#METABOLOMICS WORKBENCH BPnorman_20220926_051418 DATATRACK_ID:3476 STUDY_ID:ST002296 ANALYSIS_ID:AN003751 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 POSITIVE 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 Phenylalanine -4.92E-01 5.02E-01 -1.28E-01 -8.23E-01 0.39282158 0.20066887 -2.04E+00 0.024696834 -1.42E-01 -1.31E+00 8.85E-01 -4.45E-01 -0.3986332 -0.25179672 8.92E-01 2.45E-01 2.12E-01 7.87E-01 -6.11E+00 1.00E+00 8.45E-01 0.27766 -2.80E-01 6.50E-01 5.68E-01 4.53E-01 1.36E+00 1.12E+00 2.45E-01 2.01E-01 -2.26E+00 1.01E+00 8.04E-01 -1.28E-01 1.12E+00 -1.82E-01 1.15E+00 -0.06318467 2.23E-01 -5.41E-01 -2.95E-01 4.91E-02 2.45E-01 -6.77E-01 3.41E-01 6.94E-01 3.69E-02 1.12E+00 8.51E-02 5.40E-01 0.036936864 7.28E-01 -6.94E-01 4.13E-01 1.24E-02 -3.99E-01 7.62E-01 1.32E-01 -1.40E+00 7.37E-01 -0.73027015 -0.3834435 -9.25E-01 -1.02E-01 -7.61E-02 9.39E-01 0.16672298 -1.22E+00 -7.74E-06 -1.05E+00 -1.37E+00 1.67E-01 -1.45E+00 -5.04E-02 1.09E-01 2.45E-01 6.41E-01 6.50E-01 -9.29E-01 -0.67678875 -0.07607244 -0.28029487 -0.5907859 3.31E-01 5.58E-01 -8.90E-02 -7.74E-06 7.32E-02 -7.85E-01 0.16672298 -1.17E+00 4.13E-01 1.28E+00 2.78E-01 -4.76E-01 -1.15E-01 2.34E-01 3.10E-01 8.28E-01 -7.85E-01 5.77E-01 2.34E-01 -1.82E-01 2.34E-01 0.40296355 -4.92E-01 9.00E-01 8.77E-01 4.53E-01 -6.08E-01 1.21E-01 -7.85E-01 4.23E-01 5.02E-01 1.21E-01 4.23E-01 1.21E-01 -1.22E+00 1.67E-01 2.78E-01 -2.52E-01 2.88E-01 8.51E-02 -3.68E-01 -7.61E-02 -7.61E-02 -1.36E+00 6.85E-01 -2.66E-01 -5.74E-01 -3.39E-01 3.62E-01 -4.14E-01 -6.25E-01 -0.35341248 5.40E-01 0.5584246 6.23E-01 8.51E-02 -8.23E-01 -0.12847257 1.55E-01 -1.13E+00 4.92E-01 -1.25E-02 4.33E-01 8.28E-01 -4.92E-01 1.47E+00 3.20E-01 -1.02E-01 -0.29470265 -2.66E-01 0.6407241 -6.32E-02 7.71E-01 1.01E+00 3.52E-01 -1.15E-01 1.55E-01 -1.82E-01 6.32E-01 2.12E-01 -5.74E-01 6.05E-01 -5.74E-01 2.99E-01 -1.82E-01 -5.41E-01 2.67E-01 7.45E-01 3.83E-01 0.13217323 1.48E+00 -0.6419319 -2.95E-01 6.05E-01 -8.04E-01 4.73E-01 -5.57E-01 -4.14E-01 0.74531794 6.12E-02 2.56E-01 4.73E-01 6.12E-02 4.33E-01 2.34E-01 1.00E+00 -5.91E-01 8.28E-01 -1.96E-01 -1.43E+00 -4.29E-01 -6.59E-01 -0.025034899 3.93E-01 6.12E-02 3.20E-01 -8.99E-01 -7.61E-02 1.10E+00 -2.38E-01 7.96E-01 -3.99E-01 -2.52E-01 3.83E-01 4.91E-02 -4.92E-01 5.02E-01 -7.74E-06 -2.38E-01 -1.82E-01 -1.17E+00 -1.28E+00 -1.02E-01 6.12E-02 3.52E-01 3.93E-01 -1.23E+00 -7.85E-01 -5.91E-01 -8.92E-01 -4.29E-01 -1.55E-01 -6.77E-01 -2.95E-01 -1.28E-01 -5.57E-01 5.68E-01 4.03E-01 7.20E-01 1.21E-01 -5.04E-02 4.91E-02 3.72E-01 -3.09E-01 9.92E-01 -3.83E-01 -1.82E-01 6.76E-01 -9.93E-01 4.33E-01 -2.38E-01 -1.25E-02 4.63E-01 8.92E-01 -1.42E-01 -1.02E-01 3.69E-02 -1.02E-01 1.01E+00 -1.70E+00 -1.96E-01 8.37E-01 -5.74E-01 -3.24E-01 -1.55E-01 -1.13E+00 -1.96E-01 8.51E-02 6.94E-01 8.04E-01 4.73E-01 -6.59E-01 1.10E+00 1.28E+00 2.01E-01 -1.04E+00 9.70E-02 1.55E-01 3.69E-02 2.99E-01 5.40E-01 -8.86E-01 4.92E-01 Phenylacetylglutamine -2.2640014 0.18050127 -0.25659811 -1.1333082 2.0343068 1.801992 -1.5450883 0.46170717 -0.25777137 0.69985753 0.91684175 1.6294676 -2.3413565 -1.6546441 -0.22462991 -0.3515401 0.70299184 0.9795099 -3.2556107 0.35138386 0.35041267 -0.17556036 -0.15853542 0.18698388 1.0079803 1.7258952 1.9512144 2.2893581 -1.094066 0.5596986 -1.1966249 1.9332268 1.8161476 -0.22697641 0.13095969 0.3457519 1.4014435 1.3315628 0.6660301 -0.801946 0.008847802 0.19158182 0.05410216 0.4739542 -0.079760954 0.9563419 1.1400064 1.9167163 1.3718405 0.92986304 0.25520414 0.7011717 -0.54106236 0.8899367 0.5502599 0.15268612 -0.25494775 0.42987478 0.16538478 2.0630505 -0.26040822 0.31531522 -0.72346526 0.038019568 0.5605781 1.765745 0.18041976 -0.18685144 0.9959796 -3.3853717 -2.7583747 -1.1905565 -1.799761 -0.24211836 0.6195227 -0.10467946 0.45136184 0.90244687 0.065965444 -0.01481595 0.9702783 0.13450661 -0.16376498 1.4712768 0.14524929 1.4367753 0.21704875 1.1095985 -0.46060014 0.16955994 -0.6238524 -1.6139011 0.026030635 0.46983507 -0.48747975 0.14763145 0.46911347 -0.5797152 0.82670826 -0.27023742 0.53180027 0.25672886 0.41061202 0.75819427 1.143572 -1.0872676 -0.089388095 -0.4439114 -1.163991 -0.9755758 0.18425195 -1.4418894 -0.14055456 -0.41886556 0.23425874 0.51158494 0.24742433 -1.9077429 -0.29675537 0.6277117 0.019400302 0.50940824 0.389833 -2.4411068 -0.807982 -0.93810976 -0.8608685 0.66070545 0.5790751 -0.094520874 0.49509317 -0.2112504 0.24976574 0.2103454 0.6259374 0.6312247 -0.42349234 0.29853308 -0.3654969 -0.50719243 -0.19676383 0.6475518 -0.4887192 2.669659 0.5924988 0.4094116 0.8608023 0.21275812 2.0922596 0.18556783 0.6748796 1.1921356 0.27274355 -0.1925768 0.42886624 1.6993535 -0.17950799 -0.044677068 0.34498277 0.79426634 0.56190413 1.5218983 -0.9420353 0.18097158 0.7035488 -1.2952648 -1.516066 -2.1866686 0.18049617 0.78011256 2.4880948 2.485874 0.7126156 3.3388047 -0.6878992 -0.6983396 -1.5875088 -1.0492566 0.11574642 -3.3609064 -0.28703314 0.3914817 -1.2123271 0.015651321 0.49038655 0.6106256 -0.23753402 0.67313755 0.49978957 -0.77208996 1.4322895 0.035109352 -2.1435008 -1.663981 -1.0058715 2.2407045 2.0235572 1.871214 -0.73623013 -0.518672 -0.4789053 1.1778052 0.5589379 1.0052977 -0.5888483 -0.18882951 0.4534876 -0.3752225 -0.2677381 0.16722701 -0.44682333 -0.11547136 -0.9790548 -0.44856197 0.5911065 0.7719745 0.0561787 0.7428197 1.530522 -3.1895654 -2.2480836 -0.91071403 -1.6545202 0.43291065 0.016181068 0.4444853 -0.6113456 -0.3306643 -0.44469243 -0.71367 -0.7606478 0.17709187 -0.7196093 -2.268034 -0.52464354 0.56669563 -0.4772889 -1.1820737 0.8193835 -0.04303519 -0.44045955 -0.46329302 1.2170337 -2.4110184 -1.2987506 -0.14021838 -0.3404867 -0.92342454 0.051008567 -1.2273943 0.35194927 -0.041928153 -0.8169436 1.3679421 1.9839722 -2.3546953 -2.0357091 -1.4491904 -2.4135466 -7.41E-01 0.45961535 -1.0823606 0.31420988 -1.3363407 -1.905371 0.666312 1.4938183 -0.69350564 -1.1005708 -1.6997831 -0.12424786 0.26694688 -1.3643103 1.1874409 -0.9291278 1.5272144 Tyrosine -1.0511135 2.054132 1.6734049 -1.8930436 -0.8546566 -0.6715528 -2.7232754 -0.57573587 -1.1468861 -2.035198 -0.2475863 -1.0328622 -1.0312608 1.8448691 2.151932 -0.97546905 -0.7189149 2.1095197 -2.8822372 -0.21431883 0.72415525 -1.3610663 1.9568833 1.911354 -0.6684666 -0.46004432 0.29050285 -0.63570786 1.7385715 1.6508068 -2.0905857 2.0788429 1.9241893 -1.145767 2.143579 1.6041908 -0.16222946 -0.80863476 -0.6113625 -0.6753334 1.4277251 1.5046729 -0.60389274 1.6955518 -0.13256268 -0.82662654 1.7080127 1.9838178 -1.4270409 -0.3306459 -0.6624227 -0.92509454 -1.112234 -0.31581545 -0.9386038 1.5120838 1.946926 -0.97047204 1.4197319 1.8283061 -1.1800812 -1.1600857 -1.3683296 -0.8770748 1.6924155 2.1786585 -0.5603746 1.5555414 2.0006256 -1.4413096 -0.81974065 -0.39395466 -1.4561445 -0.49462408 -0.43076533 -1.1147687 2.3303735 2.2869866 -1.887914 1.5905061 1.6702038 -1.2896022 -0.6797863 -0.60058844 -0.72659993 -0.7991405 -1.069254 -0.99308336 -0.88750386 -0.5989886 -1.3868729 1.946926 2.2166047 -0.70889425 -0.95768815 -1.2544428 -0.79736525 -0.42547485 -0.2807668 -1.2166369 2.067678 1.8227282 -1.0212152 -0.27318347 -0.24188592 -1.0570188 2.0564027 1.9139342 -1.6149782 -0.6089193 -0.7326719 -1.9625276 -0.6912741 -0.87223846 -0.7461871 -0.5977913 -0.9617607 -1.6819865 -0.32428935 -0.22224127 -1.0201255 -0.31318495 -0.39377773 -1.5283828 1.6986806 1.7475777 -1.6427045 1.9765368 1.8338547 -1.0525599 1.7325276 1.911354 -0.76455337 1.6540639 1.7594754 -0.42447072 -0.14454736 -1.70E-01 -1.02E+00 -1.24E+00 -1.32E+00 -0.18132707 1.68E+00 1.80E+00 -5.52E-01 -3.83E-01 -5.95E-02 -1.45E+00 1.10E-01 -6.41E-01 -6.00E-01 1.50E+00 1.54E+00 -7.35E-01 -1.30E+00 -3.57E-01 -4.53E-03 -1.94E-01 -6.81E-01 -1.1587704 1.79E+00 1.95E+00 -0.6252257 1.5448351 2.143579 -9.09E-01 -7.22E-01 -1.12E+00 -1.54E+00 -4.73E-01 -2.14E-01 -1.20E+00 1.76E+00 2.24E+00 -1.17E+00 1.86E+00 2.00E+00 -1.2537587 -2.63E-01 -7.55E-01 -1.28E+00 -3.45E-01 -2.98E-01 -9.89E-01 1.81E+00 1.77E+00 -7.45E-01 -0.45079777 -0.10979359 -1.5886747 -1.60E-01 -9.25E-01 -1.6047187 1.497212 1.7264483 -1.091889 1.9444224 1.3621029 -0.5659143 1.8227282 1.9318199 -0.13589652 -0.62277657 -0.10248159 -1.3195063 -0.83038646 -0.78393406 -0.98059 1.4745299 1.8665795 -0.7733266 -0.718129 -0.7804012 -1.5714217 1.0468727 1.1985965 -0.91591436 -0.20673993 -0.66663384 -1.5116163 1.0299308 1.3407773 -1.5483075 -0.027488947 -0.5599809 -1.6428461 -1.0754013 -0.65367895 -1.5208584 -2.64E-01 -7.92E-01 -1.40E-01 1.74E+00 1.62E+00 -9.84E-01 1.90E+00 1.51E+00 -0.41247723 1.57E+00 1.58E+00 -6.50E-01 1.42E+00 1.76E+00 -1.41E+00 1.35E+00 1.87E+00 -5.85E-01 -9.52E-01 -0.5804469 -9.43E-01 -4.15E-01 8.71E-02 -1.59E+00 -6.89E-01 -1.34E-01 -1.55E+00 1.60E+00 1.74E+00 -1.54E+00 1.35E+00 1.59E+00 -6.47E-01 -3.14E-01 -6.38E-01 -1.56E+00 1.95E+00 1.91E+00 -6.17E-01 -8.80E-01 -0.36209238 -7.82E-01 1.83E+00 1.83E+00 -5.19E-01 -8.62E-01 -6.06E-01 N-Acetyl-tyrosine -0.9087431 1.841358 1.517924 -0.9763197 -0.07305611 0.12277862 -1.4208149 -0.4270934 -0.8088738 -1.348259 0.013345434 -0.37075624 -0.78822845 1.774513 3.0167146 -0.19095214 -0.28443444 3.734895 -2.0992332 -0.42626026 0.541365 -1.0020063 2.3700495 2.5185666 -0.60969573 -0.71304 0.61807805 -0.4781523 2.409104 2.1719942 -1.2986859 1.971678 3.4293995 -0.57891667 2.7968216 2.578759 -0.7891158 -0.716381 -0.04046835 -1.2497361 0.7684759 1.3560908 -0.8398139 1.0503165 -0.42220074 -0.7285201 0.86944777 1.1624612 -0.4756963 0.03904755 -0.22531687 -0.18846051 -0.7238667 -0.03720787 0.26995933 1.11012 1.9287939 -0.29638153 0.042322744 1.5014024 -0.9087756 -0.69704264 -1.322412 -0.33756995 0.8097371 1.7809055 -0.574638 1.0536304 2.2642632 -0.70915544 -1.0703695 -0.7411966 -1.2058462 -0.81967646 -0.7951025 -0.8125787 2.2207272 2.4350083 -1.6127086 1.4991632 2.0301917 -0.99274516 -1.4042531 -0.73228157 -0.6144397 -0.91172713 -0.8756366 -0.92693394 -1.3107421 -0.9065155 -0.9795639 2.3749166 4.0116496 -0.5907507 -1.1777207 -1.2359269 -0.46775067 -0.679791 -0.08494668 -0.74599165 1.4290432 1.365715 -1.2881263 -0.8663623 -0.73627216 -0.8620062 2.28738 2.1420188 -0.962481 -0.7663381 -0.5431753 -1.2285992 -0.54884917 -0.7566798 -0.8442048 -0.66286373 -0.8349336 -1.6798028 -0.6233563 -1.0070909 -0.5657284 -0.22456504 -0.5865371 -1.3572468 2.4786327 2.524648 -0.5907662 1.7097386 0.88319194 -0.7585396 0.8983368 1.0182056 -0.7291891 1.2589453 0.6879031 0.26217243 -0.27464217 -0.6429509 -0.19287544 -0.6242622 -0.104357794 -0.9065674 1.1858243 2.155592 -1.2648686 -0.5291307 -0.26049846 -1.1943908 -0.07813304 -0.8288385 -1.7583554 0.36532623 0.47526348 -0.6903227 -1.2725192 -0.4023568 -0.8577748 -0.82785827 -1.1538318 -0.88686126 1.0542514 1.3349639 -0.84427214 0.68551135 1.5988932 -0.5673126 -0.87390065 -1.0467409 -0.7766182 -0.24204898 -0.2331208 -0.52645475 1.0110158 2.3416042 -1.3890835 1.23769 1.6461039 -1.4371847 -0.674927 -0.82295555 -0.7689552 -0.6081913 -0.6578348 -1.4444512 1.2627362 1.100454 -0.80145466 -1.3091216 -0.49960285 -1.2276816 -0.45262903 -0.84508204 -1.5243179 0.7461395 0.97127676 -1.263893 1.4163496 0.027256865 -1.4501538 0.7753879 1.3384976 -0.80377746 -0.8927032 -0.70284355 -1.2812454 -1.7909114 -1.0277053 -0.068128616 2.4575226 2.6268988 -0.98613435 -1.2356141 -0.8472446 -0.91394 1.2430836 1.579928 -1.4709958 -1.014236 -0.78969264 -0.9763537 0.8320533 1.0288272 -1.1226975 -0.43757555 -0.17759587 -1.1452242 -1.1489625 -1.0535034 -1.0550272 -0.22975501 -0.3250321 0.27305412 2.8997338 2.099793 -0.60968024 2.2088869 1.5219486 -0.46544796 0.88885736 1.2202315 -0.64307714 0.4427903 1.474837 -0.5133966 0.46518084 1.2236941 0.36051255 -0.3839321 -0.39321026 -0.36950192 -0.4318072 -0.11227168 -0.94493663 -0.8907876 -0.21349289 -1.1256946 0.74760604 0.7622569 -1.0527825 1.792484 2.1912289 -0.7861921 -0.7662855 -0.56254536 -1.1962034 0.9326063 1.3193513 -0.92330956 -1.1500852 -0.27988943 -1.0430723 2.2715523 1.4396105 -0.4212476 -0.88326085 -0.48423734 HGA-sulfate -0.6490601 -1.8778499 -0.11097021 -0.9204774 0.9859997 0.7805098 -2.8241422 0.85849816 0.11984942 -2.2857354 1.3622764 0.7614407 0.6001571 -1.1352894 -0.15871882 -0.29509884 -0.5296936 -0.3026862 -0.2806864 1.5979913 1.4041361 0.64613014 -0.7144522 -1.2221773 1.2580862 2.1522117 2.2534547 0.7555292 -3.063828 -0.77761847 -6.0718584 -0.60042983 -0.9558851 0.73416436 -0.7741801 -0.8593972 1.6014857 1.3922135 1.2072563 0.71558833 -1.4482551 -0.5314714 0.9804941 -0.40114173 0.893887 0.7866279 -1.0420136 -0.37728417 0.18424721 1.838171 0.84756845 1.1034741 0.5651239 1.5511491 0.36019784 -0.8449753 -0.56071013 -6.0718584 -0.88671494 -0.20537199 -1.1007901 -0.06683162 -0.048140675 -1.0515133 -1.8354986 -0.7058581 1.1615888 -0.6505228 0.16264161 -0.5847299 0.6254752 0.76324457 -1.3784767 1.1572943 1.5255429 -0.18601039 -1.1455419 -1.4898093 -1.4945365 -0.7606362 -0.51252586 -0.69507897 0.9934867 0.78030986 -0.55122066 0.22946815 0.67631674 -0.6217838 0.19573046 0.99093646 -0.058950376 -0.97126716 -0.007209863 1.213437 0.5145443 0.6869519 0.20701079 0.94532853 1.7152026 1.1772182 -1.1590873 -1.3048419 0.28811374 0.7146995 1.4489664 0.39455816 -1.7969819 -0.7564042 -0.5715235 0.7927765 0.78813726 -2.8034377 0.72955054 0.9601745 -0.7093183 1.6122714 1.1454532 -2.610823 1.3120466 1.4719387 0.33297536 1.019754 1.1269215 0.77425796 -2.3338 -1.0332893 -0.9030237 -0.8496742 -0.51020837 -0.9123241 -0.4707898 -0.07501618 -0.26200128 -0.22622691 -0.42177916 1.2894199 1.9397703 1.2729576 -6.0718584 -0.19715033 -0.2939052 1.0795025 -0.9184385 -0.1786725 1.0644047 1.1748527 1.5156751 -0.18889304 1.6479229 1.3547553 -0.14066797 -0.5984703 -0.5642736 1.2117633 1.0160131 1.5265554 1.828862 1.2489866 1.245274 -0.9191106 -0.12851407 0.19219391 -0.002332731 -1.3589966 -0.2987089 -0.5231595 0.4649445 0.020754542 0.43278816 1.9438771 2.174886 1.0794908 -0.30548957 -1.17074 -0.46958742 -1.64487 -0.026651472 -1.2720287 1.126592 0.5061241 0.5305672 1.1203154 0.93396896 -0.10382944 -0.9927506 0.16932558 -0.17591426 0.8150571 1.7033935 -1.9885583 1.0967597 0.5708834 -0.68157357 -1.6697947 -0.98400885 0.28497216 -1.1069235 -1.2459955 1.431667 -0.85918623 -0.0635351 2.007522 1.0747045 1.4299234 -6.0718584 0.2161875 0.005684532 0.012193194 -1.5852264 -0.24027567 0.6501286 0.97062856 0.9380372 0.19249795 -1.3845788 -0.75542444 0.63910794 1.5771692 1.2242649 -0.5993533 -0.7336734 -0.3631554 -0.57392675 0.6140364 0.9714578 -1.9249345 0.67046416 1.6846756 -1.2470946 0.55424076 1.0588293 1.5609739 -0.9402412 -0.5450022 0.18911998 -1.9887308 -0.715824 1.863847 -1.097455 0.09759937 1.028981 -0.55697644 -0.7637661 -0.16478087 -2.2206066 -0.16017142 1.5244023 1.2634093 1.9291409 0.35460642 1.1226146 1.2868572 -0.75344014 0.727148 1.3331045 -0.8954298 -1.4602642 -0.86277735 0.64396834 -0.4274608 -0.39796597 1.1760973 1.5498434 1.6007344 -1.3903092 -1.1241443 -1.75678 -1.2795819 0.6141324 1.1944034 -0.1830121 -0.7327642 -0.8214378 1.0279175 0.85098785 0.8919107 MS_METABOLITE_DATA_END #METABOLITES METABOLITES_START metabolite_name retention time neutral mass formula CAS-ID KEGG-ID Phenylalanine 3.770008 165.0789 C9 H11 N O2 63-91-2 C00079 Phenylacetylglutamine 5.599985 264.1116 C13 H16 N2 O4 28047-15-6 C04148 Tyrosine 2.190002 181.074 C9 H11 N O3 60-18-4 C00082 N-Acetyl-tyrosine 4.900014 223.0852 C11 H13 N O4 537-55-3 HGA-sulfate 2.8300028 247.9995 C8 H8 O7 S METABOLITES_END #END