Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria

Ranganath, L.R.; Milan, Anna M.; Hughes, Andrew T.; Davison, Andrew S.; Khedr, Milad; Norman, Brendan P.; Bou‐Gharios, George; Gallagher, James A.; Gornall, Matthew; Jackson, Richard; Imrich, Richard; Rovenský, J; Rudebeck, Mattias; Olsson, Birgitta

doi:10.1016/j.ymgmr.2022.100846

Cited by 6 publications

(11 citation statements)

References 28 publications

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“…sPHE was highest in the > 1100 µmol/L sTYR group suggesting high sTYR increases sPHE possibly by inhibiting the phenylalanine hydroxylase; this is consistent with pathway adaptation to minimise the formation of TYR from PHE, a beneficial change proposed by us recently 25 . sHPPA and sHPLA were highest in the sTYR > 1100 µmol/L group, especially the sHPLA, and is consistent with increased HPPA flux through the HPLA pathway also as suggested by us recently 27 . Urine 24-h metabolites were similar across the sTYR threshold groups except for uHPLA 24 where the two highest groups (901–1100 and > 1100 µmol/L) were statistically higher than the two lowest groups (< 701 and 701–900 µmol/L), consistent with the importance of the HPLA generation.…”

Section: Discussionsupporting

confidence: 88%

“…Protein intake is reduced to 0.9 and 0.8 g/kg body weight for sTYR values between 501–700, and 701–900 µmol/L respectively, whereas in those with values greater than 900 µmol/L, additional PHE/TYR free amino acid supplements are also employed (Table S4 ). These intervals are used because sTYR is associated with the increase in ocular TYR, and exhibits a known relationship to it 27 – 29 .…”

Section: Discussionmentioning

confidence: 99%

“…24-h urine collections are not perfect but are however suited to prospective studies of these kinds, and several recent randomised studies have employed 24-h urine measurements as health outcomes 37 , 38 . We have also only measured serum concentrations in a single fasting morning sample, since it is impractical to use 24-h blood sampling in such a study design; however, a recent publication has shown that the average 24-h concentrations of metabolites are within 10% of the fasting values and we believe that our analyses provide reliable data 17 .…”

Section: Discussionmentioning

confidence: 99%

“…The concentrations of sNIT, sHGA, sTYR, sPHE, sHPPA, and sHPLA as well as uHGA 24 , uTYR 24 , uPHE 24 , uHPPA 24 , and uHPLA 24 were measured by liquid chromatography tandem mass spectrometry using previously published methods 7 , 17 . All analyses were performed on an Agilent 6490 Triple Quadrupole mass spectrometer with Jet-Stream electrospray ionisation coupled with an Agilent 1290 Infinity II Ultra-High Performance Liquid Chromatography system.…”

Section: Methodsmentioning

confidence: 99%

“…PHE, TYR, hydroxyphenylpyruvate (HPPA) and hydroxyphenyllactate (HPLA) are among the main tyrosine pathway metabolites proximal to HPPD inhibition that could be altered during NIT treatment 7 . In the previous paper 17 the increase per metabolite was determined, however, the understanding of the dynamic adaptive relationships was not investigated fully. In the phase 3 Suitability of Nitisinone in Alkaptonuria 2 study (SONIA 2) 4 , a dose of NIT of 10 mg daily was administered by the oral route to all nitisinone-randomised patients.…”

Section: Introductionmentioning

confidence: 99%

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Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

Ranganath

Milan

Hughes

et al. 2022

Sci Rep

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Nitisinone (NIT) produces inevitable but varying degree of tyrosinaemia. However, the understanding of the dynamic adaptive relationships within the tyrosine catabolic pathway has not been investigated fully. The objective of the study was to assess the contribution of protein intake, serum NIT (sNIT) and tyrosine pathway metabolites to nitisinone-induced tyrosinaemia in alkaptonuria (AKU). Samples of serum and 24-h urine collected during SONIA 2 (Suitability Of Nitisinone In Alkaptonuria 2) at months 3 (V2), 12 (V3), 24 (V4), 36 (V5) and 48 (V6) were included in these analyses. Homogentisic acid (HGA), tyrosine (TYR), phenylalanine (PHE), hydroxyphenylpyruvate (HPPA), hydroxyphenyllactate (HPLA) and sNIT were analysed at all time-points in serum and urine. Total body water (TBW) metabolites were derived using 60% body weight. 24-h urine and TBW metabolites were summed to obtain combined values. All statistical analyses were post-hoc. 307 serum and 24-h urine sampling points were analysed. Serum TYR from V2 to V6, ranging from 478 to 1983 µmol/L were stratified (number of sampling points in brackets) into groups < 701 (47), 701–900 (105), 901–1100 (96) and > 1100 (59) µmol/L. The majority of sampling points had values greater than 900 µmol/L. sPHE increased with increasing sTYR (p < 0.001). Tyrosine, HPPA and HPLA in serum and TBW all increased with rising sTYR (p < 0.001), while HPLA/TYR ratio decreased (p < 0.0001). During NIT therapy, adaptive response to minimise TYR formation was demonstrated. Decreased conversion of HPPA to HPLA, relative to TYR, seems to be most influential in determining the degree of tyrosinaemia.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

Ranganath

Milan

Hughes

et al. 2022

Sci Rep

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Metabolic profiles and fingerprints for the investigation of the influence of nitisinone on the metabolism of the yeast Saccharomyces cerevisiae

Barchańska

Płonka

Nowak

et al. 2023

Sci Rep

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Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC) is considered a potentially effective drug for the treatment of various metabolic diseases associated with disorders of l-tyrosine metabolism however, side-effects impede its widespread use. This work aimed to broaden the knowledge of the influence of NTBC and its metabolites 2-amino-4-(trifluoromethyl)benzoic acid (ATFA), 2-nitro-4-(trifluoromethyl)benzoic acid (NTFA), and cyclohexane-1,3-dione (CHD) on the catabolism of l-tyrosine and other endogenous compounds in Saccharomyces cerevisiae. Based on a targeted analysis performed by LC–ESI–MS/MS, based on multiple reaction monitoring, it was found that the dissipation kinetics of the parent compound and its metabolites are compatible with a first-order reaction mechanism. Moreover, it has been proven that formed NTBC metabolites, such as CHD, cause a decrease in l-tyrosine, l-tryptophan, and l-phenylalanine concentrations by about 34%, 59% and 51%, respectively, compared to the untreated model organism. The overall changes in the metabolism of yeast exposed to NTBC or its derivatives were evaluated by non-targeted analysis via LC–ESI–MS/MS in the ion trap scanning mode. Based on principal components analysis, a statistically significant similarity between metabolic responses of yeast treated with ATFA or NTFA was observed. These findings facilitate further studies investigating the influence of NTBC on the human body and the mechanism of its action.

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Structure-Function Relationship of Homogentisate 1,2-dioxygenase: Understanding the Genotype-Phenotype Correlations in the Rare Genetic Disease Alkaptonuria

Bernini

Spiga

Santucci

2023

CPPS

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Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in organs, which occurs because the homogentisate 1,2-dioxygenase (HGD) enzyme is not functional due to gene variants. Over time, HGA oxidation and accumulation cause the formation of the ochronotic pigment, a deposit that provokes tissue degeneration and organ malfunction. Here, we report a comprehensive review of the variants so far reported, the structural studies on the molecular consequences of protein stability and interaction, and molecular simulations for pharmacological chaperones as protein rescuers. Moreover, evidence accumulated so far in alkaptonuria research will be re-proposed as the bases for a precision medicine approach in a rare disease.

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Characterization of changes in the tyrosine pathway by 24-h profiling during nitisinone treatment in alkaptonuria

Cited by 6 publications

References 28 publications

Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

Determinants of tyrosinaemia during nitisinone therapy in alkaptonuria

Metabolic profiles and fingerprints for the investigation of the influence of nitisinone on the metabolism of the yeast Saccharomyces cerevisiae

Structure-Function Relationship of Homogentisate 1,2-dioxygenase: Understanding the Genotype-Phenotype Correlations in the Rare Genetic Disease Alkaptonuria

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