Biomimetic Synthesis and Chemical Proteomics Reveal the Mechanism of Action and Functional Targets of Phloroglucinol Meroterpenoids

间苯三酚 化学 蛋白质组学 蛋白质组 计算生物学 生物化学 赖氨酸 作用机理 生物 氨基酸 体外 有机化学 基因
作者
Amy K. Bracken,Colby E. Gekko,Nina O. Suss,Emma E. Lueders,Qi Cui,Qin Fu,Andy C. W. Lui,Elizabeth T. Anderson,Sheng Zhang,Mikail E. Abbasov
出处
期刊:Journal of the American Chemical Society [American Chemical Society]
卷期号:146 (4): 2524-2548 被引量:7
标识
DOI:10.1021/jacs.3c10741
摘要

Natural products perennially serve as prolific sources of drug leads and chemical probes, fueling the development of numerous therapeutics. Despite their scarcity, natural products that modulate protein function through covalent interactions with lysine residues hold immense potential to unlock new therapeutic interventions and advance our understanding of the biological processes governed by these modifications. Phloroglucinol meroterpenoids constitute one of the most expansive classes of natural products, displaying a plethora of biological activities. However, their mechanism of action and cellular targets have, until now, remained elusive. In this study, we detail the concise biomimetic synthesis, computational mechanistic insights, physicochemical attributes, kinetic parameters, molecular mechanism of action, and functional cellular targets of several phloroglucinol meroterpenoids. We harness synthetic clickable analogues of natural products to probe their disparate proteome-wide reactivity and subcellular localization through in-gel fluorescence scanning and cell imaging. By implementing sample multiplexing and a redesigned lysine-targeting probe, we streamline a quantitative activity-based protein profiling, enabling the direct mapping of global reactivity and ligandability of proteinaceous lysines in human cells. Leveraging this framework, we identify numerous lysine–meroterpenoid interactions in breast cancer cells at tractable protein sites across diverse structural and functional classes, including those historically deemed undruggable. We validate that phloroglucinol meroterpenoids perturb biochemical functions through stereoselective and site-specific modification of lysines in proteins vital for breast cancer metabolism, including lipid signaling, mitochondrial respiration, and glycolysis. These findings underscore the broad potential of phloroglucinol meroterpenoids for targeting functional lysines in the human proteome.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
网易邮箱发布了新的文献求助10
刚刚
顺利小陈发布了新的文献求助10
1秒前
佳小佳完成签到,获得积分10
1秒前
落寞代亦完成签到,获得积分10
2秒前
3秒前
哈哈哈哈完成签到,获得积分10
4秒前
佳小佳发布了新的文献求助30
5秒前
5秒前
彭于晏应助半分青蓝采纳,获得10
5秒前
橘子石榴完成签到 ,获得积分10
5秒前
今后应助echo采纳,获得10
7秒前
chriswtr发布了新的文献求助50
9秒前
斑点发布了新的文献求助10
10秒前
木樨完成签到,获得积分10
14秒前
务实的乌冬面完成签到,获得积分20
16秒前
dbq完成签到 ,获得积分10
16秒前
18秒前
Junlei完成签到,获得积分10
18秒前
19秒前
CodeCraft应助parpate采纳,获得10
19秒前
chriswtr完成签到,获得积分10
20秒前
21秒前
21秒前
粥小周发布了新的文献求助10
22秒前
23秒前
领导范儿应助羊青丝采纳,获得10
24秒前
无聊完成签到,获得积分10
24秒前
碧蓝帅哥发布了新的文献求助10
24秒前
一木发布了新的文献求助20
25秒前
今后应助无Wen3采纳,获得10
27秒前
钰钰发布了新的文献求助10
27秒前
28秒前
单薄树叶完成签到,获得积分10
28秒前
28秒前
28秒前
29秒前
parpate发布了新的文献求助10
30秒前
FATYE发布了新的文献求助10
32秒前
echo发布了新的文献求助10
33秒前
Lucky发布了新的文献求助10
34秒前
高分求助中
Continuum Thermodynamics and Material Modelling 3000
Production Logging: Theoretical and Interpretive Elements 2700
Les Mantodea de Guyane Insecta, Polyneoptera 1000
Structural Load Modelling and Combination for Performance and Safety Evaluation 1000
Conference Record, IAS Annual Meeting 1977 820
England and the Discovery of America, 1481-1620 600
電気学会論文誌D(産業応用部門誌), 141 巻, 11 号 510
热门求助领域 (近24小时)
化学 材料科学 生物 医学 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 量子力学 光电子学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3572296
求助须知:如何正确求助?哪些是违规求助? 3142501
关于积分的说明 9448015
捐赠科研通 2843973
什么是DOI,文献DOI怎么找? 1563103
邀请新用户注册赠送积分活动 731630
科研通“疑难数据库(出版商)”最低求助积分说明 718640