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在缺乏 UDP-葡萄糖焦磷酸化酶的细胞系中，半乳糖代谢和糖缀合物生物合成的缺陷可以通过在生长培养基中添加半乳糖来逆转。

Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium.

机构信息

INSERM U1149, Université de Paris, 16 rue Henri Huchard, 75018 Paris, France.

Institute for Clinical Biochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

出版信息

Int J Mol Sci. 2020 Mar 16;21(6):2028. doi: 10.3390/ijms21062028.

DOI:10.3390/ijms21062028
PMID:32188137
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7139386/
Abstract

UDP-glucose (UDP-Glc) is synthesized by -encoded UDP-Glc pyrophosphorylase (UGP) and is required for glycoconjugate biosynthesis and galactose metabolism because it is a uridyl donor for galactose-1-P (Gal1P) uridyltransferase. Chinese hamster lung fibroblasts harboring a hypomrphic UGP(G116D) variant display reduced UDP-Glc levels and cannot grow if galactose is the sole carbon source. Here, these cells were cultivated with glucose in either the absence or presence of galactose in order to investigate glycoconjugate biosynthesis and galactose metabolism. The UGP-deficient cells display < 5% control levels of UDP-Glc/UDP-Gal and > 100-fold reduction of [6-H]galactose incorporation into UDP-[6-H]galactose, as well as multiple deficits in glycoconjugate biosynthesis. Cultivation of these cells in the presence of galactose leads to partial restoration of UDP-Glc levels, galactose metabolism and glycoconjugate biosynthesis. The V for recombinant human UGP(G116D) with Glc1P is 2000-fold less than that of the wild-type protein, and UGP(G116D) displayed a mildly elevated K for Glc1P, but no activity of the mutant enzyme towards Gal1P was detectable. To conclude, although the mechanism behind UDP-Glc/Gal production in the UGP-deficient cells remains to be determined, the capacity of this cell line to change its glycosylation status as a function of extracellular galactose makes it a useful, reversible model with which to study different aspects of galactose metabolism and glycoconjugate biosynthesis.

摘要

UDP-葡萄糖 (UDP-Glc) 由编码 UDP-Glc 焦磷酸化酶 (UGP) 的基因合成，是糖缀合物生物合成和半乳糖代谢所必需的，因为它是半乳糖-1-P (Gal1P) 尿苷酰转移酶的尿苷供体。携带 UGP(G116D) 变异体的中国仓鼠肺成纤维细胞显示 UDP-Glc 水平降低，如果半乳糖是唯一的碳源，则无法生长。在这里，为了研究糖缀合物生物合成和半乳糖代谢，这些细胞在缺乏或存在葡萄糖的情况下用葡萄糖进行培养。UGP 缺陷细胞显示 UDP-Glc/UDP-Gal 的控制水平 <5%，[6-H]半乳糖掺入 UDP-[6-H]半乳糖的减少超过 100 倍，以及糖缀合物生物合成的多种缺陷。在存在半乳糖的情况下培养这些细胞会导致 UDP-Glc 水平、半乳糖代谢和糖缀合物生物合成的部分恢复。重组人 UGP(G116D) 与 Glc1P 的 V 值比野生型蛋白低 2000 倍，UGP(G116D) 对半乳糖的 K 值略有升高，但突变酶对半乳糖的活性检测不到。总之，尽管 UGP 缺陷细胞中 UDP-Glc/Gal 产生的机制仍有待确定，但该细胞系能够根据细胞外半乳糖改变其糖基化状态，使其成为研究半乳糖代谢和糖缀合物生物合成不同方面的有用、可逆模型。

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