LYPLA1

前言蛋白质脂质化是一类不同的翻译后修饰（PTM），由40多种酶调节，靶向3000多个位点的1000多种底物。脂质蛋白包括150多种癌蛋白，涉及癌症起始、进展和免疫的介质、受体激酶、转录因子、G蛋白偶联受体和细胞外信号蛋白。脂质化调节其蛋白质底物与细胞膜的物理相互作用，调节蛋白质信号传导和运输，并在代谢和免疫中发挥关键作用。蛋白质脂质化可大致分为两种类型：组成型脂质化，其中脂质作为蛋白质合成或成熟的组成部分附着；以及动态脂质化，例如在信号级联过程中，从成熟蛋白质中动态添加或去除脂质。对复杂和动态的蛋白质脂质化景观进行分析具有相当大的挑战，癌症中的脂质PTM及其失调为癌症药物发现提供了目前尚未开发的潜在靶点来源。因此，我们需要加强对癌症靶向蛋白脂质化途径的理解，推动靶向蛋白脂质化癌症药物的临床研究，提供靶向蛋白质脂质化的新型肿瘤疗法。癌症中的S-丙烯酰化S-丙烯酰化在蛋白质合成后迅速发生，并且是不可逆的，在蛋白质的一生中持续存在。这一过程是由四种蛋白质丙炔基转移酶，法尼基转移酶（FTase）和香叶基-香叶基转移酶I、II和III（GGTase I–III），在C末端或附近的半胱氨酸残基上添加类异戊二烯脂质引发的。最突出的丙酰化癌蛋白是四种RAS亚型（KRAS4A、KRAS4B、NRAS和HRAS），约占19%的突变癌症患者，尤其是那些对治疗最具耐药性的患者。有证据表明，在健康人和疾病患者中，异戊二烯化参与了这些癌蛋白的调节。RAS激活突变普遍保留了膜定位和致癌信号传导所需的CaaX盒预酰化位点，以及KRAS4A、NRAS和HRAS的二次棕榈酰化所需的位点。异丙基半胱氨酸羧甲基转移酶（ICMT）对丙酰化修饰的进一步处理影响RAS蛋白定位和RAS-驱动的恶性转化。最近的研究表明，ICMT还可能有助于癌症细胞增殖和存活、DNA损伤修复、干性和自我更新。通过靶向脂质化破坏RAS定位和下游信号传导已被广泛研究作为靶向RAS突变体的一种方法。2020年，FTase抑制剂（FTI） lonafarnib成为首个获批的抗蛋白质-脂质转移酶的药物，靶向罕见病早衰亚型中层粘连蛋白a法尼酰化的异常保留。此外，FTI  tipifarnib已被授予针对携带HRAS突变的HNSCC的突破性疗法。不幸的是，由于剂量限制、靶向血液毒性和耐药性，II期临床试验中最初表现出的高反应率很短暂。为了降低耐药性，目前正在研究联合疗法。此外，一种GGTase I抑制剂（GGTI-2418，也称为PTX-100）已进入T细胞淋巴瘤（NCT03900442）的Ib期临床试验。癌症中N-肉豆蔻酰化N-肉豆蔻酰化是一种不可逆的C14:0脂质PTM，由N-肉豆蔻基转移酶（NMT）催化，从肉豆蔻基CoA（Myr-CoA）转移到人类蛋白质组中200多种底物蛋白的N-末端甘氨酸。肉豆蔻酰化可以介导动态膜结合，触发次级PTM（如S-酰化）和蛋白质相互作用，调节蛋白质复合物的酶活性，或变构调节可溶性蛋白质。SRC家族激酶是NMT的首批鉴定底物之一，随后的研究表明，NMT通过多种致癌途径调节底物。例如，肉豆蔻酰化将脱铁抑制蛋白1（FSP1）靶向膜，在膜中它防止氧化脂质物质的积累。NMT底物包括传统方法无法治疗的致癌蛋白家族，包括ADP核糖基化因子蛋白（ARFs）、ARF样蛋白（ARLs）和高尔基体重组堆叠蛋白（GOASP），它们调节ER–高尔基体运输，参与线粒体复合体I组装等。asciminib是一种口服给药的小分子选择性变构抑制剂，靶向BCR-ABL1酪氨酸激酶的肉豆蔻酰口袋，由诺华制药研发，主要用于费城染色体阳性（Ph+）慢性粒细胞白血病（CML）。于2021年获得FDA批准，在激酶抑制剂耐药性癌症中显示出疗效，并在临床试验中显示出持久的反应（NCT02081378，NCT03106779）。NMT活性也可以直接靶向，为对抗多种其他不可治疗的癌蛋白提供了一个独特的干预点，这些癌蛋白汇聚在调节蛋白质合成的途径上。来自几项体外和体内研究的证据，包括膀胱癌和B细胞淋巴瘤的异种移植物模型，以及肺癌的同基因小鼠模型中，抑制NMT通过LAMTOR1的功能丧失诱导肿瘤细胞中的蛋白质合成阻断。最后，NMT抑制剂偶联的抗体偶联药物（ADC）显示出显著的提高疗效和耐受性的潜力，最近在乳腺癌、胃癌和前列腺癌的异种移植物模型中报道了肿瘤的完全消退。这些数据表明，NMT抑制剂的靶向递送可能扩大靶向癌症范围。癌症中的S-棕榈酰化在人类中，S-棕榈酰化由ZDHHC家族中的23种蛋白质催化，其去除可由丝氨酸水解酶超家族的多种APT催化，包括APT1、APT2和含有α/β水解酶结构域（ABHD）的蛋白质ABHD17A、ABHD17B、ABHD17 C和ABHD10，使S-棕榈酰化成为一类独特的可逆和动态的蛋白质脂质化。在超过100项蛋白质组学和生物化学研究中，超过2400种哺乳动物蛋白质发生棕榈酰化。这些蛋白质包括整合膜蛋白、外周膜蛋白、细胞质信号蛋白和转录因子。包括NRAS、KRAS4A、HRAS、EGFR和p53在内的癌蛋白依赖于S-棕榈酰化循环来调节其定位、活性或相互作用因子，已知大于150种癌蛋白是S-棕榈酰酸化的。棕榈酰化是致癌激酶的重要调节因子，包括肝细胞生长因子受体酪氨酸激酶MET，其中ER中的棕榈酰化对运输、稳定性和表达是很重要的。此外，有证据表明，EGFR信号传导对其棕榈酰化有促进和抑制作用，这可能是由于存在多个棕榈酰化位点，这些位点由不同的ZDHHC蛋白调节，并具有不同的功能效应。棕榈酰化还调节G蛋白偶联受体的活性，包括黑素皮质素-1受体（MC1R）的活性，后者在紫外线照射后驱动黑色素的产生和DNA修复。因此，棕榈酰化受损的MC1R会增加黑色素瘤的风险。S-棕榈酰化与癌症治疗的耐药性也有关。例如，ZDHHC2介导的线粒体酰甘油激酶（AGK）的棕榈酰化通过激活AKT–mTOR信号增加肾细胞癌中舒尼替尼的耐药性，而ZDHHC16介导的PCSK9的棕榈酰基化通过激活PI3K–AKT途径诱导癌症中索拉非尼的耐药性。转录增强相关结构域（TEAD）蛋白在Hippo信号传导下游调节细胞生长和增殖。GNE-7883是最近报道的一种优化的TEAD棕榈酰化抑制剂，它强烈抑制YAP/TAZ与所有四个TEAD家族成员（TEAD1–4）的结合，并在NSCLC的患者衍生异种移植物模型中逆转Hippo驱动的对KRAS-G12C抑制剂的内在和获得性耐药。第一批进入间皮瘤I期临床试验的TEAD自棕榈酰化抑制剂显示出良好的耐受性和抗肿瘤活性（NCT05228015和NCT04665206）。小结调节蛋白质脂质化为我们提供一种独特的方法，通过控制其膜结合、运输、蛋白质稳定性和蛋白质-蛋白质相互作用，靶向其他难以治疗的癌蛋白。随着我们对癌症中蛋白质脂质化相关性认识的发展，新的治疗机会可能会出现。参考文献：1.Proteinlipidation in cancer: mechanisms, dysregulation and emerging drug targets. NatRev Cancer.2024 Feb 29免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

Researchers have found that a defect in an enzyme called APT1 interferes with the ability to secrete insulin, contributing to the development of Type 2 diabetes in people who are overweight or obese. People who are overweight or obese have a significantly increased risk of developing diabetes, but exactly how that happens is not well understood. A new study at Washington University School of Medicine in St. Louis may help explain how excess weight can contribute to diabetes and may provide researchers with a target to help prevent or delay diabetes in some of those at risk. The findings suggest that many people with elevated levels of insulin -- an early marker of diabetes risk -- also have defects in an enzyme important to the processing of a key fatty acid from the diet. The research is published Jan. 11 in the journal Cell Metabolism. "Between 30 million and 40 million people in the United States have Type 2 diabetes, and another 90 million to 100 million have risk factors that make them likely to develop Type 2 diabetes in the future," said senior investigator Clay F. Semenkovich, MD, director of the Division of Endocrinology, Metabolism & Lipid Research at the School of Medicine. "Many at risk for diabetes have elevated levels of insulin, a hallmark of insulin resistance and a signal that means trouble may be brewing. If we could intervene before they actually develop diabetes, we might be able to prevent significant health problems -- such as heart disease, chronic kidney disease, nerve damage, vision loss and other problems -- in a great number of people." When a person has too much body fat, it signals beta cells in the pancreas to secrete more insulin. When insulin levels become elevated and remain high, the body can become resistant to insulin, and eventually the beta cells that secrete insulin can fail, leading to diabetes. Studying human tissue samples, Semenkovich, the Irene E. and Michael M. Karl Professor; first author Guifang Dong, PhD, a senior scientist; Xiaochao Wei, PhD, an associate professor of medicine; and other Washington University researchers found that the overproduction of insulin involves a process called palmitoylation. This is the process by which cells attach the fatty acid palmitate to proteins. Thousands of human proteins can be attached to palmitate, but the researchers found that when this fatty acid isn't removed from proteins in beta cells, diabetes is the end result. Examining tissue samples from people who were thin or overweight, and with and without diabetes, the researchers found that the people with diabetes were deficient in an enzyme that removes palmitate from beta cells. "They hyper-secrete insulin because this process goes awry, and they can't appropriately regulate the release of insulin from beta cells," Semenkovich explained. "Regulating insulin release is controlled in part by this palmitoylation process." With colleagues David W. Piston, PhD, the Edward W. Mallinckrodt Jr. Professor and head of the Department of Cell Biology & Physiology, Maria S. Remedi, PhD, a professor of medicine and of cell biology & physiology, and Fumihiko Urano, MD, PhD, a professor of medicine and of pathology & immunology, the research team also genetically engineered a mouse that was deficient in the enzyme called APT1, an enzyme responsible for palmitate removal from proteins. The engineered mice went on to develop diabetes. Because impaired APT1 function contributed to diabetes risk, the researchers worked with the university's Center for Drug Discovery to screen and identify compounds that can increase the activity of the APT1 enzyme. "We've found several candidate drugs, and we're pursuing those," Semenkovich said. "We think that by increasing APT1 activity, we might reverse this process and potentially prevent people at risk from progressing to diabetes." Although he said the new findings identifying APT1 as a target are an important step, Semenkovich explained that APT1 is only one treatment target among many. "There are several ways that Type 2 diabetes may develop," he said. "This enzyme is not the answer, but it's an answer, and it appears we have some promising tools that might keep some people with prediabetes from developing diabetes." Dong, G, Adak S, Spyropoulos G, Zhang Q, Feng C, Yin L, Speck SL, Shyr Z, Morikawa S, Ktamura RA, Kathayat RS, Dickinson BC, Ng XW, Piston DW, Urano F, Remedi MS, Wei X, Semenkovich CF. Palmitoylation couples insulin hypersecretion with beta cell failure in diabetes. Cell Metabolism, Jan. 11, 2023. The study was funded with support from the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; and the National Institute of General Medical Sciences of the National Institutes of Health (NIH). Grant numbers: DK020579, DK101392, DK056341, DK115972, DK123301, DK112921, F30 DK131830, T32 HL125241, HL157154, and GM119840. Additional funding provided by the Washington University Centene Personalized Medicine Initiative, a China Scholarship Council grant, the Manpei Suzuki Diabetes Foundation and JSPS Overseas Research Fellowships.