Glycine Cleavage System H Protein Is Essential for Embryonic Viability, Implying Additional Function Beyond the Glycine Cleavage System.
Glycine Cleavage System H Protein Is Essential for Embryonic Viability, Implying Additional Function Beyond the Glycine Cleavage System.
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DOI：
10.3389/fgene.2021.625120
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发表时间：
2021
影响因子：
3.7
通讯作者：
Greene NDE
中科院分区：
文献类型：
--
作者：
Leung KY;De Castro SCP;Galea GL;Copp AJ;Greene NDE
甘氨酸切割系统H蛋白（GCSH）是甘氨酸切割系统（GCS）的一个组成部分，GCS是一种保守的蛋白质复合物，其作用是使甘氨酸脱羧。编码GCS组分氨基甲基转移酶和甘氨酸脱羧酶的AMT或GLDC突变可导致发育中的中枢神经系统畸形（神经管缺陷（NTDs）和脑室肥大）以及出生后限制生命的神经代谢紊乱，非酮症型高糖血症。相比之下，目前尚不清楚GCSH突变是否会导致这些疾病，因此我们研究了小鼠GCSH功能丧失。gsh零等位基因杂合的小鼠存活，血浆甘氨酸不升高。此外，Gcsh的杂合突变并未增加Gldc突变胚中NTDs的频率。纯合子gsh缺失小鼠在产后未恢复。对E8.5-10.5胎仔的分析显示，纯合子零胚的存在比胎仔小得多，并且在着床后的早期阶段没有发育，没有可见的体或头褶皱。因此，与Gldc或Amt的零突变（尽管存在NTDs，但仍与胚胎存活相容）不同，gsh的缺失会导致妊娠中期之前的胚胎死亡。母体补充甲酸不能恢复E7.5以上的胚胎发育，这表明致死的主要原因不是甘氨酸裂解活性丧失或叶酸单碳代谢抑制。这些发现表明GCSH在甘氨酸切割系统中除了功能之外还有其他作用。我们假设GCSH可能在2-氧酸脱氢酶蛋白的脂酰化中起作用，正如在细菌中报道的那样。
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.
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影响因子：
3
作者：
Autuori MC;Pai YJ;Stuckey DJ;Savery D;Marconi AM;Massa V;Lythgoe MF;Copp AJ;David AL;Greene ND
通讯作者：
Greene ND
影响因子：
3.5
作者：
Narisawa A;Komatsuzaki S;Kikuchi A;Niihori T;Aoki Y;Fujiwara K;Tanemura M;Hata A;Suzuki Y;Relton CL;Grinham J;Leung KY;Partridge D;Robinson A;Stone V;Gustavsson P;Stanier P;Copp AJ;Greene ND;Tominaga T;Matsubara Y;Kure S
通讯作者：
Kure S
影响因子：
8.8
作者：
Leung KY;Pai YJ;Chen Q;Santos C;Calvani E;Sudiwala S;Savery D;Ralser M;Gross SS;Copp AJ;Greene NDE
通讯作者：
Greene NDE
DOI：
10.1073/pnas.1700934114
发表时间：
2017-06-27
影响因子：
11.1
作者：
Galea, Gabriel L.;Cho, Young-June;Copp, Andrew J.
通讯作者：
Copp, Andrew J.
影响因子：
15.9
作者：
HIRAGA, K;KOCHI, H;NYHAN, WL
通讯作者：
NYHAN, WL