Norman, Brendan P 
ORCID: 0000-0001-9293-4852, Davison, Andrew S ORCID: 0000-0001-5501-4475, Hughes, Juliette H ORCID: 0000-0001-6155-4136, Sutherland, Hazel, Wilson, Peter J, Berry, Neil G, Hughes, Andrew T, Milan, Anna M, Jarvis, Jonathan C, Roberts, Norman B et al (show 3 more authors)
(2020)
Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism.
biorxiv.
2020.04.16.044347-.
(Unpublished)
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Abstract
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background and Purpose</jats:title><jats:p>alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of the enzyme homogentisate 1,2-dioxygenase (HGD). The primary biochemical consequence of HGD-deficiency is increased circulating homogentisic acid (HGA), which is central to AKU disease pathology. The aim of this study was to investigate the wider metabolic consequences of targeted <jats:italic>Hgd</jats:italic> disruption.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p>the first metabolomic analysis of the <jats:italic>Hgd</jats:italic><jats:sup>−/−</jats:sup> AKU mouse model was performed. Urinary metabolites altered in <jats:italic>Hgd</jats:italic><jats:sup>−/−</jats:sup> were further validated by showing that the HGA-lowering drug nitisinone reversed their direction of alteration in AKU</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p>comparison of <jats:italic>Hgd</jats:italic><jats:sup>−/−</jats:sup> (AKU) versus <jats:italic>Hgd</jats:italic><jats:sup>+/−</jats:sup> (heterozygous control) urine revealed increases in HGA and a group of 8 previously unreported HGA-derived transformation products from phase I and II metabolism. HGA biotransformation products HGA-sulfate, HGA-glucuronide, HGA-hydrate and hydroxymethyl-HGA were also decreased in urine from both mice and patients with AKU on the HGA-lowering agent nitisinone. <jats:italic>Hgd</jats:italic> knockout also revealed a host of previously unrecognised associations between tyrosine, purine and TCA cycle metabolic pathways.</jats:p></jats:sec><jats:sec><jats:title>Conclusion and Implications</jats:title><jats:p>AKU is rare, but our findings further what is currently understood about tyrosine metabolism more generally, and show for the first time that phase I and II detoxification is recruited to prevent accumulation of endogenously-produced metabolites in inborn errors of metabolism. The data highlight the misconception that phase I and II metabolic biotransformations are reserved solely for drug clearance; these are ancient mechanisms, which represent new potential treatment targets in inherited metabolic diseases.</jats:p></jats:sec><jats:sec><jats:title>Abstract Figure</jats:title><jats:fig id="ufig1" position="float" fig-type="figure" orientation="portrait"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="044347v1_ufig1" position="float" orientation="portrait" /></jats:fig></jats:sec><jats:sec><jats:title>Bullet point summary</jats:title><jats:p>What is already known <jats:list list-type="bullet"><jats:list-item><jats:p>Increased circulating homogentisic acid is central to disease pathology in the inherited metabolic disease alkaptonuria</jats:p></jats:list-item><jats:list-item><jats:p>The <jats:italic>Hgd</jats:italic> knockout mouse, created in our laboratory, accurately models human alkaptonuria</jats:p></jats:list-item></jats:list></jats:p><jats:p>What this study adds <jats:list list-type="bullet"><jats:list-item><jats:p>Phase I and II biotransformations are recruited in alkaptonuria for detoxification of homogentisic acid</jats:p></jats:list-item><jats:list-item><jats:p>These data challenge misconceptions that phase I and II metabolism is solely for drug clearance</jats:p></jats:list-item></jats:list></jats:p><jats:p>Clinical significance <jats:list list-type="bullet"><jats:list-item><jats:p>Phase I and II metabolic processes represent new treatment targets in inherited metabolic diseases</jats:p></jats:list-item><jats:list-item><jats:p>The molecular pathology of AKU extends much further than the known alteration to tyrosine metabolism</jats:p></jats:list-item></jats:list></jats:p></jats:sec>
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Clinical Research, Metabolic and endocrine |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 29 May 2020 10:51 |
| Last Modified: | 14 Mar 2024 17:45 |
| DOI: | 10.1101/2020.04.16.044347 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3089178 |
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