疟原虫与人宿主之间二氢叶酸还原酶的不同调控
Divergent regulation of dihydrofolate reductase between malaria parasite and human host.
作者信息
Zhang Kai, Rathod Pradipsinh K
机构信息
Department of Biology, The Catholic University of America, Washington, DC 20064, USA.
出版信息
Science. 2002 Apr 19;296(5567):545-7. doi: 10.1126/science.1068274.
Abstract
For half a century, successful antifolate therapy against Plasmodium falciparum malaria has been attributed to host-parasite differences in drug binding to dihydrofolate reductase-thymidylate synthase (DHFR-TS). Selectivity may also arise through previously unappreciated differences in regulation of this drug target. The DHFR-TS of Plasmodium binds its cognate messenger RNA (mRNA) and inhibits its own translation. However, unlike translational regulation of DHFR or TS in humans, DHFR-TS mRNA binding is not coupled to enzyme active sites. Thus, antifolate treatment does not relieve translational inhibition and parasites cannot replenish dead enzyme.
摘要
半个世纪以来，针对恶性疟原虫疟疾的成功抗叶酸治疗一直归因于宿主与寄生虫在药物与二氢叶酸还原酶 - 胸苷酸合成酶（DHFR - TS）结合方面的差异。选择性也可能源于此前未被重视的该药物靶点调控差异。疟原虫的DHFR - TS与其同源信使核糖核酸（mRNA）结合并抑制自身翻译。然而，与人类中DHFR或TS的翻译调控不同，DHFR - TS mRNA结合并不与酶活性位点偶联。因此，抗叶酸治疗不能解除翻译抑制，寄生虫无法补充死亡的酶。
相似文献
1
Divergent regulation of dihydrofolate reductase between malaria parasite and human host.疟原虫与人宿主之间二氢叶酸还原酶的不同调控
Science. 2002 Apr 19;296(5567):545-7. doi: 10.1126/science.1068274.
2
Parasitology. When the host is smarter than the parasite.寄生虫学。当宿主比寄生虫更聪明时。
Science. 2002 Apr 19;296(5567):482-3. doi: 10.1126/science.1071206.
3
Probing the role of parasite-specific, distant structural regions on communication and catalysis in the bifunctional thymidylate synthase-dihydrofolate reductase from Plasmodium falciparum.探究恶性疟原虫双功能胸苷酸合酶-二氢叶酸还原酶中寄生虫特异性的远距离结构区域在通讯和催化中的作用。
Biochemistry. 2008 Feb 5;47(5):1336-45. doi: 10.1021/bi701624u. Epub 2008 Jan 12.
4
Identifying antimalarial compounds targeting dihydrofolate reductase-thymidylate synthase (DHFR-TS) by chemogenomic profiling.通过化学基因组学分析鉴定靶向二氢叶酸还原酶-胸苷酸合成酶（DHFR-TS）的抗疟化合物。
Int J Parasitol. 2016 Jul;46(8):527-35. doi: 10.1016/j.ijpara.2016.04.002. Epub 2016 May 2.
5
Cell-free production of functional Plasmodium falciparum dihydrofolate reductase-thymidylate synthase.恶性疟原虫二氢叶酸还原酶-胸苷酸合成酶的无细胞功能生产
Mol Biochem Parasitol. 2007 Feb;151(2):216-9. doi: 10.1016/j.molbiopara.2006.10.016. Epub 2006 Nov 15.
6
Characterization of Plasmodium knowlesi dihydrofolate reductase-thymidylate synthase and sensitivity to antifolates.诺氏疟原虫二氢叶酸还原酶-胸苷酸合成酶的特性及其对抗叶酸药物的敏感性
Parasitol Int. 2018 Dec;67(6):787-792. doi: 10.1016/j.parint.2018.08.004. Epub 2018 Aug 14.
7
Genetic and metabolic analysis of folate salvage in the human malaria parasite Plasmodium falciparum.人类疟原虫恶性疟原虫中叶酸补救的遗传与代谢分析。
Mol Biochem Parasitol. 2004 May;135(1):77-87. doi: 10.1016/j.molbiopara.2004.01.008.
8
Translational up-regulation of antifolate drug targets in the human malaria parasite Plasmodium falciparum upon challenge with inhibitors.在受到抑制剂挑战时，人类疟原虫恶性疟原虫中抗叶酸药物靶点的翻译上调。
Mol Biochem Parasitol. 2004 Jul;136(1):63-70. doi: 10.1016/j.molbiopara.2004.02.013.
9
Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase: structural basis for antifolate resistance and development of effective inhibitors.疟疾（恶性疟原虫）二氢叶酸还原酶-胸苷酸合成酶：抗叶酸耐药性的结构基础及有效抑制剂的研发
Parasitology. 2005 Mar;130(Pt 3):249-59. doi: 10.1017/s003118200400664x.
10
The dihydrofolate reductase-thymidylate synthetase gene in the drug resistance of malaria parasites.二氢叶酸还原酶-胸苷酸合成酶基因与疟原虫的耐药性
Pharmacol Ther. 1990;48(1):45-59. doi: 10.1016/0163-7258(90)90017-v.
引用本文的文献
1
Covalent inhibition of Ubc13 impairs global protein synthesis.对Ubc13进行共价抑制会损害整体蛋白质合成。
iScience. 2025 Apr 28;28(6):112545. doi: 10.1016/j.isci.2025.112545. eCollection 2025 Jun 20.
2
Expanding the Landscape of Dual Action Antifolate Antibacterials through 2,4-Diamino-1,6-dihydro-1,3,5-triazines.通过2,4-二氨基-1,6-二氢-1,3,5-三嗪拓展双重作用抗叶酸抗菌药物的领域
ACS Infect Dis. 2025 Mar 14;11(3):689-702. doi: 10.1021/acsinfecdis.4c00768. Epub 2025 Feb 14.
3
The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase.抗菌药物氨苯砜通过靶向酶二氢叶酸还原酶抑制 STAT3 的转录活性。
J Biol Chem. 2022 Feb;298(2):101531. doi: 10.1016/j.jbc.2021.101531. Epub 2021 Dec 23.
4
Reproduction, Cell Size, and Transcription: How to Cope With Increasing DNA Content?繁殖、细胞大小和转录：如何应对不断增加的 DNA 含量？
Front Cell Infect Microbiol. 2021 Apr 9;11:660679. doi: 10.3389/fcimb.2021.660679. eCollection 2021.
5
Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant .针对在耐甲氧西林临床分离株中鉴定出的对甲氧苄啶耐药酶的广谱二氢叶酸还原酶抑制剂研究
ACS Infect Dis. 2019 Nov 8;5(11):1896-1906. doi: 10.1021/acsinfecdis.9b00222. Epub 2019 Oct 15.
6
Drugging the Folate Pathway in Mycobacterium tuberculosis: The Role of Multi-targeting Agents.抗结核分枝杆菌多靶位药物：靶向叶酸代谢途径。
Cell Chem Biol. 2019 Jun 20;26(6):781-791.e6. doi: 10.1016/j.chembiol.2019.02.013. Epub 2019 Mar 28.
7
Scalable, Continuous Evolution of Genes at Mutation Rates above Genomic Error Thresholds.可扩展的、高于基因组错误阈值的基因以突变率持续进化。
Cell. 2018 Dec 13;175(7):1946-1957.e13. doi: 10.1016/j.cell.2018.10.021. Epub 2018 Nov 8.
8
A dual regulatory circuit consisting of S-adenosylmethionine decarboxylase protein and its reaction product controls expression of the paralogous activator prozyme in Trypanosoma brucei.一个由 S-腺苷甲硫氨酸脱羧酶蛋白及其反应产物组成的双调控回路控制着在布氏锥虫中同工酶激活剂的表达。
PLoS Pathog. 2018 Oct 26;14(10):e1007404. doi: 10.1371/journal.ppat.1007404. eCollection 2018 Oct.
9
Indispensable malaria genes.不可或缺的疟疾基因。
Science. 2018 May 4;360(6388):490-491. doi: 10.1126/science.aat5092.
10
A New Trick for a Conserved Enzyme: Mevalonate Kinase, a Glycosomal Enzyme, Can Be Secreted by and Modulate Cell Invasion and Signaling. Is It Another Moonlighting Enzyme?一种保守酶的新功能：甲羟戊酸激酶，一种糖体酶，可被分泌并调节细胞侵袭和信号传导。它是另一种兼职酶吗？
Front Cell Infect Microbiol. 2017 Sep 29;7:426. doi: 10.3389/fcimb.2017.00426. eCollection 2017.
本文引用的文献
1
STUDIES ON THE INHIBITION OF DIHYDROFOLATE REDUCTASE BY THE FOLATE ANTAGONISTS.叶酸拮抗剂对二氢叶酸还原酶抑制作用的研究。
J Biol Chem. 1964 Feb;239:479-85.
2
The intolerable burden of malaria: a new look at the numbers.疟疾的沉重负担：重新审视相关数据。
Am J Trop Med Hyg. 2001 Jan-Feb;64(1-2 Suppl):iv-vii. doi: 10.4269/ajtmh.2001.64.iv.
3
Allelic modifications of the cg2 and cg1 genes do not alter the chloroquine response of drug-resistant Plasmodium falciparum.cg2和cg1基因的等位基因修饰不会改变耐药恶性疟原虫对氯喹的反应。
Mol Biochem Parasitol. 2000 Sep;110(1):1-10. doi: 10.1016/s0166-6851(00)00249-8.
4
Essential protein-protein interactions between Plasmodium falciparum thymidylate synthase and dihydrofolate reductase domains.恶性疟原虫胸苷酸合成酶与二氢叶酸还原酶结构域之间的必需蛋白质-蛋白质相互作用。
J Biol Chem. 1999 Dec 31;274(53):37781-6. doi: 10.1074/jbc.274.53.37781.
5
Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil.用人类二氢叶酸还原酶进行转化会使疟原虫对WR99210不敏感，但不会影响氯胍的内在活性。
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6. doi: 10.1073/pnas.94.20.10931.
6
Dihydrofolate reductase protein inhibits its own translation by binding to dihydrofolate reductase mRNA sequences within the coding region.二氢叶酸还原酶蛋白通过与编码区内的二氢叶酸还原酶mRNA序列结合来抑制自身翻译。
Biochemistry. 1997 Oct 7;36(40):12317-22. doi: 10.1021/bi971026e.
7
Plasmodium falciparum: direct cloning and expression of pyrimethamine-sensitive and pyrimethamine-resistant dihydrofolate reductase domains.恶性疟原虫：乙胺嘧啶敏感和耐药二氢叶酸还原酶结构域的直接克隆与表达
Exp Parasitol. 1997 Mar;85(3):303-5. doi: 10.1006/expr.1997.4145.
8
Chemical synthesis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene.恶性疟原虫二氢叶酸还原酶-胸苷酸合成酶基因的化学合成
Mol Biochem Parasitol. 1996 Dec 2;83(1):93-106. doi: 10.1016/s0166-6851(96)02756-9.
9
Kinetics of Plasmodium falciparum thymidylate synthase: interactions with high-affinity metabolites of 5-fluoroorotate and D1694.恶性疟原虫胸苷酸合成酶的动力学：与5-氟乳清酸和D1694的高亲和力代谢物的相互作用
Antimicrob Agents Chemother. 1996 Jul;40(7):1628-32. doi: 10.1128/AAC.40.7.1628.
10
Specific binding of human dihydrofolate reductase protein to dihydrofolate reductase messenger RNA in vitro.人二氢叶酸还原酶蛋白与二氢叶酸还原酶信使核糖核酸的体外特异性结合。
Biochemistry. 1993 May 11;32(18):4756-60. doi: 10.1021/bi00069a009.
Zotero 插件