Targeting phospholipase D in cancer, infection and neurodegenerative disorders.
Targeting phospholipase D in cancer, infection and neurodegenerative disorders.
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DOI：
10.1038/nrd.2016.252
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Lindsley CW
中科院分区：
文献类型：
--
作者：
Brown HA;Thomas PG;Lindsley CW
磷脂酶D（PLD）酶是受体产生的磷脂酸（PtdOH）的一种来源，其随后可代谢为二酰基甘油（DAG）和溶血磷脂酸。还有其他途径导致PtdOH的产生，但途径和产物的酰基组成的差异似乎提供了一些特异性。PLD活性的直接和间接抑制剂都已被鉴定，尽管长期以来一直怀疑该途径是不可治疗的。雷洛昔芬和卤培胺作为直接抑制剂的鉴定之后，系统开发了用于进一步区分PLD 1和PLD 2功能的同工酶偏好化合物。宿主细胞中的PLD 2与病毒进入过程和先天免疫应答途径相关，使得抑制阻断有效感染。该PLD 2途径已通过AKT激酶与自噬相关联。作为抗逆转录病毒治疗中的潜在靶点，PLD 1通过CAD酶（其含有氨基甲酰基天冬氨酸合酶、天冬氨酸转氨甲酰酶和二氢乳清酸酶结构域）来调节嘧啶生物合成。PLD活性和表达已显示在几种类型的人类癌症中上调，其中PLD酶在多种已知癌基因的下游起作用。抑制PtdOH的产生对肿瘤发生和恶性侵袭具有显著影响。PLD 1、PLD 2和PLD 3均被认为在阿尔茨海默病和其他神经退行性疾病中起作用，但尚未出现解释这些蛋白质在中枢神经系统病理生理学中的作用的机制。本文的在线版本（doi：10.1038/nrd.2016.252）包含补充材料，可供授权用户使用。脂质第二信使如磷脂酸（PtdOH）在广泛的病理过程中发挥作用，磷脂酶D（PLD）酶是信号激活PtdOH产生的主要来源之一。在这篇综述中，Brown、托马斯和Lindsley讨论了PLD抑制剂的发展，重点是异构体特异性抑制剂，以及它们在治疗癌症、神经变性和感染中的潜在应用。本文的在线版本（doi：10.1038/nrd.2016.252）包含补充材料，可供授权用户使用。脂质第二信使在细胞功能中具有重要作用，并有助于炎症、恶性转化、侵袭性、神经退行性疾病以及感染和其他病理生理过程的分子机制。磷脂酶D（PLD）同工酶PLD 1和PLD 2是多种细胞表面受体下游信号激活磷脂酸（PtdOH）生成的主要来源之一，包括G蛋白偶联受体（GPCR）、受体酪氨酸激酶（RTK）和整联蛋白。同工酶选择性PLD抑制剂的发展和分子遗传学的最新进展表明，PLD同工酶在哺乳动物细胞和病原生物体可能是治疗几种人类疾病的有价值的目标。同工酶选择性抑制剂揭示了PtdOH生物合成途径和PtdOH在病理生理学中的作用之间复杂的相互关系。PLD酶曾经被认为是不可药用的，因为PtdOH在细胞信号传导中无处不在，并且担心抑制剂对人类使用毒性太大。然而，最近有希望的发现表明，小分子同工酶选择性抑制剂可以提供一种独特的方法来治疗癌症，神经退行性疾病和中枢神经系统的其他痛苦的新化合物，并可能作为广谱抗病毒和抗微生物治疗。本文的在线版本（doi：10.1038/nrd.2016.252）包含补充材料，可供授权用户使用。
Phospholipase D (PLD) enzymes are one source of receptor-generated phosphatidic acid (PtdOH),which may subsequently be metabolized to diacylglycerol (DAG) and lysophosphatidic acid. There are other pathways that lead to PtdOH generation, but differences in pathways and in the acyl composition of the products seem to provide some specificity. Both direct and indirect inhibitors of PLD activity have been identified despite a long-held suspicion that this pathway was undruggable. The identification of raloxifene and halopemide as direct inhibitors was followed by the systematic development of isoenzyme-preferring compounds that have been used to further differentiate the functions of PLD1 and PLD2. PLD2 in host cells has been associated with viral entry processes and innate immune response pathways such that inhibition blocks efficient infection. This PLD2 pathway has been linked to autophagy via AKT kinases. As a potential target in antiretroviral therapy, PLD1 works through the CAD enzyme (which contains carbamoyl aspartate synthase, aspartate transcarbamylase and dihydro-orotase domains) to modulate pyrimidine biosynthesis. PLD activity and expression have been shown to be upregulated in several types of human cancers, in which PLD enzymes function downstream of a variety of known oncogenes. Inhibition of PtdOH production has a marked effect on tumorigenesis and malignant invasion. PLD1, PLD2 and PLD3 have each been suggested to have a role in Alzheimer disease and other neurodegenerative conditions, but a mechanism has not yet emerged to explain the roles of these proteins in central nervous system pathophysiology. The online version of this article (doi:10.1038/nrd.2016.252) contains supplementary material, which is available to authorized users. Lipid second messengers such as phosphatidic acid (PtdOH) have a role in a wide range of pathological processes, and phospholipase D (PLD) enzymes are one of the major sources of signal-activated PtdOH generation. In this Review, Brown, Thomas and Lindsley discuss the development of PLD inhibitors, with a focus on isoform-specific inhibitors, and their potential applications in the treatment of cancer, neurodegeneration and infection. The online version of this article (doi:10.1038/nrd.2016.252) contains supplementary material, which is available to authorized users. Lipid second messengers have essential roles in cellular function and contribute to the molecular mechanisms that underlie inflammation, malignant transformation, invasiveness, neurodegenerative disorders, and infectious and other pathophysiological processes. The phospholipase D (PLD) isoenzymes PLD1 and PLD2 are one of the major sources of signal-activated phosphatidic acid (PtdOH) generation downstream of a variety of cell-surface receptors, including G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and integrins. Recent advances in the development of isoenzyme-selective PLD inhibitors and in molecular genetics have suggested that PLD isoenzymes in mammalian cells and pathogenic organisms may be valuable targets for the treatment of several human diseases. Isoenzyme-selective inhibitors have revealed complex inter-relationships between PtdOH biosynthetic pathways and the role of PtdOH in pathophysiology. PLD enzymes were once thought to be undruggable owing to the ubiquitous nature of PtdOH in cell signalling and concerns that inhibitors would be too toxic for use in humans. However, recent promising discoveries suggest that small-molecule isoenzyme-selective inhibitors may provide novel compounds for a unique approach to the treatment of cancers, neurodegenerative disorders and other afflictions of the central nervous system, and potentially serve as broad-spectrum antiviral and antimicrobial therapeutics. The online version of this article (doi:10.1038/nrd.2016.252) contains supplementary material, which is available to authorized users.
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