Summary of Study ST002297

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001471. The data can be accessed directly via it's Project DOI: 10.21228/M8KH70 This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002297
Study TitleComprehensive biotransformation analysis of phenylalanine-tyrosine metabolism reveals alternative routes of metabolite clearance in nitisinone-treated alkaptonuria (Urine metabolomic analysis)
Study TypeUrine metabolomic analysis (study 2 of 2)
Study SummaryBackground: Metabolomic analyses in alkaptonuria (AKU) have recently revealed alternative pathways in phenylalanine-tyrosine (phe-tyr) metabolism from biotransformation of homo-gentisic acid (HGA), the active molecule in this disease. The aim of this research was to study the phe-tyr metabolic pathway and whether the metabolites upstream of HGA, increased in nitisinone-treated patients, also undergo phase 1 and 2 biotransformation reactions. Methods: Metabolomic analyses were performed on serum and urine from patients partaking in the SONIA 2 phase 3 international randomised-controlled trial of nitisinone in AKU (EudraCT no. 2013-001633-41). Serum and urine samples were taken from the same patients at baseline (pre-nitisinone) then at 24 and 48 months on nitisinone treatment (patients N = 47 serum; 53 urine) or no treatment (patients N = 45 serum; 50 urine). Targeted feature extraction was per-formed to specifically mine data for the entire complement of theoretically predicted phase 1 and 2 biotransformation products derived from phenylalanine, tyrosine, 4-hydroxyphenylpyruvic acid and 4-hydroxyphenyllactic acid, in addition to phenylalanine-derived metabolites with known increases in phenylketonuria. Results: In total, we ob-served 13 phase 1 and 2 biotransformation products from phenylalanine through to HGA. Each of these products were observed in urine and two were detected in serum. The derivatives of the metabolites upstream of HGA were markedly increased in urine of nitisinone-treated patients (fold change 1.2-16.2) and increases in 12 of these compounds were directly proportional to the degree of nitisinone-induced hypertyrosinaemia (correlation coefficient with serum tyrosine = 0.2-0.7). Increases in the urinary phenylalanine metabolites were also observed across consecutive visits in the treated group. Conclusions: Nitisinone treatment results in marked increases in a wider network of phe-tyr metabolites than shown before. This network comprises alternative biotransformation products from the major metabolites of this pathway, produced by reactions including hydration (phase 1) and bioconjugation (phase 2) of acetyl, methyl, acetylcysteine, glucuronide, glycine and sulfate groups. We propose that these alternative routes of phe-tyr metabolism, predominantly in urine, minimise tyrosinaemia as well as phenylalanaemia.
Institute
University of Liverpool Institute of Life Course & Medical Sciences
DepartmentDepartment of Musculoskeletal & Ageing Science
Last NameBrendan
First NameNorman
AddressWilliam Henry Duncan Building, 6 West Derby Street, Liverpool, UK. L7 8TX
Emailbnorman@liverpool.ac.uk
Phone+447809606497
Submit Date2022-09-28
Num Groups2
Total Subjects103
Num Males65
Num Females38
Raw Data AvailableYes
Raw Data File Type(s)d
Analysis Type DetailLC-MS
Release Date2022-10-14
Release Version1
Norman Brendan Norman Brendan
https://dx.doi.org/10.21228/M8KH70
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Treatedrial arm
SA220649P03_V4Treated
SA220650P03_V1Treated
SA220651P03_V6Treated
SA220652P07_V1Treated
SA220653P07_V4Treated
SA220654P02_V6Treated
SA220655P02_V4Treated
SA220656L40_V1Treated
SA220657L40_V4Treated
SA220658L40_V6Treated
SA220659P02_V1Treated
SA220660P07_V6Treated
SA220661P11_V4Treated
SA220662P18_V6Treated
SA220663P18_V4Treated
SA220664P22_V1Treated
SA220665P22_V4Treated
SA220666P22_V6Treated
SA220667P18_V1Treated
SA220668P15_V6Treated
SA220669L35_V6Treated
SA220670P11_V6Treated
SA220671P15_V1Treated
SA220672P15_V4Treated
SA220673P11_V1Treated
SA220674L35_V1Treated
SA220675L16_V6Treated
SA220676L16_V4Treated
SA220677L18_V1Treated
SA220678L18_V4Treated
SA220679L18_V6Treated
SA220680L16_V1Treated
SA220681L14_V6Treated
SA220682L12_V4Treated
SA220683L12_V6Treated
SA220684L14_V1Treated
SA220685L14_V4Treated
SA220686L22_V1Treated
SA220687L22_V4Treated
SA220688L33_V1Treated
SA220689L30_V6Treated
SA220690L33_V4Treated
SA220691L33_V6Treated
SA220692P23_V1Treated
SA220693L30_V4Treated
SA220694L30_V1Treated
SA220695L22_V6Treated
SA220696L28_V1Treated
SA220697L28_V4Treated
SA220698L28_V6Treated
SA220699F01_V1Treated
SA220700P23_V4Treated
SA220701P48_V4Treated
SA220702P48_V1Treated
SA220703P48_V6Treated
SA220704P52_V1Treated
SA220705P52_V4Treated
SA220706P47_V6Treated
SA220707P47_V4Treated
SA220708P46_V1Treated
SA220709P46_V4Treated
SA220710P46_V6Treated
SA220711P47_V1Treated
SA220712P52_V6Treated
SA220713P55_V1Treated
SA220714P62_V6Treated
SA220715P62_V4Treated
SA220716P64_V1Treated
SA220717P64_V4Treated
SA220718P64_V6Treated
SA220719P62_V1Treated
SA220720P60_V6Treated
SA220721P55_V4Treated
SA220722P55_V6Treated
SA220723P60_V1Treated
SA220724P60_V4Treated
SA220725P44_V6Treated
SA220726P44_V4Treated
SA220727P31_V1Treated
SA220728P30_V6Treated
SA220729P31_V4Treated
SA220730P31_V6Treated
SA220731P34_V1Treated
SA220732P30_V4Treated
SA220733P30_V1Treated
SA220734P23_V6Treated
SA220735P26_V1Treated
SA220736P26_V4Treated
SA220737P26_V6Treated
SA220738P34_V4Treated
SA220739P34_V6Treated
SA220740P43_V1Treated
SA220741P43_V4Treated
SA220742P43_V6Treated
SA220743P44_V1Treated
SA220744P40_V6Treated
SA220745P40_V4Treated
SA220746P39_V1Treated
SA220747P39_V4Treated
SA220748P39_V6Treated
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