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