胃饥饿素O-酰基转移酶测定与抑制
Ghrelin O-acyltransferase assays and inhibition.
作者信息
Taylor Martin S, Hwang Yousang, Hsiao Po-Yuan, Boeke Jef D, Cole Philip A
机构信息
Department of Pharmacology & Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
出版信息
Methods Enzymol. 2012;514:205-28. doi: 10.1016/B978-0-12-381272-8.00013-1.
Abstract
Ghrelin O-acyltransferase (GOAT) is responsible for catalyzing the attachment of the eight-carbon fatty acid octanoyl to the Ser3 side chain of the peptide ghrelin to generate the active form of this metabolic hormone. As such, GOAT is viewed as a potential therapeutic target for the treatment of obesity and diabetes mellitus. Here, we review recent progress in the development of cell and in vitro assays to measure GOAT action and the identification of several synthetic GOAT inhibitors. In particular, we discuss the design, synthesis, and characterization of the bisubstrate analog GO-CoA-Tat and its ability to modulate weight and blood glucose in mice. We also highlight current challenges and future research directions in our biomedical understanding of this fascinating ghrelin processing enzyme.
摘要
胃饥饿素O-酰基转移酶（GOAT）负责催化八碳脂肪酸辛酰基连接到肽类胃饥饿素的Ser3侧链上，以生成这种代谢激素的活性形式。因此，GOAT被视为治疗肥胖症和糖尿病的潜在治疗靶点。在此，我们综述了用于测量GOAT活性的细胞和体外测定方法的最新进展，以及几种合成GOAT抑制剂的鉴定。特别是，我们讨论了双底物类似物GO-CoA-Tat的设计、合成和表征及其调节小鼠体重和血糖的能力。我们还强调了在对这种迷人的胃饥饿素加工酶的生物医学理解方面当前面临的挑战和未来的研究方向。
相似文献
1
Ghrelin O-acyltransferase assays and inhibition.胃饥饿素O-酰基转移酶测定与抑制
Methods Enzymol. 2012;514:205-28. doi: 10.1016/B978-0-12-381272-8.00013-1.
2
Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor.设计的生长激素释放肽-O-酰基转移酶抑制剂对小鼠的葡萄糖和体重控制作用。
Science. 2010 Dec 17;330(6011):1689-92. doi: 10.1126/science.1196154. Epub 2010 Nov 18.
3
Biochemical Assays for Ghrelin Acylation and Inhibition of Ghrelin O-Acyltransferase.胃饥饿素酰化的生化检测及胃饥饿素O-酰基转移酶的抑制
Methods Mol Biol. 2019;2009:227-241. doi: 10.1007/978-1-4939-9532-5_18.
4
Enzymatic characterization of GOAT, ghrelin O-acyltransferase.胃饥饿素O-酰基转移酶（GOAT）的酶学特性
Methods Enzymol. 2012;514:147-63. doi: 10.1016/B978-0-12-381272-8.00010-6.
5
Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation.合成三萜类化合物对人胃饥饿素O-酰基转移酶的抑制作用：功能必需半胱氨酸的参与为胃饥饿素酰化提供了机制性见解。
Biochemistry. 2017 Feb 21;56(7):919-931. doi: 10.1021/acs.biochem.6b01008. Epub 2017 Feb 7.
6
A fluorescent peptide substrate facilitates investigation of ghrelin recognition and acylation by ghrelin O-acyltransferase.一种荧光肽底物促进了生长激素释放肽酰基转移酶对生长激素释放肽的识别和酰化研究。
Anal Biochem. 2013 Jun 1;437(1):68-76. doi: 10.1016/j.ab.2013.02.013. Epub 2013 Feb 27.
7
Ghrelin acylation and metabolic control.胃饥饿素酰化和代谢控制。
Peptides. 2011 Nov;32(11):2301-8. doi: 10.1016/j.peptides.2011.08.020. Epub 2011 Aug 27.
8
Ghrelin octanoylation by ghrelin -acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling.生长激素释放肽酰基转移酶对生长激素释放肽的辛酰化作用：影响代谢和神经内分泌信号转导的蛋白质酰化作用。
Open Biol. 2021 Jul;11(7):210080. doi: 10.1098/rsob.210080. Epub 2021 Jul 28.
9
Shedding light on the ghrelin/GOAT metabolism saga.揭示胃饥饿素/GOAT 代谢之谜。
Chembiochem. 2011 Mar 7;12(4):523-5. doi: 10.1002/cbic.201000777. Epub 2011 Jan 20.
10
Structure-activity analysis of human ghrelin O-acyltransferase reveals chemical determinants of ghrelin selectivity and acyl group recognition.人胃饥饿素O-酰基转移酶的结构-活性分析揭示了胃饥饿素选择性和酰基识别的化学决定因素。
Biochemistry. 2015 Feb 3;54(4):1100-10. doi: 10.1021/bi5010359. Epub 2015 Jan 21.
引用本文的文献
1
Discovery of new oxadiazolo pyridine derivatives as potent ghrelin O-acyltransferase inhibitors using molecular modeling techniques.利用分子建模技术发现新型恶二唑并吡啶衍生物作为强效胃饥饿素O-酰基转移酶抑制剂
In Silico Pharmacol. 2023 Nov 9;11(1):35. doi: 10.1007/s40203-023-00167-z. eCollection 2023.
2
Crucial Regulatory Role of Organokines in Relation to Metabolic Changes in Non-Diabetic Obesity.有机因子在非糖尿病性肥胖代谢变化中的关键调节作用
Metabolites. 2023 Feb 14;13(2):270. doi: 10.3390/metabo13020270.
3
Recent progress in the discovery of ghrelin -acyltransferase (GOAT) inhibitors.胃饥饿素酰基转移酶（GOAT）抑制剂发现方面的最新进展。
RSC Med Chem. 2020 Sep 4;11(10):1136-1144. doi: 10.1039/d0md00210k. eCollection 2020 Oct 1.
4
Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver.禁食通过肝脏中胃饥饿素/GHSR1α/丝裂原活化蛋白激酶途径调节铁转运蛋白1的表达来增加铁输出。
Biol Trace Elem Res. 2021 Jan;199(1):267-277. doi: 10.1007/s12011-020-02114-x. Epub 2020 Mar 25.
5
Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia.载有胃饥饿素的包衣脂质体用于鼻脑给药治疗恶病质的研发。
Int J Nanomedicine. 2017 Nov 28;12:8531-8543. doi: 10.2147/IJN.S147650. eCollection 2017.
6
Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation.合成三萜类化合物对人胃饥饿素O-酰基转移酶的抑制作用：功能必需半胱氨酸的参与为胃饥饿素酰化提供了机制性见解。
Biochemistry. 2017 Feb 21;56(7):919-931. doi: 10.1021/acs.biochem.6b01008. Epub 2017 Feb 7.
7
Mechanistic analysis of ghrelin-O-acyltransferase using substrate analogs.使用底物类似物对胃饥饿素O-酰基转移酶进行机制分析。
Bioorg Chem. 2015 Oct;62:64-73. doi: 10.1016/j.bioorg.2015.07.003. Epub 2015 Jul 13.
8
Circulating ghrelin level is higher in HNF1A-MODY and GCK-MODY than in polygenic forms of diabetes mellitus.与多基因形式的糖尿病相比，肝细胞核因子1A-成熟型糖尿病青年发病型（HNF1A-MODY）和葡萄糖激酶-成熟型糖尿病青年发病型（GCK-MODY）患者的循环胃饥饿素水平更高。
Endocrine. 2015 Dec;50(3):643-9. doi: 10.1007/s12020-015-0627-5. Epub 2015 May 19.
9
Ghrelin O Acyl Transferase (GOAT) as a Novel Metabolic Regulatory Enzyme.胃饥饿素O-酰基转移酶（GOAT）作为一种新型代谢调节酶。
J Clin Diagn Res. 2015 Feb;9(2):LE01-5. doi: 10.7860/JCDR/2015/9787.5514. Epub 2015 Feb 1.
10
Protein lysine acetylation by p300/CBP.由p300/CBP介导的蛋白质赖氨酸乙酰化。
Chem Rev. 2015 Mar 25;115(6):2419-52. doi: 10.1021/cr500452k. Epub 2015 Jan 16.
本文引用的文献
1
The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction.生长激素促分泌素受体-ghrelin 系统对于长时间限制热量摄入期间预防低血糖不是必需的。
PLoS One. 2012;7(2):e32100. doi: 10.1371/journal.pone.0032100. Epub 2012 Feb 21.
2
Topology of 1-acyl-sn-glycerol-3-phosphate acyltransferases SLC1 and ALE1 and related membrane-bound O-acyltransferases (MBOATs) of Saccharomyces cerevisiae.酿酒酵母 1-酰基-sn-甘油-3-磷酸酰基转移酶 SLC1 和 ALE1 及其相关的膜结合 O-酰基转移酶（MBOATs）的拓扑结构。
J Biol Chem. 2011 Oct 21;286(42):36438-47. doi: 10.1074/jbc.M111.256511. Epub 2011 Aug 17.
3
The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation.AML1-ETO 的白血病发生能力依赖于特定位点的赖氨酸乙酰化。
Science. 2011 Aug 5;333(6043):765-9. doi: 10.1126/science.1201662. Epub 2011 Jul 14.
4
A small molecule antagonist of ghrelin O-acyltransferase (GOAT).一种胃饥饿素 O-酰基转移酶（GOAT）的小分子拮抗剂。
Chem Commun (Camb). 2011 Jul 14;47(26):7512-4. doi: 10.1039/c1cc11817j. Epub 2011 May 19.
5
Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300.通过抑制组蛋白乙酰转移酶 p300，增强恐惧消退记忆和突触可塑性的矛盾现象。
J Neurosci. 2011 May 18;31(20):7486-91. doi: 10.1523/JNEUROSCI.0133-11.2011.
6
Ghrelin: a gut hormonal basis of motility regulation and functional dyspepsia.胃饥饿素：调节动力和功能性消化不良的肠道激素基础。
J Gastroenterol Hepatol. 2011 Apr;26 Suppl 3:67-72. doi: 10.1111/j.1440-1746.2011.06630.x.
7
Chromatin remodeling pathways in smooth muscle cell differentiation, and evidence for an integral role for p300.染色质重塑途径在平滑肌细胞分化中的作用及 p300 的重要作用证据。
PLoS One. 2010 Dec 13;5(12):e14301. doi: 10.1371/journal.pone.0014301.
8
Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor.设计的生长激素释放肽-O-酰基转移酶抑制剂对小鼠的葡萄糖和体重控制作用。
Science. 2010 Dec 17;330(6011):1689-92. doi: 10.1126/science.1196154. Epub 2010 Nov 18.
9
Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice.盐诱导激酶 2 将转录共激活因子 p300 的磷酸化与预防小鼠 ChREBP 依赖性肝脂肪变性联系起来。
J Clin Invest. 2010 Dec;120(12):4316-31. doi: 10.1172/JCI41624. Epub 2010 Nov 15.
10
BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy.在人类弥漫性大B细胞淋巴瘤细胞中，BCL6对EP300的抑制作用为合理的联合治疗提供了基础。
J Clin Invest. 2010 Dec 1;120(12):4569-82. doi: 10.1172/JCI42869. Epub 2010 Nov 1.
Zotero 插件