Amino Acid Conjugation: A Novel Route of Xenobiotic Carboxylic Acid Metabolism in Man

Knights, Kathleen M.; Miners, John O.

doi:10.1002/9780470921920.edm020

Cited by 9 publications

(12 citation statements)

References 62 publications

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“…Hippuric acid and acetylglycine are products of the conjugation of glycine with benzoyl-CoA and acetyl-CoA, respectively, which is catalyzed by glycine N-acyltransferase (Dempsey et al ., 2014; Schachter and Taggart, 1954). Degradation of dietary polyphenols by gut microorganisms is thought to be a major source of benzoic acid and other glycine conjugation substrates (Knights and Miners, 2012; Lees et al ., 2013). Elimination of the gut bacteria using antibiotics or germ-free mice was shown to eliminate hippuric acid excretion (Lees et al ., 2013; Nicholls et al ., 2003; Yap et al ., 2008).…”

Section: Discussionmentioning

confidence: 99%

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure

Huang

Douillet

et al. 2016

Arch Toxicol

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Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and As3mt-KO (KO) C57BL6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate (L-sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex-specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that As3mt KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that As3mt may be involved in other cellular processes beyond iAs methylation.

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Section: Discussionmentioning

confidence: 99%

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure

Huang

Douillet

et al. 2016

Arch Toxicol

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“…It is also worth noting the potential HGA biotransformation products that were not detected in Hgd -/in this study (see Appendix 3 for the full list of potential HGA-derived products predicted in silico). A particularly notable example is the absence of a glycine conjugate of HGA, as glycine conjugation is a known detoxification mechanism of a number of other aromatic acids (Knights et al, 2007;Knights and Miners, 2012).…”

Section: Hga Biotransformation Products From Phases I and Ii Metabolismmentioning

confidence: 99%

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

Norman

Davison

Hughes

et al. 2020

Preprint

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Bullet point summaryWhat is already known  Increased circulating homogentisic acid is central to disease pathology in the inherited metabolic disease alkaptonuria  The Hgd knockout mouse, created in our laboratory, accurately models human alkaptonuria What this study adds  Phase I and II biotransformations are recruited in alkaptonuria for detoxification of homogentisic acid  These data challenge misconceptions that phase I and II metabolism is solely for drug clearance Clinical significance  Phase I and II metabolic processes represent new treatment targets in inherited metabolic diseases  The molecular pathology of AKU extends much further than the known alteration to tyrosine metabolism 3 4 Abstract Background and Purpose: 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 Hgd disruption. Experimental Approach: the first metabolomic analysis of the Hgd -/-AKU mouse model was performed. Urinary metabolites altered in Hgd -/were further validated by showing that the HGA-lowering drug nitisinone reversed their direction of alteration in AKU Key Results: comparison of Hgd -/-(AKU) versus Hgd +/-(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. Hgd knockout also revealed a host of previously unrecognised associations between tyrosine, purine and TCA cycle metabolic pathways.Conclusion and Implications: 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 endogenouslyproduced 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.

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“…The rate-limiting step in degradation is the conversion of salicylic acid to salicyl-CoA catalyzed by medium chain acyl-Coenzyme A synthase, and the final step is the conversion of salicyl-CoA to salicylurate, catalyzed by glycine-N-acyltransferase [ 2 ]. The conversion to salicylurate is a key step toward renal clearance, accounting for 50% [ 3 , 4 ] to 85% [ 5 ] of ingested salicylate. Only about 10% is urinary salicylate [ 6 ].…”

Section: Overview Of the Kineticsmentioning

confidence: 99%

Diverse Data Sets Can Yield Reliable Information through Mechanistic Modeling: Salicylic Acid Clearance

2015

BJPR

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This is a practical example of a powerful research strategy: putting together data from studies covering a diversity of conditions can yield a scientifically sound grasp of the phenomenon when the individual observations failed to provide definitive understanding. The rationale is that defining a realistic, quantitative, explanatory hypothesis for the whole set of studies, brings about a “consilience” of the often competing hypotheses considered for individual data sets. An internally consistent conjecture linking multiple data sets simultaneously provides stronger evidence on the characteristics of a system than does analysis of individual data sets limited to narrow ranges of conditions. Our example examines three very different data sets on the clearance of salicylic acid from humans: a high concentration set from aspirin overdoses; a set with medium concentrations from a research study on the influences of the route of administration and of sex on the clearance kinetics, and a set on low dose aspirin for cardiovascular health. Three models were tested: (1) a first order reaction, (2) a Michaelis-Menten (M-M) approach, and (3) an enzyme kinetic model with forward and backward reactions. The reaction rates found from model 1 were distinctly different for the three data sets, having no commonality. The M-M model 2 fitted each of the three data sets but gave a reliable estimates of the Michaelis constant only for the medium level data (Km = 24±5.4 mg/L); analyzing the three data sets together with model 2 gave Km = 18±2.6 mg/L. (Estimating parameters using larger numbers of data points in an optimization increases the degrees of freedom, constraining the range of the estimates). Using the enzyme kinetic model (3) increased the number of free parameters but nevertheless improved the goodness of fit to the combined data sets, giving tighter constraints, and a lower estimated Km = 14.6±2.9 mg/L, demonstrating that fitting diverse data sets with a single model improves confidence in the results. This modeling effort is also an example of reproducible science available at html://www.physiome.org/jsim/models/webmodel/NSR/SalicylicAcidClearance

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Amino Acid Conjugation: A Novel Route of Xenobiotic Carboxylic Acid Metabolism in Man

Cited by 9 publications

References 62 publications

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure

Studies in alkaptonuria reveal new roles beyond drug clearance for phase I and II biotransformations in tyrosine metabolism

Diverse Data Sets Can Yield Reliable Information through Mechanistic Modeling: Salicylic Acid Clearance

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