Abstract
Glycine cleavage system H protein (GCSH) is a component of the glycine cleavage system (GCS), a conserved protein complex that acts to decarboxylate glycine. Mutation of AMT or GLDC, encoding the GCS components aminomethyltransferase and glycine decarboxylase, can cause malformations of the developing CNS (neural tube defects (NTDs) and ventriculomegaly) as well as a post-natal life-limiting neurometabolic disorder, Non-Ketotic Hyperglycinemia. In contrast, it is unclear whether mutation of GCSH contributes to these conditions and we therefore investigated GCSH loss of function in mice. Mice that were heterozygous for a Gcsh null allele were viable and did not exhibit elevated plasma glycine. Moreover, heterozygous mutation of Gcsh did not increase the frequency of NTDs in Gldc mutant embryos. Homozygous Gcsh null mice were not recovered at post-natal stages. Analysis of litters at E8.5-10.5, revealed the presence of homozygous null embryos which were much smaller than littermates and had failed to develop beyond early post-implantation stages with no visible somites or head-folds. Hence, unlike null mutations of Gldc or Amt, which are compatible with embryonic survival despite the presence of NTDs, loss of Gcsh causes embryonic death prior to mid-gestation. Maternal supplementation with formate did not restore embryonic development beyond E7.5, suggesting that the primary cause of lethality was not loss of glycine cleavage activity or suppression of folate one-carbon metabolism. These findings suggest that GCSH has additional roles beyond function in the glycine cleavage system. We hypothesize that GCSH potentially acts in lipoylation of 2-oxoacid dehydrogenase proteins, as reported in bacteria.
Highlights
Glycine cleavage system H-protein (GCSH) is one of four enzymes which, together with glycine decarboxylase (GLDC), aminomethyltransferase (AMT), and dehydrolipamide dehydrogenase (DLD), make up the glycine cleavage system (GCS)
We investigated the effect of Gcsh loss of function in mice, in order to ask whether this revealed a potential role in neural tube defects (NTDs) and/or features of Non-Ketotic Hyperglycinemia (NKH)
The Gcsh gene consists of 5 exons which generate a 1,192 nucleotide transcript encoding a polypeptide of 173 amino acids that is processed to give a mature protein of 125 amino acids
Summary
Glycine cleavage system H-protein (GCSH) is one of four enzymes which, together with glycine decarboxylase (GLDC), aminomethyltransferase (AMT), and dehydrolipamide dehydrogenase (DLD), make up the glycine cleavage system (GCS). GCSH plays a central role in the catalytic process, forming an amino-methyl intermediate with GLDC and acting as the acceptor of the methylamine group which is transferred as the substrate for AMT (Figure 1A). This function of GCSH depends on modification by covalent addition of lipoic acid, as a cofactor, to form the active lipoylenzyme. DLD mediates reduction of NAD+ and oxidation of the lipoyl group of GCSH (Figure 1A)
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