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Urine metabolomics reveals novel physiologic functions of human aldehyde oxidase and provides biomarkers for typing xanthinuria

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Abstract

Classical xanthinuria is a rare inherited metabolic disorder caused by either isolated xanthine dehydrogenase (XDH) deficiency (type I) or combined XDH and aldehyde oxidase (AO) deficiency (type II). XDH and AO are evolutionary related enzymes that share a sulfurated molybdopterin cofactor. While the role of XDH in purine metabolism is well established, the physiologic functions of AO are mostly unknown. XDH and AO are important drug metabolizing enzymes. Urine metabolomic analysis by high pressure liquid chromatography and mass spectrometry of xanthinuric patients was performed to unveil physiologic functions of XDH and AO and provide biomarkers for typing xanthinuria. Novel endogenous products of AO, hydantoin propionic acid, N1-methyl-8-oxoguanine and N-(3-acetamidopropyl) pyrrolidin-2-one formed in the histidine, nucleic acid and spermidine metabolic pathways, respectively, were identified as being lowered in type II xanthinuria. Also lowered were the known AO products, N1-methyl-2-pyridone-5-carboxamide and N1-methyl-4-pyridone-5-carboxamide in the nicotinamide degradation pathway. In contrast to the KEGG annotations, the results suggest minor role of human AO in the conversion of pyridoxal to pyridoxate and gentisaldehyde to gentisate in the vitamin B6 and tyrosine metabolic pathways, respectively. The perturbations in purine degradation due to XDH deficiency radiated further from the previously known metabolites, uric acid, xanthine and hypoxanthine to guanine, methyl guanine, xanthosine and inosine. Possible pathophysiological implications of the observed metabolic perturbations are discussed. The identified biomarkers have the potential to replace the allopurinol-loading test used in the past to type xanthinuria, thus facilitating appropriate pharmacogenetic counseling and gene directed search for causative mutations.

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Abbreviations

XDH:

Xanthine dehydrogenase

XO:

Xanthine oxidase

HMCS:

Human molybdenum cofactor sulfurase

MS2 :

Tandem mass spectra

KEGG:

Kyoto encyclopedia of genes and genomes

2PY:

N1-methyl-2-pyridone-5-carboxamide

4PY:

N1-methyl-4-pyridone-5-carboxamide

NMN:

N1-methylnicotinamide

HPA:

Hydantoin propionic acid

NMOG:

N-methyl-8-oxoguanine

APP:

N-(3-acetamidopropyl) pyrrolidin-2-one

ADH:

Aldehyde dehydrogenase

TPMT:

Thiopurine methyl transferase

6-MP:

6-Mercaptopurine

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Acknowledgments

We thank Scottish Life Sciences Alliance for funding scholarship of GB and acquisition of the Exactive mass spectrometer. Thanks are due to the referring physicians Drs. Renate Yakobov, Halil Heib and Dganit Dinour.

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Authors and Affiliations

  1. Clinical Biochemistry Laboratory, Tel Aviv Sourasky Medical Center, Human Molecular Genetics and Biochemistry, Tel Aviv University, 6 Weizmann, Tel Aviv, Israel, 64239

    Hava Peretz, Ayala Lagziel, Meirav Shtauber-Naamati, Tova Morad, Elena Keren-Tardai, Victoria Greenshpun & Sali Usher

  2. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

    David G. Watson, Gavin Blackburn & Tong Zhang

  3. Department of Pediatrics, Soroka Medical Center, Ben Gurion University, Beer Sheva, Israel

    Hanna Shalev & Daniel Landau

  4. Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel

    David Levartovsky

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  1. Hava Peretz
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  2. David G. Watson
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Correspondence to Hava Peretz.

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Peretz, H., Watson, D.G., Blackburn, G. et al. Urine metabolomics reveals novel physiologic functions of human aldehyde oxidase and provides biomarkers for typing xanthinuria. Metabolomics 8, 951–959 (2012). https://doi.org/10.1007/s11306-011-0391-3

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  • DOI: https://doi.org/10.1007/s11306-011-0391-3

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