Pristup, Julika, Schaeffeler, Elke, Arjune, Sita 
ORCID: 0000-0002-6121-4614, Hofmann, Ute, Santamaria-Araujo, Jose Angel, Leuthold, Patrick, Friedrich, Nele, Nauck, Matthias, Mayr, Simon, Haag, Mathias, Muerdter, Thomas, Marner, Franz-Josef, Relling, Mary, V, Evans, William E., Schwarz, Guenter and Schwab, Matthias
(2022).
Molybdenum Cofactor Catabolism Unravels the Physiological Role of the Drug Metabolizing Enzyme Thiopurine S-Methyltransferase.
Clin. Pharmacol. Ther., 112 (4).
S. 808 - 817.
HOBOKEN:
WILEY.
ISSN 1532-6535
Abstract
Therapy of molybdenum cofactor (Moco) deficiency has received US Food and Drug Administration (FDA) approval in 2021. Whereas urothione, the urinary excreted catabolite of Moco, is used as diagnostic biomarker for Moco-deficiency, its catabolic pathway remains unknown. Here, we identified the urothione-synthesizing methyltransferase using mouse liver tissue by anion exchange/size exclusion chromatography and peptide mass fingerprinting. We show that the catabolic Moco S-methylating enzyme corresponds to thiopurine S-methyltransferase (TPMT), a highly polymorphic drug-metabolizing enzyme associated with drug-related hematotoxicity but unknown physiological role. Urothione synthesis was investigated in vitro using recombinantly expressed human TPMT protein, liver lysates from Tpmt wild -type and knock-out (Tpmt(-/-)) mice as well as human liver cytosol. Urothione levels were quantified by liquid-chromatography tandem mass spectrometry in the kidneys and urine of mice. TPMT-genotype/phenotype and excretion levels of urothione were investigated in human samples and validated in an independent population-based study. As Moco provides a physiological substrate (thiopterin) of TPMT, thiopterin-methylating activity was associated with TPMT activity determined with its drug substrate (6-thioguanin) in mice and humans. Urothione concentration was extremely low in the kidneys and urine of Tpmt-/- mice. Urinary urothione concentration in TPMT-deficient patients depends on common TPMT polymorphisms, with extremely low levels in homozygous variant carriers (TPMT*3A/*3A) but normal levels in compound heterozygous carriers (TPMT*3A/*3C) as validated in the population-based study. Our work newly identified an endogenous substrate for TPMT and shows an unprecedented link between Moco catabolism and drug metabolism. Moreover, the TPMT example indicates that phenotypic consequences of genetic polymorphisms may differ between drug-and endogenous substrates.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URN: | urn:nbn:de:hbz:38-687865 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.1002/cpt.2637 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Clin. Pharmacol. Ther. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Volume: | 112 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Number: | 4 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Page Range: | S. 808 - 817 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date: | 2022 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publisher: | WILEY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Place of Publication: | HOBOKEN | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 1532-6535 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Language: | English | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URI: | http://kups.ub.uni-koeln.de/id/eprint/68786 |
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