Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
Identification of a natural inhibitor of methionine adenosyltransferase 2A regulating one-carbon metabolism in keratinocytes
复制标题
鉴定调节角质形成细胞中一碳代谢的甲硫氨酸腺苷转移酶 2A 天然抑制剂。
DOI：
10.1016/j.ebiom.2018.12.036
复制
发表时间：
2019-01-01
期刊：
影响因子：
11.1
通讯作者：
Wang, Honglin
中科院分区：
文献类型：
--
作者：
Bai, Jing;Gao, Yuanyuan;Wang, Honglin
背景：银屑病是一种常见的慢性炎症性皮肤病，目前尚无有效的治疗方法。具有生物活性的天然化合物是发现具有治疗潜力的新靶点的良好工具。乙酰基-11-酮基-β-乳香酸（AKBA）是乳香酸中最具生物活性的成分，乳香酸是一组具有抗炎和抗癌特性的化合物。AKBA的靶点鉴定和银屑病的代谢组学分析有助于阐明其作用的分子机制，为银屑病的治疗提供新的靶点。方法：通过亲和纯化、代谢组学分析AKBA作用的HaCaT细胞、咪喹莫特（imiquimod，IMQ）诱导的银屑病小鼠模型和银屑病患者表皮，探讨AKBA的作用靶点和分子机制。AKBA可直接与甲硫氨酸腺苷转移酶2A（MAT 2A）相互作用，抑制其酶活性，降低S-腺苷甲硫氨酸（SAM）水平和SAM/SAH比值，重编程HaCaT细胞的一碳代谢。表皮非靶向代谢组学研究显示银屑病患者的一碳代谢被激活。局部使用AKBA改善IMQ诱导的银屑病样小鼠模型的炎症表型。分子对接和定点突变显示AKBA结合在MAT 2A二聚体界面的变构位点上。解释：我们的研究通过揭示一个新的相互作用蛋白MAT 2A扩展了AKBA的分子机制。基金：国家自然科学基金，国家重点基础研究项目，上海市科委，上海市教委重点学科项目，国家自然科学基金项目。(c)2018作者由爱思唯尔公司出版
Background: Psoriasis is a common chronic inflammatory skin disease which lacks effective strategies for the treatment. Natural compounds with biological activities are good tools to identify new targets with therapeutic potentials. Acetyl-11-keto-beta-boswellic acid (AKBA) is the most bioactive ingredient of boswellic acids, a group of compounds with anti-inflammatory and anti-cancer properties. Target identification of AKBA and metabolomics analysis of psoriasis helped to elucidate the molecular mechanism underlying its effect, and provide new target(s) to treat the disease.Methods: To explore the targets and molecular mechanism of AKBA, we performed affinity purification, metabolomics analysis of HaCaT cells treated with AKBA, and epidermis of imiquimod (IMQ) induced mouse model of psoriasis and psoriasis patients.Findings: AKBA directly interacts with methionine adenosyltransferase 2A (MAT2A), inhibited its enzyme activity, decreased level of S-adenosylmethionine (SAM) and SAM/SAH ratio, and reprogrammed one-carbon metabolism in HaCaT cells. Untargeted metabolomics of epidermis showed one-carbon metabolism was activated in psoriasis patients. Topical use of AKBA improved inflammatory phenotype of IMQ induced psoriasis-like mouse model. Molecular docking and site-directed mutagenesis revealed AKBA bound to an allosteric site at the interface of MAT2A dimer.Interpretation: Our study extends the molecular mechanism of AKBA by revealing a new interacting protein MAT2A. And this leads us to find out the dysregulated one-carbon metabolism in psoriasis, which indicates the therapeutic potential of AKBA in psoriasis.Fund: The National Natural Science Foundation, the National Program on Key Basic Research Project, the Shanghai Municipal Commission, the Leading Academic Discipline Project of the Shanghai Municipal Education Commission. (c) 2018 The Authors. Published by Elsevier B.V.