Glycine abundance is modulated in a tissue-specific manner by use in biosynthetic reactions, catabolism by the
glycine cleavage system (GCS), and excretion via
glycine conjugation. Dysregulation of
glycine metabolism is associated with multiple disorders including
epilepsy, developmental delay, and
birth defects. Mutation of the GCS component
glycine decarboxylase (GLDC) in
non-ketotic hyperglycinemia (NKH) causes accumulation of
glycine in body fluids, but there is a gap in our knowledge regarding the effects on
glycine metabolism in tissues. Here, we analysed mice carrying mutations in Gldc that result in severe or mild elevations of plasma
glycine and model NKH. Liver of Gldc-deficient mice accumulated
glycine and numerous
glycine derivatives, including multiple acylglycines, indicating increased flux through reactions mediated by
enzymes including
glycine-N-acyltransferase and
arginine: glycine amidinotransferase. Levels of dysregulated metabolites increased with age and were normalised by liver-specific rescue of Gldc expression. Brain tissue exhibited increased abundance of
glycine, as well as derivatives including
guanidinoacetate, which may itself be epileptogenic. Elevation of brain tissue
glycine occurred even in the presence of only mildly elevated plasma
glycine in mice carrying a missense allele of Gldc. Treatment with
benzoate enhanced hepatic
glycine conjugation thereby lowering plasma and tissue
glycine. Moreover, administration of a
glycine conjugation pathway intermediate,
cinnamate, similarly achieved normalisation of liver
glycine derivatives and circulating
glycine. Although exogenous
benzoate and
cinnamate impact
glycine levels via activity of
glycine-N-acyltransferase, that is not expressed in brain, they are sufficient to lower levels of
glycine and derivatives in brain tissue of treated Gldc-deficient mice.