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

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.