.6294026 -2.6352873 0.4897735 -2.5650012 -2.2581694 1.0078652 -2.5105438 -2.9139028 1.5115762 1.1675012 1.4348087 -1.0234317 -1.6808797 -1.3346391 1.0120624 -2.9231234 -2.189563 0.7288473 1.0338576 1.5843803 0.6422166 1.2460048 1.52258 0.7479294 -2.2862659 -2.2618837 0.6595574 0.33738735 0.62460446 1.6900381 1.3048937 1.597475 0.72338355 -2.7346983 -0.51882 0.38993418 -2.8582153 -2.692621 0.7224687 0.3783398 0.4512953 1.0247353 1.0519964 2.2833154 1.0519465 -2.3330796 -2.8740861 -0.36122316 -2.8111143 -3.142213 0.40923685 0.99936306 0.89440453 1.2407738 1.7474794 1.0325919 0.2988735 -3.022208 -2.9392164 0.75576675 1.2312684 1.8413193 0.87983274 0.6711711 0.6460387 0.968222 -2.9447117 -3.1311178 0.7161266 -2.6801255 -2.8926117 0.3774971 -2.697365 -2.8089483 2.4728715 1.7632152 1.7207543 0.24433124 0.3219149 0.60651755 0.54508835 -2.4593556 -2.8644226 0.6400362 0.47334254 0.59351015 1.4669734 -2.5019984 -2.4698176 2.1720262 1.3738289 1.5612687 0.95952773 -3.13128 -2.1756525 1.4624052 1.6713057 1.4634563 1.8000233 1.9091098 2.6296706 1.9072242 1.1689528 1.8650916 1.4167341 -2.554118 -1.7058587 1.8669702 -2.7204242 -2.355566 2.3966703 -2.7288613 -2.2436209 1.9015561 -2.6780462 -2.423171 1.1203713 -2.8357487 -0.96308506 2.5922353 1.5320377 2.358789 1.3132932 1.2376968 1.932992 1.3592387 0.7672158 0.63192946 1.5775472 -2.9902267 -1.501406 2.096024 -2.354765 -2.2949042 1.2523428 -0.8878175 1.4702182 1.6130145 -2.8374162 -2.8530803 0.9249783 1.002935 1.0873224 0.15897729 -2.6097062 -2.5821006 1.3492484 0.8874617 0.25543365 MS_METABOLITE_DATA_END #METABOLITES METABOLITES_START metabolite_name retention time neutral mass formula CAS-ID KEGG-ID HPPA 3.9000113 180.0422 C9 H8 O4 C01179 HPLA 4.859988 182.0577 C9 H10 O4 6482-98-0 HGA 3.669996 168.0423 C8 H8 O4 451-13-8 C00544 METABOLITES_END #END