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Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New...
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Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 11476

Special Issue Editors

Dr. Andrew S. Davison

E-Mail Website
Guest Editor
1. Department of Clinical Biochemistry and Metabolic Medicine, Liverpool Clinical Laboratories, Royal Liverpool University Hospitals Trust, Liverpool L69 3GA, UK
2. Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK
Interests: clinical mass spectrometry; alkaptonuria; adrenal disease; clinical chemistry; metabolomics
Dr. Brendan P. Norman

E-Mail Website
Guest Editor
Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
Interests: tyrosine metabolism; alkaptonuria; metabolomics; mass spectrometry; extracellular matrix

Special Issue Information

Dear Colleagues,

Evaluating metabolic disease is commonplace in clinical practice, but is often fraught with the pitfalls that are associated with some of the tests available in the clinical laboratory. Developments in analytical techniques over the 10 years has seen a renewed interest in exploring the metabolic basis of disease and its response to treatment using mass spectrometry-based techniques, in a quest to discover new biomarkers that will eventually be translated for use in clinical practice. Alkaptonuria, whilst seen as an iconic disease, serves as a great example of where this renewed interest has seen significant developments in the understanding of this rare condition, and has provided insight into mechanisms that underlie this disease and its response to treatment. It has also allowed scientists and clinicians in the field to learn lessons about other more common diseases like osteoarthritis.

This Special Issue of Metabolites, "Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease" will be dedicated to reviews and original articles covering the latest developments relating to the metabolic consequences that occur in Alkaptonuria and the impact of treatment with nitisinone.

Dr. Andrew S. Davison
Dr. Brendan P. Norman
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • alkaptonuria
  • tyrosine
  • homogentisic acid
  • in born error of metabolism
  • biotransformation
  • nitisinone

Published Papers (6 papers)

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Research

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10 pages, 1147 KiB  
Article
Analysis of the Phenotype Differences in Siblings with Alkaptonuria
by Andrea Zatkova, Birgitta Olsson, Lakshminarayan R. Ranganath and Richard Imrich
Metabolites 2022, 12(10), 990; https://doi.org/10.3390/metabo12100990 - 19 Oct 2022
Cited by 4 | Viewed by 1275
Abstract
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), [...] Read more.
Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by mutations within a gene coding for homogentisate 1,2-dioxygenase (HGD). To date, 251 different variants of this gene have been reported. The metabolic disorder in AKU leads to the accumulation of homogentisic acid (HGA), resulting in ochronosis (pigmentation of the connective tissues) and severe ochronotic spondylo-arthropathy, which usually manifests in the mid-thirties. An earlier genotype–phenotype correlation study showed no differences in serum HGA levels, absolute urinary excretion of HGA, or in the clinical symptoms between patients carrying HGD variants leading to 1% or >30% residual HGD activity. Still, as reported previously, the variance of the excretion of the HGA was smaller within affected siblings that share a common genotype. The present study is the first ever to systematically analyze the baseline clinical data of 24 AKU sibling pairs/groups collected in the SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) study to evaluate phenotypical differences between patients carrying the same HGD genetic variants. We show that even between siblings there was considerable variability in the disease severity. This indicates that some other yet unidentified genetic, biomechanical, or environmental modifying factors may contribute to accelerated pigmentation and connective tissue damage observed in some patients. Full article
(This article belongs to the Special Issue Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease)
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20 pages, 2453 KiB  
Article
Comprehensive Biotransformation Analysis of Phenylalanine-Tyrosine Metabolism Reveals Alternative Routes of Metabolite Clearance in Nitisinone-Treated Alkaptonuria
by Brendan P. Norman, Andrew S. Davison, Bryony Hickton, Gordon A. Ross, Anna M. Milan, Andrew T. Hughes, Peter J. M. Wilson, Hazel Sutherland, Juliette H. Hughes, Norman B. Roberts, George Bou-Gharios, James A. Gallagher and Lakshminarayan R. Ranganath
Metabolites 2022, 12(10), 927; https://doi.org/10.3390/metabo12100927 - 29 Sep 2022
Cited by 3 | Viewed by 2708
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease)
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15 pages, 5131 KiB  
Article
Revisiting Quantification of Phenylalanine/Tyrosine Flux in the Ochronotic Pathway during Long-Term Nitisinone Treatment of Alkaptonuria
by Lakshminarayan R. Ranganath, Andrew T. Hughes, Andrew S. Davison, Milad Khedr, Richard Imrich, Mattias Rudebeck, Birgitta Olsson, Brendan P. Norman, George Bou-Gharios, James A. Gallagher and Anna M. Milan
Metabolites 2022, 12(10), 920; https://doi.org/10.3390/metabo12100920 - 29 Sep 2022
Cited by 1 | Viewed by 1354
Abstract
Changes in the phenylalanine (PHE)/tyrosine (TYR) pathway metabolites before and during homogentisic acid (HGA)-lowering by nitisinone in the Suitability of Nitisinone in Alkaptonuria (AKU) 2 (SONIA 2) study enabled the magnitude of the flux in the pathway to be examined. SONIA 2 was [...] Read more.
Changes in the phenylalanine (PHE)/tyrosine (TYR) pathway metabolites before and during homogentisic acid (HGA)-lowering by nitisinone in the Suitability of Nitisinone in Alkaptonuria (AKU) 2 (SONIA 2) study enabled the magnitude of the flux in the pathway to be examined. SONIA 2 was a 48-month randomised, open-label, evaluator-blinded, parallel-group study performed in the UK, France and Slovakia recruiting patients with confirmed AKU to receive either 10 mg nitisinone or no treatment. Site visits were performed at 3 months and yearly thereafter. Results from history, photographs of eyes/ears, whole body scintigraphy, echocardiography and abdomen/pelvis ultrasonography were combined to produce the Alkaptonuria Severity Score Index (cAKUSSI). PHE, TYR, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and HGA metabolites were analysed by liquid chromatography/tandem mass spectrometry in 24 h urine and serum samples collected before and during nitisinone. Serum metabolites were corrected for total body water (TBW), and the sum of 24 h urine plus total body water metabolites of PHE, TYR, HPPA, HPLA and HGA were determined. The sum of urine metabolites (PHE, TYR, HPPA, HPLA and HGA) were similar pre- and peri-nitisinone. The sum of TBW metabolites and sum TBW + URINE metabolites were significantly higher peri-nitisinone (p < 0.001 for both) compared with pre-nitisinone baseline. Significantly higher concentrations of metabolites from the tyrosine metabolic pathway were observed during treatment with nitisinone. Arguments for unmasking of the ochronotic pathway and biliary elimination of HGA are put forward. Full article
(This article belongs to the Special Issue Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease)
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15 pages, 1371 KiB  
Article
Comparing the Phenylalanine/Tyrosine Pathway and Related Factors between Keratopathy and No-Keratopathy Groups as Well as between Genders in Alkaptonuria during Nitisinone Treatment
by Lakshminarayan R. Ranganath, Anna M. Milan, Andrew T. Hughes, Andrew S. Davison, Milad Khedr, Richard Imrich, Mattias Rudebeck, Birgitta Olsson, Brendan P. Norman, George Bou-Gharios and James A. Gallagher
Metabolites 2022, 12(8), 772; https://doi.org/10.3390/metabo12080772 - 22 Aug 2022
Cited by 2 | Viewed by 1290
Abstract
Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic pathway during KP is not understood. The objective of this study is to assess potential differences in the PHE/TYR pathway during KP and [...] Read more.
Nitisinone (NIT) causes tyrosinaemia and corneal keratopathy (KP), especially in men. However, the adaptation within the phenylalanine (PHE)/tyrosine (TYR) catabolic pathway during KP is not understood. The objective of this study is to assess potential differences in the PHE/TYR pathway during KP and the influence of gender in NIT-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24 h urine collected from patients treated with NIT during a 4-year randomized study in NIT vs. no-treatment controls (SONIA 2; Suitability Of Nitisinone In Alkaptonuria 2; EudraCT no. 2013-001633-41) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), TYR, PHE, hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine in the NIT-group. All statistical analyses were post hoc. Keratopathy occurred in 10 out of 69 AKU patients, eight of them male. Thirty-five sampling points (serum and 24 h urine) were analysed in patients experiencing KP and 272 in those with no-KP (NKP) during NIT therapy. The KP group had a lower HPLA/TYR ratio and a higher TYR/PHE ratio compared with the NKP group (p < 0.05 for both). There were 24, 45, 100 and 207 sampling points (serum and 24 h urine) in the NIT group which were pre-NIT female, pre-NIT male, NIT female and NIT male, respectively. The PHE/TYR ratio and the HPLA/TYR ratio were lower in males (p < 0.001 and p < 0.01, respectively). In the KP group and in the male group during NIT therapy, adaptive responses to minimise TYR formation were impaired compared to NKP group and females, respectively. Full article
(This article belongs to the Special Issue Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease)
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14 pages, 1974 KiB  
Article
Impact of Nitisinone on the Cerebrospinal Fluid Metabolome of a Murine Model of Alkaptonuria
by Andrew S. Davison, Brendan P. Norman, Hazel Sutherland, Anna M. Milan, James A. Gallagher, Jonathan C. Jarvis and Lakshminarayan R. Ranganath
Metabolites 2022, 12(6), 477; https://doi.org/10.3390/metabo12060477 - 25 May 2022
Cited by 2 | Viewed by 1993
Abstract
Background: Nitisinone-induced hypertyrosinaemia is well documented in Alkaptonuria (AKU), and there is uncertainty over whether it may contribute to a decline in cognitive function and/or mood by altering neurotransmitter metabolism. The aim of this work was to evaluate the impact of nitisinone on [...] Read more.
Background: Nitisinone-induced hypertyrosinaemia is well documented in Alkaptonuria (AKU), and there is uncertainty over whether it may contribute to a decline in cognitive function and/or mood by altering neurotransmitter metabolism. The aim of this work was to evaluate the impact of nitisinone on the cerebrospinal fluid (CSF) metabolome in a murine model of AKU, with a view to providing additional insight into metabolic changes that occur following treatment with nitisinone. Methods: 17 CSF samples were collected from BALB/c Hgd−/− mice (n = 8, treated with nitisinone—4 mg/L and n = 9, no treatment). Samples were diluted 1:1 with deionised water and analysed using a 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time-of-flight mass spectrometry (Agilent, Cheadle, UK). Raw data were processed using a targeted feature extraction algorithm and an established in-house accurate mass retention time database. Matched entities (±10 ppm theoretical accurate mass and ±0.3 min retention time window) were filtered based on their frequency and variability. Experimental groups were compared using a moderated t-test with Benjamini–Hochberg false-discovery rate adjustment. Results: L-Tyrosine, N-acetyl-L-tyrosine, γ-glutamyl-L-tyrosine, p-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)lactic acid were shown to increase in abundance (log2 fold change 2.6–6.9, 3/5 were significant p < 0.05) in the mice that received nitisinone. Several other metabolites of interest were matched, but no significant differences were observed, including the aromatic amino acids phenylalanine and tryptophan, and monoamine metabolites adrenaline, 3-methoxy-4-hydroxyphenylglycol, and octopamine. Conclusions: Evaluation of the CSF metabolome of a murine model of AKU revealed a significant increase in the abundance of a limited number of metabolites following treatment with nitisinone. Further work is required to understand the significance of these findings and the mechanisms by which the altered metabolite abundances occur. Full article
(This article belongs to the Special Issue Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease)
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Review

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5 pages, 533 KiB  
Review
The Discovery of the Mode of Action of Nitisinone
by Edward A. Lock
Metabolites 2022, 12(10), 902; https://doi.org/10.3390/metabo12100902 - 25 Sep 2022
Cited by 6 | Viewed by 1413
Abstract
This review briefly discusses the discovery of the mode of action of the triketone herbicide, 2-(2-nitro-4-trifluormethylbenzoyl)-1,3-cyclohexanedione and its use as a drug Nitisinone for the treatment of inborn errors of tyrosine metabolism. Nitisinone is a potent reversible tight-binding inhibitor of the enzyme 4-hydroxyphenylpyruvate [...] Read more.
This review briefly discusses the discovery of the mode of action of the triketone herbicide, 2-(2-nitro-4-trifluormethylbenzoyl)-1,3-cyclohexanedione and its use as a drug Nitisinone for the treatment of inborn errors of tyrosine metabolism. Nitisinone is a potent reversible tight-binding inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, involved in the catabolism of the amino acid tyrosine. Nitisinone is used to treat the rare disease hereditary tyrosinaemia type 1 where the last enzyme in the breakdown of tyrosine, fumarylacetoacetase is deficient. Nitisinone is also used to treat patients with alkaptonuria where the enzyme homogentisic acid oxidase is deficient. Articles in this issue discuss metabolites of tyrosine catabolism in healthy patients and those with alkaptonuria. Full article
(This article belongs to the Special Issue Metabolomic Studies into the Inborn Error of Metabolism Alkaptonuria: New Insights into an Iconic Disease)
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