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Nucleotide sugar profiles throughout development in wildtype and galt knockout zebrafish.
Journal of Inherited Metabolic Disease ( IF 4.2 ) Pub Date : 2020-05-22 , DOI: 10.1002/jimd.12265
Minela Haskovic 1, 2, 3 , Ana I Coelho 1, 2, 3 , Martijn Lindhout 2 , Fokje Zijlstra 4 , Raisa Veizaj 5 , Rein Vos 6 , Jo M Vanoevelen 2, 3 , Jörgen Bierau 2 , Dirk J Lefeber 4, 5 , M Estela Rubio-Gozalbo 1, 2, 3
Affiliation  

Nucleotide sugars (NS) are fundamental molecules in life and play a key role in glycosylation reactions and signal conduction. Several pathways are involved in the synthesis of NS. The Leloir pathway, the main pathway for galactose metabolism, is crucial for production of uridine diphosphate (UDP)‐glucose and UDP‐galactose. The most common metabolic disease affecting this pathway is galactose‐1‐phosphate uridylyltransferase (GALT) deficiency, that despite a lifelong galactose‐restricted diet, often results in chronically debilitating complications. Alterations in the levels of UDP‐sugars leading to galactosylation abnormalities have been hypothesized as a key pathogenic factor. However, UDP‐sugar levels measured in patient cell lines have shown contradictory results. Other NS that might be affected, differences throughout development, as well as tissue specific profiles have not been investigated. Using recently established UHPLC‐MS/MS technology, we studied the complete NS profiles in wildtype and galt knockout zebrafish (Danio rerio). Analyses of UDP‐hexoses, UDP‐hexosamines, CMP‐sialic acids, GDP‐fucose, UDP‐glucuronic acid, UDP‐xylose, CDP‐ribitol, and ADP‐ribose profiles at four developmental stages and in tissues (brain and gonads) in wildtype zebrafish revealed variation in NS levels throughout development and differences between examined tissues. More specifically, we found higher levels of CMP‐N‐acetylneuraminic acid, GDP‐fucose, UDP‐glucuronic acid, and UDP‐xylose in brain and of CMP‐N‐glycolylneuraminic acid in gonads. Analysis of the same NS profiles in galt knockout zebrafish revealed no significant differences from wildtype. Our findings in galt knockout zebrafish, even when challenged with galactose, do not support a role for abnormalities in UDP‐glucose or UDP‐galactose as a key pathogenic factor in GALT deficiency, under the tested conditions.

中文翻译:

野生型和 galt 敲除斑马鱼在整个发育过程中的核苷酸糖谱。

核苷酸糖(NS)是生命中的基本分子,在糖基化反应和信号传导中起关键作用。NS的合成涉及多种途径。Leloir 途径是半乳糖代谢的主要途径,对尿苷二磷酸 (UDP)-葡萄糖和 UDP-半乳糖的产生至关重要。影响该途径的最常见代谢疾病是 1-磷酸半乳糖尿苷酰转移酶 (GALT) 缺乏症,尽管终生限制半乳糖饮食,但通常会导致慢性衰弱并发症。UDP-糖水平的改变导致半乳糖基化异常已被假设为一个关键的致病因素。然而,在患者细胞系中测量的 UDP 糖水平显示出相互矛盾的结果。其他可能受影响的 NS,整个开发过程中的差异,以及组织特异性谱尚未研究。使用最近建立的 UHPLC-MS/MS 技术,我们研究了野生型和galt淘汰斑马鱼 ( Danio rerio )。UDP-己糖、UDP-己糖胺、CMP-唾液酸、GDP-岩藻糖、UDP-葡萄糖醛酸、UDP-木糖、CDP-核糖醇和 ADP-核糖在四个发育阶段和组织(大脑和性腺)中的分析野生型斑马鱼揭示了整个发育过程中 NS 水平的变化以及检查组织之间的差异。更具体地说,我们发现较高水平的CMP- Ñ在大脑和CMP- -acetylneuraminic酸,GDP-岩藻糖,UDP葡糖醛酸和UDP-木糖Ñ在性腺-glycolylneuraminic酸。对galt敲除斑马鱼的相同 NS 谱的分析显示与野生型没有显着差异。我们在galt 中的发现 在测试条件下,敲除斑马鱼,即使受到半乳糖挑战,也不支持 UDP-葡萄糖或 UDP-半乳糖异常作为 GALT 缺乏症的关键致病因素。
更新日期:2020-05-22
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