原药 C13 通过两种不同的机制激活 AMPK。

IF 4.4 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemical Journal Pub Date : 2024-09-18 DOI:10.1042/BCJ20240425
Jordana B Freemantle, Dinesh Shah, Dylan M Lynch, Alessio Ciulli, Harinder S Hundal, D Grahame Hardie
{"title":"原药 C13 通过两种不同的机制激活 AMPK。","authors":"Jordana B Freemantle, Dinesh Shah, Dylan M Lynch, Alessio Ciulli, Harinder S Hundal, D Grahame Hardie","doi":"10.1042/BCJ20240425","DOIUrl":null,"url":null,"abstract":"<p><p>The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in almost all eukaryotic cells. In the canonical activation mechanism, it is activated by increases in AMP:ATP and ADP:ATP ratios that signify declining cellular energy status. Once activated, AMPK phosphorylates numerous targets that promote catabolic pathways generating ATP, while inhibiting anabolic and other processes that consume ATP, thus acting to restore energy homeostasis. Pharmacological agents that activate AMPK have been useful in identifying downstream targets and have potential as drugs for treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. One such agent is C13, a pro-drug with a phosphonate bis(isobutyryloxymethyl) ester moiety, with the isobutyryloxymethyl groups increasing membrane permeability. Following cellular uptake, C13 is cleaved to release C2, an AMP analogue and potent AMPK activator that is specific for complexes containing the α1 (but not the α2) catalytic subunit isoform. This has previously been assumed to be the sole mechanism by which C13 activates AMPK, with potential roles for the isobutyryloxymethyl groups being ignored. We now report that, following cleavage from C13, these protective groups are metabolized to formaldehyde, an agent that inhibits mitochondrial function and increases cellular AMP:ATP ratios, thus providing additional AMPK activation by the canonical mechanism.</p>","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"1203-1219"},"PeriodicalIF":4.4000,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555695/pdf/","citationCount":"0","resultStr":"{\"title\":\"The pro-drug C13 activates AMPK by two distinct mechanisms.\",\"authors\":\"Jordana B Freemantle, Dinesh Shah, Dylan M Lynch, Alessio Ciulli, Harinder S Hundal, D Grahame Hardie\",\"doi\":\"10.1042/BCJ20240425\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in almost all eukaryotic cells. In the canonical activation mechanism, it is activated by increases in AMP:ATP and ADP:ATP ratios that signify declining cellular energy status. Once activated, AMPK phosphorylates numerous targets that promote catabolic pathways generating ATP, while inhibiting anabolic and other processes that consume ATP, thus acting to restore energy homeostasis. Pharmacological agents that activate AMPK have been useful in identifying downstream targets and have potential as drugs for treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. One such agent is C13, a pro-drug with a phosphonate bis(isobutyryloxymethyl) ester moiety, with the isobutyryloxymethyl groups increasing membrane permeability. Following cellular uptake, C13 is cleaved to release C2, an AMP analogue and potent AMPK activator that is specific for complexes containing the α1 (but not the α2) catalytic subunit isoform. This has previously been assumed to be the sole mechanism by which C13 activates AMPK, with potential roles for the isobutyryloxymethyl groups being ignored. We now report that, following cleavage from C13, these protective groups are metabolized to formaldehyde, an agent that inhibits mitochondrial function and increases cellular AMP:ATP ratios, thus providing additional AMPK activation by the canonical mechanism.</p>\",\"PeriodicalId\":8825,\"journal\":{\"name\":\"Biochemical Journal\",\"volume\":\" \",\"pages\":\"1203-1219\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555695/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biochemical Journal\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1042/BCJ20240425\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biochemical Journal","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1042/BCJ20240425","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

AMP 激活蛋白激酶(AMPK)是细胞能量状态的传感器,几乎在所有真核细胞中都有表达。在典型的激活机制中,AMP:ATP 和 ADP:ATP 比率的增加意味着细胞能量状态的下降,从而激活 AMPK。一旦被激活,AMPK 就会使许多靶点磷酸化,促进产生 ATP 的分解代谢途径,同时抑制消耗 ATP 的合成代谢和其他过程,从而起到恢复能量平衡的作用。激活 AMPK 的药剂有助于确定下游靶点,并有可能成为治疗 2 型糖尿病和非酒精性脂肪肝等代谢性疾病的药物。C13 就是这样一种药物,它是一种具有膦酸二(异丁酰氧基甲基)酯分子的原药,其中的异丁酰氧基甲基增加了膜渗透性。细胞吸收 C13 后,C13 会被裂解释放出 C2,这是一种 AMP 类似物和强效 AMPK 激活剂,对含有 a1(而非 a2)催化亚基同工酶的复合物具有特异性。以前人们认为这是 C13 激活 AMPK 的唯一机制,而忽略了异丁酰氧基甲基的潜在作用。我们现在报告说,从 C13 裂解后,这些保护基团会代谢为甲醛,而甲醛是一种抑制线粒体功能并增加细胞 AMP:ATP 比率的物质,从而通过典型机制提供额外的 AMPK 激活。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
The pro-drug C13 activates AMPK by two distinct mechanisms.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that is expressed in almost all eukaryotic cells. In the canonical activation mechanism, it is activated by increases in AMP:ATP and ADP:ATP ratios that signify declining cellular energy status. Once activated, AMPK phosphorylates numerous targets that promote catabolic pathways generating ATP, while inhibiting anabolic and other processes that consume ATP, thus acting to restore energy homeostasis. Pharmacological agents that activate AMPK have been useful in identifying downstream targets and have potential as drugs for treatment of metabolic disorders such as Type 2 diabetes and non-alcoholic fatty liver disease. One such agent is C13, a pro-drug with a phosphonate bis(isobutyryloxymethyl) ester moiety, with the isobutyryloxymethyl groups increasing membrane permeability. Following cellular uptake, C13 is cleaved to release C2, an AMP analogue and potent AMPK activator that is specific for complexes containing the α1 (but not the α2) catalytic subunit isoform. This has previously been assumed to be the sole mechanism by which C13 activates AMPK, with potential roles for the isobutyryloxymethyl groups being ignored. We now report that, following cleavage from C13, these protective groups are metabolized to formaldehyde, an agent that inhibits mitochondrial function and increases cellular AMP:ATP ratios, thus providing additional AMPK activation by the canonical mechanism.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Biochemical Journal
Biochemical Journal 生物-生化与分子生物学
CiteScore
8.00
自引率
0.00%
发文量
255
审稿时长
1 months
期刊介绍: Exploring the molecular mechanisms that underpin key biological processes, the Biochemical Journal is a leading bioscience journal publishing high-impact scientific research papers and reviews on the latest advances and new mechanistic concepts in the fields of biochemistry, cellular biosciences and molecular biology. The Journal and its Editorial Board are committed to publishing work that provides a significant advance to current understanding or mechanistic insights; studies that go beyond observational work using in vitro and/or in vivo approaches are welcomed. Painless publishing: All papers undergo a rigorous peer review process; however, the Editorial Board is committed to ensuring that, if revisions are recommended, extra experiments not necessary to the paper will not be asked for. Areas covered in the journal include: Cell biology Chemical biology Energy processes Gene expression and regulation Mechanisms of disease Metabolism Molecular structure and function Plant biology Signalling
期刊最新文献
ATP-competitive inhibitors of PI3K enzymes demonstrate an isoform selective dual action by controlling membrane binding. Divergent roles of DRY and NPxxY motifs in selective activation of downstream signalling by the apelin receptor. Sequence variation in the active site of mobile colistin resistance proteins is evolutionarily accommodated through inter-domain interactions. The uncharacterized protein ZNF200 interacts with PRMT3 and aids its stability and nuclear translocation. Mitigating methylglyoxal-induced glycation stress: the protective role of iron, copper, and manganese coordination compounds in Saccharomyces cerevisiae.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1