Catalysis by KDM6 Histone Demethylases - A Synergy between the Non-Heme Iron(II) Center, Second Coordination Sphere, and Long-Range Interactions.
Catalysis by KDM6 Histone Demethylases - A Synergy between the Non-Heme Iron(II) Center, Second Coordination Sphere, and Long-Range Interactions.
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KDM6 组蛋白去甲基酶的催化 - 非血红素铁 (II) 中心、第二配位球和长程相互作用之间的协同作用。
DOI：
10.1002/chem.202301305
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Christov,ChristoZ
中科院分区：
文献类型：
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作者：
Rifayee,SimahudeenBathirJaberSathik;Chaturvedi,ShobhitS;Warner,Cait;Wildey,Jon;White,Walter;Thompson,Martin;Schofield,ChristopherJ;Christov,ChristoZ
KDM6A(UTX)和KDM6B(JMJD3)是人类非血红素铁(II)和2-氧戊二酸(2OG)依赖的JMjC加氧酶，催化组蛋白 H3 N端三甲基化赖氨酸27的去甲基化，这是一种调节转录的翻译后修饰。结合量子力学/分子力学(QM/MM)和分子动力学(MD)对KDM6A/B催化机理的研究表明，KDM6A催化限速氢原子转移(HAT)反应的过渡态是由极性残基(Asn217)和芳香族(Trp369)/非极性(Pro274)残基稳定的，而KDM4、KDM6B和KDM7脱甲基酶则涉及带电残基(Glu、Arg、Asp)。KDM6A对HAT采用σ电子转移途径和π电子转移途径，而KDM6B采用σ电子转移途径。铁螯合Glu252(KDM6B)的氢键差异是KDM6B与KDM6A相比能垒较低的原因之一。研究表明，在KDM6A的过渡态中，反弹羟化反应的活化势垒与Fe−O−C角有关。锌结合结构域与活性位点残基的反相关性是KDM6A/B区别于KDM7/4S的关键因素。这些结果揭示了铁中心、第二配位球和长程相互作用在KDMS和其他2OG加氧酶催化中的重要性。
KDM6A (UTX) and KDM6B (JMJD3) are human non‐heme Fe(II) and 2‐oxoglutarate (2OG) dependent JmjC oxygenases that catalyze the demethylation of trimethylated lysine 27 in the N‐terminal tail of histone H3, a post‐translational modification that regulates transcription. A Combined Quantum Mechanics/ Molecular Mechanics (QM/MM) and Molecular Dynamics (MD) study on the catalytic mechanism of KDM6A/B reveals that the transition state for the rate‐limiting hydrogen atom transfer (HAT) reaction in KDM6A catalysis is stabilized by polar (Asn217) and aromatic (Trp369)/non‐polar (Pro274) residues in contrast to KDM4, KDM6B and KDM7 demethylases where charged residues (Glu, Arg, Asp) are involved. KDM6A employs both σ‐ and π‐electron transfer pathways for HAT, whereas KDM6B employs the σ‐electron pathway. Differences in hydrogen bonding of the Fe‐chelating Glu252(KDM6B) contribute to the lower energy barriers in KDM6B vs. KDM6A. The study reveals a dependence of the activation barrier of the rebound hydroxylation on the Fe−O−C angle in the transition state of KDM6A. Anti‐correlation of the Zn‐binding domain with the active site residues is a key factor distinguishing KDM6A/B from KDM7/4s. The results reveal the importance of communication between the Fe center, second coordination sphere, and long‐range interactions in catalysis by KDMs and, by implication, other 2OG oxygenases.