GADL1 is a multifunctional decarboxylase with tissue specific roles in β-alanine and carnosine production

Mahootchi, E.; Himaei, S. C.; Kleppe, R.; Winge, I.; Hegvik, T.-A.; Megias-Perez, R.; Totland, C.; Mogavero, F.; Baumann, A.; Glennon, J.; Miletic, H.; Kursula, P.; Haavik, J.

doi:10.1101/2020.02.18.954438

bioRxiv · 10.1101/2020.02.18.954438

GADL1 is a multifunctional decarboxylase with tissue specific roles in β-alanine and carnosine production

Mahootchi, E.·Himaei, S. C.·Kleppe, R.·Winge, I.·Hegvik, T.-A.·Megias-Perez, R.·Totland, C.·Mogavero, F.·Baumann, A.·Glennon, J.·Miletic, H.·Kursula, P.·Haavik, J.

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Abstract

Carnosine and related {beta}-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 {beta}-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, compatible with organ-specific functions. Human genetic studies show strong associations of the GADL1 locus with plasma levels of carnosine, subjective well-being, and muscle strength, also indicating a role for {beta}-alanine and its peptide derivatives in these traits. 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.

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Mahootchi, E., Himaei, S. C., Kleppe, R., Winge, I., Hegvik, T.-A., Megias-Perez, R., Totland, C., Mogavero, F., Baumann, A., Glennon, J., Miletic, H., Kursula, P., Haavik, J.. 2020-02-18. GADL1 is a multifunctional decarboxylase with tissue specific roles in β-alanine and carnosine production. https://doi.org/10.1101/2020.02.18.954438

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