دورية أكاديمية
Structural and Functional Analyses of Inhibition of Human Dihydroorotate Dehydrogenase by Antiviral Furocoumavirin.
| العنوان: | Structural and Functional Analyses of Inhibition of Human Dihydroorotate Dehydrogenase by Antiviral Furocoumavirin. |
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| المؤلفون: | Nakahara M; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan., Watanabe S; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan., Sato M; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan., Okumura H; SPring-8/JASRI, Hyogo 679-5198, Japan., Kawatani M; Chemical Resource Development Research Unit, RIKEN Center for Sustainable Resource Science, Wako-shi 351-0198, Japan., Osada H; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan., Hara K; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan., Hashimoto H; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan., Watanabe K; Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan. |
| المصدر: | Biochemistry [Biochemistry] 2024 May 21; Vol. 63 (10), pp. 1241-1245. Date of Electronic Publication: 2024 May 09. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 0370623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4995 (Electronic) Linking ISSN: 00062960 NLM ISO Abbreviation: Biochemistry Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Chemical Society. |
| مواضيع طبية MeSH: | Antiviral Agents*/pharmacology , Antiviral Agents*/chemistry , Dihydroorotate Dehydrogenase*/antagonists & inhibitors , Dihydroorotate Dehydrogenase*/chemistry, Humans ; Crystallography, X-Ray ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/chemistry ; Furocoumarins/pharmacology ; Furocoumarins/chemistry ; Models, Molecular |
| مستخلص: | Natural products are important sources of seed compounds for drug discovery. However, it has become difficult in recent years to discover new compounds with valuable pharmacological activities. On the other hand, among the vast number of natural products that have been isolated so far, a considerable number of compounds with specific biological activities are thought to be overlooked in screening that uses biological activity as an index. Therefore, it is conceivable that such overlooked useful compounds may be found by screening compound libraries that have been amassed previously through specific assays. Previously, NPD723, a member of the Natural Products Depository library comprised of a mixture of natural and non-natural products developed at RIKEN, and its metabolite H-006 were found to inhibit growth of various cancer cells at low nanomolar half-maximal inhibitory concentration. Subsequent analysis revealed that H-006 strongly inhibited human dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the de novo pyrimidine biosynthetic pathway. Here, we elucidated the crystal structure of the DHODH-flavin mononucleotide-orotic acid-H-006 complex at 1.7 Å resolution to determine that furocoumavirin, the S-enantiomer of H-006, was the actual inhibitor. The overall mode of interaction of furocoumavirin with the inhibitor binding pocket was similar to that described for previously reported tight-binding inhibitors. However, the structural information together with kinetic characterizations of site-specific mutants identified key unique features that are considered to contribute to the sub-nanomolar inhibition of DHODH by furocoumavirin. Our finding identified new chemical features that could improve the design of human DHODH inhibitors. |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (Dihydroorotate Dehydrogenase) 0 (Enzyme Inhibitors) 0 (Furocoumarins) |
| تواريخ الأحداث: | Date Created: 20240509 Date Completed: 20240521 Latest Revision: 20240725 |
| رمز التحديث: | 20240726 |
| DOI: | 10.1021/acs.biochem.4c00120 |
| PMID: | 38724483 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4995 |
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| DOI: | 10.1021/acs.biochem.4c00120 |