AMP 激活蛋白激酶 (AMPK) 是一种进化上保守的能量代谢调节因子。 AMPK 对细胞能量状态的急性扰动敏感，并利用基本的生物能量途径来维持细胞稳态。 AMPK 是由 αβγ 亚基组成的异三聚体，在人类中由 7 个单独的基因（亚型 α1、α2、β1、β2、γ1、γ2 和 γ3）编码，允许形成至少 12 种具有个性化生化指纹和组织表达的不同复合物模式。虽然 AMPK 的经典激活机制已明确定义，但异源 AMPK 复合物调节中细微和实质性差异的描述仍不清楚。在这里，利用多学科研究结果，我们剖析了亚型特异性的许多方面AMPK 的功能以及与健康和疾病的联系。这些包括但不限于腺嘌呤核苷酸和小分子的变构激活、共翻译肉豆蔻酰化和翻译后修饰（特别是磷酸化）、亚细胞定位的治理以及转录网络的控制。最后，我们深入探讨了当前关于 AMPK 是否可以形成新型蛋白质复合物（例如，缺乏 α 亚基的二聚体）的争论，共同强调了未来和有影响力的研究的机会。 α1-AMPK 的基线活性高于其 α2 对应物，并且更丰富。对代谢物和小分子的协同变构激活敏感。然而，α2 复合物对能量应激（即 AMP 产生）表现出更大的响应，并且似乎是 LKB1 和 mTORC1 上游更好的底物。这些差异可能在一定程度上解释了为什么在某些癌症中α1是肿瘤促进剂而α2是肿瘤抑制因子。 β1-AMPK 活性由“肉豆蔻酰开关”机制切换，该机制可能先于一系列信号事件发生，最终导致 ULK1 磷酸化和对小分子或内源配体（如脂肪酸）的敏感性。 β2-AMPK并不完全依赖于这种肉豆蔻酰开关，它更倾向于浸润细胞核，我们怀疑这有助于其在某些癌症中的致癌性。最后，γ2 和 γ3 亚型独特的 N 端延伸是 AMPK 的主要调控域。 mTORC1 可能直接磷酸化 γ2 中的该区域，尽管这是否具有抑制作用，特别是在疾病状态下，尚不清楚。相反，γ3 复合物可能会优先受 mTORC1 调节以响应体育锻炼。版权所有 © 2024 作者。由 Elsevier GmbH 出版。保留所有权利。

AMP-activated protein kinase (AMPK) is an evolutionarily conserved regulator of energy metabolism. AMPK is sensitive to acute perturbations to cellular energy status and leverages fundamental bioenergetic pathways to maintain cellular homeostasis. AMPK is a heterotrimer comprised of αβγ-subunits that in humans are encoded by seven individual genes (isoforms α1, α2, β1, β2, γ1, γ2 and γ3), permitting formation of at least 12 different complexes with personalised biochemical fingerprints and tissue expression patterns. While the canonical activation mechanisms of AMPK are well-defined, delineation of subtle, as well as substantial, differences in the regulation of heterogenous AMPK complexes remain poorly defined.Here, taking advantage of multidisciplinary findings, we dissect the many aspects of isoform-specific AMPK function and links to health and disease. These include, but are not limited to, allosteric activation by adenine nucleotides and small molecules, co-translational myristoylation and post-translational modifications (particularly phosphorylation), governance of subcellular localisation, and control of transcriptional networks. Finally, we delve into current debate over whether AMPK can form novel protein complexes (e.g., dimers lacking the α-subunit), altogether highlighting opportunities for future and impactful research.Baseline activity of α1-AMPK is higher than its α2 counterpart and is more sensitive to synergistic allosteric activation by metabolites and small molecules. α2 complexes however, show a greater response to energy stress (i.e., AMP production) and appear to be better substrates for LKB1 and mTORC1 upstream. These differences may explain to some extent why in certain cancers α1 is a tumour promoter and α2 a suppressor. β1-AMPK activity is toggled by a 'myristoyl-switch' mechanism that likely precedes a series of signalling events culminating in phosphorylation by ULK1 and sensitisation to small molecules or endogenous ligands like fatty acids. β2-AMPK, not entirely beholden to this myristoyl-switch, has a greater propensity to infiltrate the nucleus, which we suspect contributes to its oncogenicity in some cancers. Last, the unique N-terminal extensions of the γ2 and γ3 isoforms are major regulatory domains of AMPK. mTORC1 may directly phosphorylate this region in γ2, although whether this is inhibitory, especially in disease states, is unclear. Conversely, γ3 complexes might be preferentially regulated by mTORC1 in response to physical exercise.Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.