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

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

doi:10.1016/j.gendis.2021.02.007

Cited by 15 publications

(20 citation statements)

References 52 publications

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“…The authors suggested that deficiency of phospholipids (secondary to serine deficiency) may be contributing to the neurological manifestations of the condition, and this could lend itself to additional targeted therapies in the future. As exemplified by this study, and others, untargeted methods allow for a better understanding of disease pathogenesis, as whole pathways can be analyzed, rather than individual metabolites (32,56,57,(65)(66)(67)(68)(69). The use of untargeted approaches can also help generate a 'metabolomic signature' similar to the increasing utility of methylation episignatures for detection of BAFopathies (70).…”

Section: Biomarker Discovery and Increased Understanding Of Disease P...mentioning

confidence: 89%

A narrative review of metabolomics in the era of “-omics”: integration into clinical practice for inborn errors of metabolism

Hertzog¹,

Selvanathan²,

Devanapalli³

et al. 2022

Transl Pediatr

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Background and Objective: Traditional targeted metabolomic investigations identify a pre-defined list of analytes in samples and have been widely used for decades in the diagnosis and monitoring of inborn errors of metabolism (IEMs). Recent technological advances have resulted in the development and maturation of untargeted metabolomics: a holistic, unbiased, analytical approach to detecting metabolic disturbances in human disease. We aim to provide a summary of untargeted metabolomics [focusing on tandem mass spectrometry (MS-MS)] and its application in the field of IEMs.Methods: Data for this review was identified through a literature search using PubMed, Google Scholar, and personal repositories of articles collected by the authors. Findings are presented within several sections describing the metabolome, the current use of targeted metabolomics in the diagnostic pathway of patients with IEMs, the more recent integration of untargeted metabolomics into clinical care, and the limitations of this newly employed analytical technique.

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Section: Biomarker Discovery and Increased Understanding Of Disease P...mentioning

confidence: 89%

A narrative review of metabolomics in the era of “-omics”: integration into clinical practice for inborn errors of metabolism

Hertzog¹,

Selvanathan²,

Devanapalli³

et al. 2022

Transl Pediatr

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“…In a mouse model of alkaptonuria (AKU), the urinary profiles of homozygous AKU mice were compared to those of heterozygous healthy mice [ 47 ]. This disease is characterized by urine that turns black when exposed to air, discoloration in the eyes, ears and skin, early-onset osteoarthritis, and kidney and prostate stones.…”

Section: In Vivo and Ex Vivo Metabolomicsmentioning

confidence: 99%

“…Falk and co-workers published a series of metabolomic studies on the use of C. elegans with different mitochondrial disorders [ 47 , 48 , 49 ]. Mitochondrial disorders are a large group of diseases, but common symptoms include stunted growth, low muscle tone, intellectual disability, and impaired vision and hearing.…”

Section: In Vivo and Ex Vivo Metabolomicsmentioning

confidence: 99%

Understanding Inborn Errors of Metabolism through Metabolomics

Driesen

Witters

2022

Metabolites

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Inborn errors of metabolism (IEMs) are rare diseases caused by a defect in a single enzyme, co-factor, or transport protein. For most IEMs, no effective treatment is available and the exact disease mechanism is unknown. The application of metabolomics and, more specifically, tracer metabolomics in IEM research can help to elucidate these disease mechanisms and hence direct novel therapeutic interventions. In this review, we will describe the different approaches to metabolomics in IEM research. We will discuss the strengths and weaknesses of the different sample types that can be used (biofluids, tissues or cells from model organisms; modified cell lines; and patient fibroblasts) and when each of them is appropriate to use.

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“…Recently, significant advances have been made in understanding the wider metabolic consequences caused by genetic mutations in phe-tyr metabolism and treatment with nitisinone beyond the traditional pathway. Untargeted metabolomic approaches revealed an extensive pattern of alteration to serum and urine metabolite pathways in patients and mice on nitisinone, which extends far beyond immediate phe-tyr metabolism and into metabolic pathways including those of purine, tryptophan and the TCA cycle [ 15 , 17 , 19 , 22 , 23 ]. A metabolomic approach has also elucidated previously undescribed pathways derived from HGA, including phase 1 and 2 biotransformation reactions of HGA which appear to be active in untreated AKU for adaptive detoxification [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…Untargeted metabolomic approaches revealed an extensive pattern of alteration to serum and urine metabolite pathways in patients and mice on nitisinone, which extends far beyond immediate phe-tyr metabolism and into metabolic pathways including those of purine, tryptophan and the TCA cycle [ 15 , 17 , 19 , 22 , 23 ]. A metabolomic approach has also elucidated previously undescribed pathways derived from HGA, including phase 1 and 2 biotransformation reactions of HGA which appear to be active in untreated AKU for adaptive detoxification [ 23 ]. Biotransformations are reactions through which an endogenous or exogenous molecule is metabolised by one or more enzymes to a more hydrophilic moiety which is more easily eliminated [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

et al. 2022

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Metabolomic analyses in alkaptonuria (AKU) have recently revealed alternative pathways in phenylalanine-tyrosine (phe-tyr) metabolism from biotransformation of homogentisic 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. 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 performed 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. In total, we observed 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. 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.

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

Cited by 15 publications

References 52 publications

A narrative review of metabolomics in the era of “-omics”: integration into clinical practice for inborn errors of metabolism

A narrative review of metabolomics in the era of “-omics”: integration into clinical practice for inborn errors of metabolism

Understanding Inborn Errors of Metabolism through Metabolomics

Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria

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