Outer sphere contributions within the thiol dioxygenase active site: a combined structure-function study

硫醇双加氧酶活性位点内外球的贡献:结构-功能组合研究

基本信息

  • 批准号:
    10579496
  • 负责人:
  • 金额:
    $ 41.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-15 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

TITLE. Outer sphere contributions within the thiol dioxygenase active site: a combined structure-function study PROJECT SUMMARY. Thiol dioxygenases (TDOs) are a subset of non-heme mononuclear iron oxygenases that catalyze the O2-dependent oxidation of thiol-bearing substrates to yield the corresponding sulfinic acid. Cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO) are the only known mammalian TDOs. These enzymes catalyze the oxidation of L-cysteine (CYS) and cysteamine (2-aminoethanthiol, CA) to produce cysteine sulfinic acid (CSA) and hypotaurine (HT), respectively. Ultimately, CSA and HT feed into the mammalian biosynthetic pathways for taurine (TAU). As the most abundant (sulfonic) amino acid derivative in the body, TAU plays a variety of essential functions including osmoregulation, conjugation substrate in the synthesis of bile salts, stabilization of skeletal muscle, maintenance of cardiac rhythm, and an essential neurotransmitter in embryonic central nervous system development. Despite having structurally similar substrates, CDO and ADO exhibit remarkable substrate-specificity; exhibiting no (or negligible) cross-reactivity. Significantly, changes in the cellular expression and/or activity of mammalian TDOs (CDO and ADO) have been correlated with the onset of various human diseases (cancer, neurodegenerative disorders, rheumatoid arthritis, as well as other metabolic disorders). An emerging subset of TDOs are referred to as N-terminal cysteinyl dioxygenases (NCOs). These enzymes are believed to function as physiologic O2-sensors by catalyzing the oxidation of protein N-terminal CYS-residues to initiate protein degradation. A similar function has recently been reported for mammalian ADO in controlling regulators of G protein signaling. Therefore ADO functions both as a small molecule TDO, specific for cysteamine (CA), as well as a NCO by regulating the stability of specific proteins in an O2-dependent fashion. A notable distinction within the NCO active site is the absence of a conserved sequence of spatially adjacent amino acids (Ser-His-Tyr) forming a hydrogen bonding network. This structural motif is highly conserved among structurally characterized TDOs and it is believed to regulate oxygen and thiol-substrate binding affinity at the TDO Fe-site. The absence of this conserved sequence among NCOs suggests a novel mechanism for O2-sensing in this class of enzymes. The central theme of the proposed activities is to investigate the role of outer-sphere interactions within the TDO active site that influence substrate efficiency and recognition. The experiments proposed involve a series of careful kinetic measurements to identify catalytically essential residues within the enzymatic active site. In parallel, spectroscopic and computational methods will be employed to develop a structural model for active site hydrogen-bonding interactions. Similar studies will be performed on members of the NCO class of enzymes to provide a valuable counterpoint to results obtained for TDOs. Potentially these studies will shed light on the mechanisms by which TDOs (and NCOs) regulate specificity of small molecule thiols, polypeptide substrates, and molecular oxygen.
头衔。硫醇双加氧酶活性部位的外球贡献:结构-功能组合 学习 项目总结。硫醇双加氧酶(TDO)是非血红素单核铁加氧酶的一个亚类 它催化含硫基底物的O2依赖的氧化,以产生相应的亚磺酸。 半胱氨酸双加氧酶(CDO)和半胱胺双加氧酶(ADO)是目前已知的哺乳动物TDO。这些 酶催化L半胱氨酸(Cys)和半胱胺(2-氨基乙硫醇,CA)氧化生成半胱氨酸 亚磺酸(CsA)和次牛磺酸(HT)。最终,环孢素A和羟色胺进入哺乳动物体内 牛磺酸的生物合成途径。作为体内含量最丰富的(磺酸)氨基酸衍生物, Tau在细胞的合成过程中发挥着渗透调节、结合底物等多种重要功能。 胆盐、稳定骨骼肌、维持心律和人体必需的神经递质。 胚胎中枢神经系统发育。尽管具有结构相似的衬底,CDO和ADO 表现出显著的底物专一性;没有(或可忽略)交叉反应。值得注意的是, 哺乳动物TDO(CDO和ADO)的细胞表达和/或活性与疾病的发生有关 人类的各种疾病(癌症、神经退行性疾病、类风湿性关节炎以及其他代谢疾病) 紊乱)。一个新出现的TDO子集被称为N-末端半胱氨酰双加氧酶(NCOs)。这些 酶被认为通过催化蛋白质N-末端的氧化来起到生理上的O2-感受器的作用 半胱氨酸残基启动蛋白质降解。最近有报道称哺乳动物的ADO也有类似的功能 在控制G蛋白信号的调节方面。因此,ADO既是一种小分子tdo,又是一种特异的 对于半胱胺(CA),以及一种NCO,通过以O2依赖的方式调节特定蛋白质的稳定性。 NCO活性中心内的一个显著区别是缺乏空间上相邻的保守序列 形成氢键网络的氨基酸(Ser-His-Tyr)。这一结构主题在 TDO的结构特征,据信它调节氧和硫醇-底物在 Tdo Fe-Site。NCO中这种保守序列的缺失提示了一种新的O2传感机制 在这类酶中。拟议活动的中心主题是调查外层空间的作用。 影响底物效率和识别的TDO活性部位内的相互作用。这些实验 建议涉及一系列仔细的动力学测量,以确定在 酶活性部位。同时,将使用光谱和计算方法来开发一种 活性中心氢键相互作用的结构模型。将对以下成员进行类似的研究 NCO类别的酶提供了与TDO结果相对应的有价值的结果。潜在的这些 研究将阐明TDO(和NCOS)调节小分子特异性的机制 硫醇、多肽底物和分子氧。

项目成果

期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cyanide replaces substrate in obligate-ordered addition of nitric oxide to the non-heme mononuclear iron AvMDO active site.
  • DOI:
    10.1007/s00775-023-01990-7
  • 发表时间:
    2023-04
  • 期刊:
  • 影响因子:
    3
  • 作者:
    York, Nicholas J. J.;Lockart, Molly M. M.;Schmittou, Allison N. N.;Pierce, Brad S. S.
  • 通讯作者:
    Pierce, Brad S. S.
Outer-Sphere Tyrosine 159 within the 3-Mercaptopropionic Acid Dioxygenase S-H-Y Motif Gates Substrate-Coordination Denticity at the Non-Heme Iron Active Site.
  • DOI:
    10.1021/acs.biochem.9b00674
  • 发表时间:
    2019-12-24
  • 期刊:
  • 影响因子:
    2.9
  • 作者:
    Sardar, Sinjinee;Weitz, Andrew;Hendrich, Michael P.;Pierce, Brad S.
  • 通讯作者:
    Pierce, Brad S.
Nitroxyl Modified Tobacco Mosaic Virus as a Metal-Free High-Relaxivity MRI and EPR Active Superoxide Sensor.
  • DOI:
    10.1021/acs.molpharmaceut.8b00262
  • 发表时间:
    2018-08-06
  • 期刊:
  • 影响因子:
    4.9
  • 作者:
    Dharmarwardana M;Martins AF;Chen Z;Palacios PM;Nowak CM;Welch RP;Li S;Luzuriaga MA;Bleris L;Pierce BS;Sherry AD;Gassensmith JJ
  • 通讯作者:
    Gassensmith JJ
Low-Spin Cyanide Complexes of 3-Mercaptopropionic Acid Dioxygenase (MDO) Reveal the Impact of Outer-Sphere SHY-Motif Residues.
  • DOI:
    10.1021/acs.inorgchem.1c01519
  • 发表时间:
    2021-12-20
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    York, Nicholas J.;Lockart, Molly M.;Pierce, Brad S.
  • 通讯作者:
    Pierce, Brad S.
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Bradley S Pierce其他文献

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