eprintid: 10106990 rev_number: 41 eprint_status: archive userid: 608 dir: disk0/10/10/69/90 datestamp: 2020-08-07 15:19:56 lastmod: 2021-12-10 23:58:31 status_changed: 2020-12-09 12:10:13 type: article metadata_visibility: show creators_name: Leung, K-Y creators_name: De Castro, SCP creators_name: Santos, C creators_name: Savery, D creators_name: Prunty, H creators_name: Gold-Diaz, D creators_name: Bennett, S creators_name: Heales, S creators_name: Copp, AJ creators_name: Greene, NDE title: Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of Non-Ketotic Hyperglycinemia ispublished: pub subjects: GOSH divisions: UCL divisions: B02 divisions: D13 divisions: G22 divisions: G23 keywords: Glycine cleavage system, glycine decarboxylase, glycine conjugation, Non-Ketotic Hyperglycinemia, benzoate, cinnamate note: © 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. abstract: 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. date: 2020-11 date_type: published official_url: https://doi.org/10.1002/jimd.12295 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1806266 doi: 10.1002/jimd.12295 lyricists_name: Castro, Sandra lyricists_name: Copp, Andrew lyricists_name: Greene, Nicholas lyricists_name: Heales, Simon lyricists_name: Leung, Kit-Yi lyricists_name: Santos, Chloe lyricists_id: SCPDC76 lyricists_id: ACOPP78 lyricists_id: NDEGR34 lyricists_id: SJRHE78 lyricists_id: KYLEU59 lyricists_id: CSANT19 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Journal of Inherited Metabolic Disease volume: 43 number: 6 pagerange: 1186-1198 event_location: United States citation: Leung, K-Y; De Castro, SCP; Santos, C; Savery, D; Prunty, H; Gold-Diaz, D; Bennett, S; ... Greene, NDE; + view all <#> Leung, K-Y; De Castro, SCP; Santos, C; Savery, D; Prunty, H; Gold-Diaz, D; Bennett, S; Heales, S; Copp, AJ; Greene, NDE; - view fewer <#> (2020) Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of Non-Ketotic Hyperglycinemia. Journal of Inherited Metabolic Disease , 43 (6) pp. 1186-1198. 10.1002/jimd.12295 <https://doi.org/10.1002/jimd.12295>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10106990/7/Castro_jimd.12295%20%281%29.pdf