Discovery and characterization of natural product luteolin as an effective inhibitor of human pyridoxal kinase

作者全名："Zhu, Yunmei; Bao, Guangsen; Zhu, Gaolin; Zhang, Kai; Zhu, Sanyong; Hu, Junchi; He, Jia; Jiang, Wei; Fan, Jianjun; Dang, Yongjun"

作者地址："[Zhu, Yunmei; Zhu, Gaolin; Zhang, Kai; Zhu, Sanyong; Hu, Junchi; He, Jia; Fan, Jianjun; Dang, Yongjun] Chongqing Med Univ, Affiliated Hosp 2, Inst Life Sci, Basic Med Res & Innovat Ctr Novel Target & Therape, Chongqing 400010, Peoples R China; [Bao, Guangsen; Jiang, Wei] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Biochem & Mol Biol,Key Lab Metab & Mol Med,Mi, Shanghai 200032, Peoples R China; [Dang, Yongjun] Chongqing Med Univ, Coll Pharm, Chongqing 400010, Peoples R China; [Dang, Yongjun] Chongqing Med Univ, Inst Life Sci, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Chongqing 400010, Peoples R China"

通信作者："Fan, JJ; Dang, YJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Life Sci, Basic Med Res & Innovat Ctr Novel Target & Therape, Chongqing 400010, Peoples R China.; Jiang, W (通讯作者)，Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Biochem & Mol Biol,Key Lab Metab & Mol Med,Mi, Shanghai 200032, Peoples R China.; Dang, YJ (通讯作者)，Chongqing Med Univ, Inst Life Sci, Basic Med Res & Innovat Ctr Novel Target & Therape, Minist Educ, Chongqing 400010, Peoples R China."

来源：BIOORGANIC CHEMISTRY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001147020700001

JCR分区：Q1

影响因子：5.1

年份：2024

卷号：143

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Pyridoxal kinase; High-throughput screening; Luteolin; Protein crystal structure; Leukemia cell

摘要："Pyridoxal kinase (PDXK) is an essential enzyme in the synthesis of pyridoxal 5-phosphate (PLP), the active form of vitamin B6, which plays a pivotal role in maintaining the enzyme activity necessary for cell metabolism. Thus, PDXK has garnered attention as a potential target for metabolism regulation and tumor therapy. Despite this interest, existing PDXK inhibitors have faced limitations, including weak suppressive activity, unclear mechanisms of action, and associated toxic side effects. In this study, we present the discovery of a novel PDXK inhibitor, luteolin, through a high-throughput screening approach based on enzyme activity. Luteolin, a natural product, exhibits micromolar-level affinity for PDXK and effectively inhibits the enzyme's activity in vitro. Our crystal structures reveal that luteolin occupies the ATP binding pocket through hydrophobic interactions and a weak hydrogen bonding pattern, displaying reversible characteristics as confirmed by biochemical assays. Moreover, luteolin disrupts vitamin B6 metabolism by targeting PDXK, thereby inhibiting the proliferation of leukemia cells. This research introduces a novel screening method for identifying high-affinity and potent PDXK inhibitors and sheds light on clarification of the structural mechanism of PDXK-luteolin for subsequent structure optimization of inhibitors."

基金机构："National Natural Science Foundation of China [22137002, 92253305]; Science and Technology Commission of Shanghai Municipality [20JC1410900]; University Innovation Research Group in Chongqing [CXQT21016]; Chongqing Talent Program Project [CSTB2022NSCQ-LZX0058]; High-Level Innovation Platform Cultivation Plan of Chongqing; Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing; Scientific and Technological Research Program of Chongqing Municipal Education Commission [CSTB2022NSCQ-BHX0676]; Chongqing Municipal Education Commission, Program of Chongqing Talents; Natural Science Foundation of Chongqing [CQYC20200302119]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (No. 22137002 to Y.D. and 92253305 to W.J.) , the Science and Technology Commission of Shanghai Municipality (Grant 20JC1410900 to Y.D.) , the University Innovation Research Group in Chongqing (No. CXQT21016 to Y.D.) , the Chongqing Talent Program Project (No. CQYC20200302119 to Y.D.) , High-Level Innovation Platform Cultivation Plan of Chongqing (to Y.D.) , Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing (to Y.D.) , the Scientific and Technological Research Program of Chongqing Municipal Education Commission (No. CSTB2022NSCQ-LZX0058 to Y.D.) , the Chongqing Municipal Education Commission, Program of Chongqing Talents (No. CQYC20200302119 to H.J.) , and the Natural Science Foundation of Chongqing (No. CSTB2022NSCQ-BHX0676 to F.J.) ."