Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

Brendan P. Norman; Andrew S. Davison; Juliette H. Hughes; Hazel Sutherland; Peter JM. Wilson; Neil G. Berry; Andrew T. Hughes; Anna M. Milan; Jonathan C. Jarvis; Norman B. Roberts; Lakshminarayan R. Ranganath; George Bou-Gharios; James A. Gallagher

doi:10.1016/j.gendis.2021.02.007

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Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

Full-length article | 更新时间：2022-06-24

- Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism
- Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism
- Genes & Diseases 2022年9卷第4期
- 作者机构：
  
  1. Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street,Liverpool,UK,L7 8TX
  2. Department of Clinical Biochemistry & Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospital, Prescot Street,Liverpool,UK,L7 8XP
  3. School of Sport & Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, Byrom Street,Liverpool,UK,L3 3AF
  4. Department of Chemistry, University of Liverpool, Crown Street,Liverpool,UK,L69 7ZD
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2021.02.007
  中图分类号：
- 纸质出版日期：2022，
  
  网络出版日期：2022-7-1，
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Brendan P. Norman, Andrew S. Davison, Juliette H. Hughes, 等. Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism[J]. Genes & Diseases, 2022,9(4).

Brendan P. Norman, Andrew S. Davison, Juliette H. Hughes, et al. Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism[J]. Genes & Diseases, 2022,9(4).
Brendan P. Norman, Andrew S. Davison, Juliette H. Hughes, 等. Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism[J]. Genes & Diseases, 2022,9(4). DOI： 10.1016/j.gendis.2021.02.007.

Brendan P. Norman, Andrew S. Davison, Juliette H. Hughes, et al. Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism[J]. Genes & Diseases, 2022,9(4). DOI： 10.1016/j.gendis.2021.02.007.

摘要

Abstract

lkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1

2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA)

the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous

Hgd

knockout (

Hgd

−/−

) mice to model the wider metabolic effects of

Hgd

deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from

Hgd

−/−

AKU (

= 15) and

Hgd

+/−

non-AKU control (

= 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in

Hgd

−/−

were further investigated in AKU mice (

= 18) and patients from the UK National AKU Centre (

= 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of

C-labelled HGA to

Hgd

−/−

(

= 4) and

Hgd

+/−

(

= 4) mice (Experiment 3) to confirm direct association with HGA.

Hgd

−/−

mice showed the expected increase in HGA

together with unexpected alterations in tyrosine

purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in

Hgd

−/−

were HGA and previously unreported sulfate and glucuronide HGA conjugates

these were decreased in mice and patients on nitisinone and shown to be products from HGA by the

C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism

demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism.

关键词

Keywords

AlkaptonuriaBiotransformationMetabolismMetabolomicsMice

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