多组学揭示了果糖胺-3-激酶(FN3K)与核心代谢途径之间的新联系。

IF 3.5 2区 生物学 Q1 MATHEMATICAL & COMPUTATIONAL BIOLOGY
Safal Shrestha, Rahil Taujale, Samiksha Katiyar, Natarajan Kannan
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引用次数: 0

摘要

果糖胺-3-激酶(FN3Ks)是一个保守的修复酶家族,可将肽和蛋白质中赖氨酸残基上的活性糖磷酸化。虽然 FN3Ks 存在于整个生命之树,并且与真核生物蛋白激酶具有可检测到的序列相似性,但这些激酶调控的生物过程在很大程度上还不为人所知。为了填补这一知识空白,我们利用 FN3K CRISPR Knock-Out (KO) HepG2 细胞系,并结合转录组学、代谢组学和相互作用组学进行多组学综合研究,将这些酶置于通路背景中。综合分析表明,与氧化应激反应、脂质生物合成(胆固醇和脂肪酸)以及碳和辅助因子代谢相关的通路得到了丰富。此外,烟酰胺腺嘌呤二核苷酸(NAD)结合蛋白的富集以及人 FN3K(HsFN3K)在线粒体的定位表明,FN3K 与 NAD 介导的能量代谢和氧化还原平衡之间存在潜在联系。我们报告了 HsFN3K 以金属和浓度依赖的方式与 NAD 化合物的特异性结合,并通过建模和实验性定点突变深入了解了它们的结合模式。我们的研究为糖尿病并发症和新陈代谢紊乱(氧化还原平衡和依赖 NAD 的新陈代谢过程会发生改变)中以这些未被充分研究的激酶为靶点提供了一个框架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways.

Multi-omics reveals new links between Fructosamine-3-Kinase (FN3K) and core metabolic pathways.

Fructosamine-3-kinases (FN3Ks) are a conserved family of repair enzymes that phosphorylate reactive sugars attached to lysine residues in peptides and proteins. Although FN3Ks are present across the Tree of Life and share detectable sequence similarity to eukaryotic protein kinases, the biological processes regulated by these kinases are largely unknown. To address this knowledge gap, we leveraged the FN3K CRISPR Knock-Out (KO) HepG2 cell line alongside an integrative multi-omics study combining transcriptomics, metabolomics, and interactomics to place these enzymes in a pathway context. The integrative analyses revealed the enrichment of pathways related to oxidative stress response, lipid biosynthesis (cholesterol and fatty acids), and carbon and co-factor metabolism. Moreover, enrichment of nicotinamide adenine dinucleotide (NAD) binding proteins and localization of human FN3K (HsFN3K) to mitochondria suggests potential links between FN3K and NAD-mediated energy metabolism and redox balance. We report specific binding of HsFN3K to NAD compounds in a metal and concentration-dependent manner and provide insight into their binding mode using modeling and experimental site-directed mutagenesis. Our studies provide a framework for targeting these understudied kinases in diabetic complications and metabolic disorders where redox balance and NAD-dependent metabolic processes are altered.

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来源期刊
NPJ Systems Biology and Applications
NPJ Systems Biology and Applications Mathematics-Applied Mathematics
CiteScore
5.80
自引率
0.00%
发文量
46
审稿时长
8 weeks
期刊介绍: npj Systems Biology and Applications is an online Open Access journal dedicated to publishing the premier research that takes a systems-oriented approach. The journal aims to provide a forum for the presentation of articles that help define this nascent field, as well as those that apply the advances to wider fields. We encourage studies that integrate, or aid the integration of, data, analyses and insight from molecules to organisms and broader systems. Important areas of interest include not only fundamental biological systems and drug discovery, but also applications to health, medical practice and implementation, big data, biotechnology, food science, human behaviour, broader biological systems and industrial applications of systems biology. We encourage all approaches, including network biology, application of control theory to biological systems, computational modelling and analysis, comprehensive and/or high-content measurements, theoretical, analytical and computational studies of system-level properties of biological systems and computational/software/data platforms enabling such studies.
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