• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

人脯氨酰羟化酶结构域 2 与 O 和 2-氧代戊二酸反应，使 Fe(III).2OG.缺氧诱导因子α复合物形成无活性状态。

Human prolyl hydroxylase domain 2 reacts with O and 2-oxoglutarate to enable formation of inactive Fe(III).2OG.hypoxia-inducible-factor α complexes.

机构信息

Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Inorganic Chemistry Laboratory, Department of Chemistry, South Parks Road, Oxford, OX1 3QR, UK.

出版信息

Sci Rep. 2024 Oct 30;14(1):26162. doi: 10.1038/s41598-024-75761-y.

DOI:10.1038/s41598-024-75761-y
PMID:39478091
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11525979/
Abstract

Hypoxia inducible transcription factors (HIFs) mediate the hypoxic response in metazoans. When sufficient O is present, Fe(II)/2-oxoglutarate (2OG)-dependent oxygenases (human PHD1-3) promote HIFα degradation via prolyl-hydroxylation. We report crystallographic, spectroscopic, and biochemical characterization of stable and inactive PHD2.Fe(III).2OG complexes. Aerobic incubation of PHD2 with Fe(II) and 2OG enables formation of PHD2.Fe(III).2OG complexes which bind HIF1-2α to give inactive PHD2.Fe(III).2OG.HIF1-2α complexes. The Fe(III) oxidation state in the inactive complexes was shown by EPR spectroscopy. L-Ascorbate hinders formation of the PHD2.Fe(III).2OG.(+/-HIFα) complexes and slowly regenerates them to give the catalytically active PHD2.Fe(II).2OG complex. Crystallographic comparison of the PHD2.Fe(III).2OG.HIF2α complex with the analogous anaerobic Fe(II) complex reveals near identical structures. Exposure of the anaerobic PHD2.Fe(II).2OG.HIF2α crystals to O enables in crystallo hydroxylation. The resulting PHD2.product structure, manifests conformational changes compared to the substrate structures. The results have implications for the role of the PHDs in hypoxia sensing and open new opportunities for inhibition of the PHDs and other 2OG dependent oxygenases by promoting formation of stable Fe(III) complexes.

摘要

缺氧诱导转录因子 (HIFs) 在后生动物中介导缺氧反应。当有足够的 O 存在时，Fe(II)/2-酮戊二酸 (2OG)-依赖性氧合酶（人类 PHD1-3）通过脯氨酰羟化促进 HIFα 降解。我们报告了稳定和无活性 PHD2.Fe(III).2OG 复合物的晶体学、光谱学和生物化学表征。在有氧条件下，PHD2 与 Fe(II) 和 2OG 孵育可形成 PHD2.Fe(III).2OG 复合物，该复合物结合 HIF1-2α 形成无活性 PHD2.Fe(III).2OG.HIF1-2α 复合物。无活性复合物中的 Fe(III) 氧化态通过 EPR 光谱证明。L-抗坏血酸阻碍 PHD2.Fe(III).2OG.(+/-HIFα) 复合物的形成，并缓慢将其再生为具有催化活性的 PHD2.Fe(II).2OG 复合物。与类似的厌氧 Fe(II) 复合物的 PHD2.Fe(III).2OG.HIF2α 复合物的晶体学比较显示出几乎相同的结构。将厌氧 PHD2.Fe(II).2OG.HIF2α 晶体暴露于 O 可在晶体中进行羟化。与底物结构相比，所得 PHD2.产物结构表现出构象变化。结果对 PHDs 在缺氧感应中的作用具有启示意义，并为通过促进稳定 Fe(III) 复合物的形成来抑制 PHDs 和其他 2OG 依赖性氧合酶开辟了新的机会。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/13083a969343/41598_2024_75761_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/19eeebe64206/41598_2024_75761_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/9637f1834971/41598_2024_75761_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/74bff5532b78/41598_2024_75761_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/7e767e15e313/41598_2024_75761_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/4d20dc862b52/41598_2024_75761_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/9929dea74a28/41598_2024_75761_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/13083a969343/41598_2024_75761_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/19eeebe64206/41598_2024_75761_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/9637f1834971/41598_2024_75761_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/74bff5532b78/41598_2024_75761_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/7e767e15e313/41598_2024_75761_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/4d20dc862b52/41598_2024_75761_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/9929dea74a28/41598_2024_75761_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7762/11525979/13083a969343/41598_2024_75761_Fig7_HTML.jpg

相似文献

1
Human prolyl hydroxylase domain 2 reacts with O and 2-oxoglutarate to enable formation of inactive Fe(III).2OG.hypoxia-inducible-factor α complexes.人脯氨酰羟化酶结构域 2 与 O 和 2-氧代戊二酸反应，使 Fe(III).2OG.缺氧诱导因子α复合物形成无活性状态。
Sci Rep. 2024 Oct 30;14(1):26162. doi: 10.1038/s41598-024-75761-y.
2
Investigating the contribution of the active site environment to the slow reaction of hypoxia-inducible factor prolyl hydroxylase domain 2 with oxygen.研究活性位点环境对缺氧诱导因子脯氨酰羟化酶结构域2与氧气缓慢反应的贡献。
Biochem J. 2014 Nov 1;463(3):363-72. doi: 10.1042/BJ20140779.
3
Substrate preference of the HIF-prolyl hydroxylase-2 (PHD2) and substrate-induced conformational change.HIF-脯氨酰羟化酶-2（PHD2）的底物偏好性和底物诱导的构象变化。
J Inorg Biochem. 2013 Sep;126:55-60. doi: 10.1016/j.jinorgbio.2013.05.006. Epub 2013 May 21.
4
Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.肾癌靶蛋白缺氧诱导因子 2α 与脯氨酰羟化酶结构域 2 结合的结构基础。
Proteins. 2023 Nov;91(11):1510-1524. doi: 10.1002/prot.26541. Epub 2023 Jul 14.
5
Human oxygen sensing may have origins in prokaryotic elongation factor Tu prolyl-hydroxylation.人类的氧感知可能起源于原核生物延伸因子Tu的脯氨酰羟化作用。
Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13331-6. doi: 10.1073/pnas.1409916111. Epub 2014 Sep 2.
6
2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2.2-氧代戊二酸调节羟基化缺氧诱导因子与脯氨酰羟化酶结构域2的结合。
Chem Commun (Camb). 2018 Mar 28;54(25):3130-3133. doi: 10.1039/c8cc00387d. Epub 2018 Mar 9.
7
Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases.缺氧诱导因子与氧感应脯氨酰羟化酶结合的结构基础。
Structure. 2009 Jul 15;17(7):981-9. doi: 10.1016/j.str.2009.06.002.
8
Studies on the Substrate Selectivity of the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Catalytic Domain.缺氧诱导因子脯氨酰羟化酶 2 催化结构域的底物选择性研究。
Chembiochem. 2018 Nov 2;19(21):2262-2267. doi: 10.1002/cbic.201800246. Epub 2018 Sep 26.
9
Mechanism of Molecular Oxygen Diffusion in a Hypoxia-Sensing Prolyl Hydroxylase Using Multiscale Simulation.利用多尺度模拟研究缺氧感应脯氨酰羟化酶中分子氧扩散的机制。
J Am Chem Soc. 2020 Feb 5;142(5):2253-2263. doi: 10.1021/jacs.9b09236. Epub 2020 Jan 23.
10
Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2).细胞氧感知：缺氧诱导因子脯氨酰羟化酶（PHD2）的晶体结构
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9814-9. doi: 10.1073/pnas.0601283103. Epub 2006 Jun 16.

引用本文的文献

1
Evidence human FTO catalyses hydroxylation of N6-methyladenosine without direct formation of a demethylated product contrasting with ALKBH5/2/3 and bacterial AlkB.有证据表明，与ALKBH5/2/3和细菌AlkB不同，人类FTO催化N6-甲基腺苷的羟基化反应，但不会直接形成去甲基化产物。
Nucleic Acids Res. 2025 Aug 27;53(16). doi: 10.1093/nar/gkaf813.
2
Biochemical investigations using mass spectrometry to monitor JMJD6-catalysed hydroxylation of multi-lysine containing bromodomain-derived substrates.使用质谱法进行生化研究，以监测JMJD6催化的含多赖氨酸的溴结构域衍生底物的羟基化反应。
RSC Chem Biol. 2025 Feb 24;6(4):642-656. doi: 10.1039/d4cb00311j. eCollection 2025 Apr 2.

本文引用的文献

1
Biochemistry of the hypoxia-inducible factor hydroxylases.缺氧诱导因子羟化酶的生物化学。
Curr Opin Chem Biol. 2024 Apr;79:102428. doi: 10.1016/j.cbpa.2024.102428. Epub 2024 Feb 7.
2
Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.肾癌靶蛋白缺氧诱导因子 2α 与脯氨酰羟化酶结构域 2 结合的结构基础。
Proteins. 2023 Nov;91(11):1510-1524. doi: 10.1002/prot.26541. Epub 2023 Jul 14.
3
Kinetic and inhibition studies on human Jumonji-C (JmjC) domain-containing protein 5.
人含Jumonji-C（JmjC）结构域蛋白5的动力学及抑制研究
RSC Chem Biol. 2023 Mar 20;4(6):399-413. doi: 10.1039/d2cb00249c. eCollection 2023 Jun 7.
4
The ribosomal chaperone NACA recruits PHD2 to cotranslationally modify HIF-α.核糖体伴侣 NACA 招募 PHD2 进行共翻译修饰 HIF-α。
EMBO J. 2022 Nov 17;41(22):e112059. doi: 10.15252/embj.2022112059. Epub 2022 Oct 11.
5
Ascorbate as a Bioactive Compound in Cancer Therapy: The Old Classic Strikes Back.抗坏血酸作为癌症治疗中的生物活性化合物：老经典卷土重来。
Molecules. 2022 Jun 14;27(12):3818. doi: 10.3390/molecules27123818.
6
The Asparagine Hydroxylase FIH: A Unique Oxygen Sensor.天冬酰胺羟化酶 FIH：一种独特的氧传感器。
Antioxid Redox Signal. 2022 Nov;37(13-15):913-935. doi: 10.1089/ars.2022.0003. Epub 2022 Apr 29.
7
2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases.2-氧戊二酸衍生物可以选择性地增强或抑制人体加氧酶的活性。
Nat Commun. 2021 Nov 10;12(1):6478. doi: 10.1038/s41467-021-26673-2.
8
High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer.大剂量静脉注射维生素 C，一种有前途的癌症多靶点治疗药物。
J Exp Clin Cancer Res. 2021 Oct 30;40(1):343. doi: 10.1186/s13046-021-02134-y.
9
X-ray free-electron laser studies reveal correlated motion during isopenicillin synthase catalysis.X 射线自由电子激光研究揭示了异青霉素合成酶催化过程中的关联运动。
Sci Adv. 2021 Aug 20;7(34). doi: 10.1126/sciadv.abh0250. Print 2021 Aug.
10
Synthesis of 2-oxoglutarate derivatives and their evaluation as cosubstrates and inhibitors of human aspartate/asparagine-β-hydroxylase.2-氧代戊二酸衍生物的合成及其作为人天冬氨酸/天冬酰胺-β-羟化酶的共底物和抑制剂的评价。
Chem Sci. 2020 Dec 7;12(4):1327-1342. doi: 10.1039/d0sc04301j.