Mahootchi, E., Cannon Homaei, S., Kleppe, R., Winge, I., Hegvik, T., Megias-Perez, R., Totland, C., Mogavero, F., Baumann, A., Glennon, J., Miletic, H., Kursula, P., Haavik, J. (2020) GADL1 is a multifunctional decarboxylase with tissue-specific roles in β-alanine and carnosine production. Science Advances, 6 (29), eabb3713. https://doi.org/10.1126/sciadv.abb3713
GADL1 is a multifunctional decarboxylase with tissue-specific roles in β-alanine and carnosine production
|Author:||Mahootchi, Elaheh1; Homaei, Selina Cannon1,2; Kleppe, Rune2;|
1Department of Biomedicine, University of Bergen, Bergen, Norway
2Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
3Department of Chemistry, University of Bergen, Bergen, Norway
4Norwegian Geotechnical Institute, Oslo, Norway
5Department of Cognitive Neuroscience, Donders Institute for Brain Cognition and Behavior, Radboud University Medical Center, Nijmegen, Netherlands
6Conway Institute of Biomolecular and Biomedical Research, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
7Department of Pathology, Haukeland University Hospital, Bergen, Norway
8Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 4.9 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020120399201
American Association for the Advancement of Science,
|Publish Date:|| 2020-12-03
Carnosine and related β-alanine–containing peptides are believed to be important antioxidants, pH buffers, and neuromodulators. However, their biosynthetic routes and therapeutic potential are still being debated. This study describes the first animal model lacking the enzyme glutamic acid decarboxylase–like 1 (GADL1). We show that Gadl1−/− mice are deficient in β-alanine, carnosine, and anserine, particularly in the olfactory bulb, cerebral cortex, and skeletal muscle. Gadl1−/− mice also exhibited decreased anxiety, increased levels of oxidative stress markers, alterations in energy and lipid metabolism, and age-related changes. Examination of the GADL1 active site indicated that the enzyme may have multiple physiological substrates, including aspartate and cysteine sulfinic acid. Human genetic studies show strong associations of the GADL1 locus with plasma levels of carnosine, subjective well-being, and muscle strength. Together, this shows the multifaceted and organ-specific roles of carnosine peptides and establishes Gadl1 knockout mice as a versatile model to explore carnosine biology and its therapeutic potential.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work has received funding from Stiftelsen Kristian Gerhard Jebsen (SKJ-MED-02), the Regional Health Authority of Western Norway (no. 25048), and the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no 115916 (PRISM). This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. The Genomics Core Facility (GCF) at the University of Bergen, which is a part of the NorSeq consortium, provided services on RNA sequencing. GCF is supported in part by major grants from the Research Council of Norway (grant no. 245979/F50) and Trond Mohn Stiftelse (grant no. BFS2016-genom).
© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).