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Article

Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1)

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Research Institute for Biomedical Aging Research, University of Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria
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Department of Organic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Straße 38, A-1090 Vienna, Austria
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Campus Tulln, University of Applied Sciences Wiener Neustadt, Konrad-Lorenz-Straße 10, A-3430 Tulln an der Donau, Austria
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Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria
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Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 58, A-6020 Innsbruck, Austria
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Department of Pharmaceutical Sciences, Pharmaceutical Chemistry Division, Faculty of Life Sciences, University of Vienna, Althanstraße 14, UZ2 E349, A-1090 Vienna, Austria
*
Authors to whom correspondence should be addressed.
Academic Editor: Gyorgy M. Keseru
Molecules 2021, 26(16), 5009; https://doi.org/10.3390/molecules26165009
Received: 5 July 2021 / Revised: 13 August 2021 / Accepted: 15 August 2021 / Published: 18 August 2021
FAH domain containing protein 1 (FAHD1) acts as oxaloacetate decarboxylase in mitochondria, contributing to the regulation of the tricarboxylic acid cycle. Guided by a high-resolution X-ray structure of FAHD1 liganded by oxalate, the enzymatic mechanism of substrate processing is analyzed in detail. Taking the chemical features of the FAHD1 substrate oxaloacetate into account, the potential inhibitor structures are deduced. The synthesis of drug-like scaffolds afforded first-generation FAHD1-inhibitors with activities in the low micromolar IC50 range. The investigations disclosed structures competing with the substrate for binding to the metal cofactor, as well as scaffolds, which may have a novel binding mode to FAHD1. View Full-Text
Keywords: FAHD1; enzyme inhibitor; mitochondria; ODx; oxaloacetate FAHD1; enzyme inhibitor; mitochondria; ODx; oxaloacetate
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MDPI and ACS Style

Weiss, A.K.H.; Wurzer, R.; Klapec, P.; Eder, M.P.; Loeffler, J.R.; von Grafenstein, S.; Monteleone, S.; Liedl, K.R.; Jansen-Dürr, P.; Gstach, H. Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1). Molecules 2021, 26, 5009. https://doi.org/10.3390/molecules26165009

AMA Style

Weiss AKH, Wurzer R, Klapec P, Eder MP, Loeffler JR, von Grafenstein S, Monteleone S, Liedl KR, Jansen-Dürr P, Gstach H. Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1). Molecules. 2021; 26(16):5009. https://doi.org/10.3390/molecules26165009

Chicago/Turabian Style

Weiss, Alexander K.H., Richard Wurzer, Patrycia Klapec, Manuel P. Eder, Johannes R. Loeffler, Susanne von Grafenstein, Stefania Monteleone, Klaus R. Liedl, Pidder Jansen-Dürr, and Hubert Gstach. 2021. "Inhibitors of Fumarylacetoacetate Hydrolase Domain Containing Protein 1 (FAHD1)" Molecules 26, no. 16: 5009. https://doi.org/10.3390/molecules26165009

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