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
- 来源:
- 关键词:Active SitesAddressAffinityAminesAmino AcidsAnionsBindingBinding SitesCatalysisCategoriesCentral Nervous SystemChargeComputing MethodologiesConserved SequenceCoupledCysteamineCysteineCysteine dioxygenaseDiagnosticDioxygenDioxygenasesElectron TransportEmbryoEnzymesExhibitsGTP-Binding Protein RegulatorsHealthHumanHydrogen BondingIntuitionInvestigationIronKineticsKnowledgeLigandsMaintenanceMalignant NeoplasmsMammalsMeasurementMetabolic DiseasesModelingMolecularMononuclearN-terminalNeurodegenerative DisordersNeurotransmittersOsmoregulationOxygenOxygenasesPathway interactionsPhysiologicalPlayPositioning AttributeProteinsReactionReportingRheumatoid ArthritisRoleSamplingSchemeSeriesSiteSkeletal MuscleSpecificityStructural ModelsStructureSubstrate SpecificitySulfhydryl CompoundsSulfinic AcidsTaurinebile saltscarboxylatecarboxylationcross reactivitycysteine sulfinic acidcysteinyltyrosineenzyme mechanismenzyme substrate complexexperimental studyfallsheart rhythmhuman diseasehypotaurineiron nitrosylmembernervous system developmentnoveloxidationpolypeptideposttranscriptionalprotein degradationsensorseryl-histidinesmall moleculespectroscopic surveytool
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.
标题.硫醇双加氧酶活性位点的外球贡献:结构-功能组合
研究
项目摘要。巯基双加氧酶(TDO)是非血红素单核铁加氧酶的一个亚类
其催化含硫醇底物的O2依赖性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)是已知的仅有的哺乳动物TDO。这些
酶催化L-半胱氨酸(CYS)和半胱胺(2-氨基乙硫醇,CA)氧化产生半胱氨酸
亚磺酸(CSA)和亚牛磺酸(HT)。最终,CSA和HT进入哺乳动物体内,
牛磺酸(TAU)的生物合成途径。作为体内最丰富的(磺酸)氨基酸衍生物,
TAU具有多种重要功能,包括转录调控、结合底物等,在合成
胆盐,稳定骨骼肌,维持心律,以及一种重要的神经递质,
胚胎中枢神经系统发育尽管CDO和ADO具有结构相似的底物,
表现出显著的底物特异性;表现出无(或可忽略的)交叉反应性。值得注意的是,
哺乳动物TDO(CDO和ADO)的细胞表达和/或活性与
各种人类疾病(癌症、神经退行性疾病、类风湿性关节炎以及其他代谢性疾病)的治疗。
疾病)。TDO的新兴子集被称为N-末端半胱氨酰双加氧酶(NCO)。这些
酶被认为通过催化蛋白质N-末端的氧化而起到生理O2-传感器的作用
启动蛋白质降解的CYP-残基。最近报道了哺乳动物ADO的类似功能
控制G蛋白信号的调节器。因此,ADO既作为小分子TDO,又作为特异性TDO,
对于半胱胺(CA),以及NCO,通过以O2依赖性方式调节特定蛋白质的稳定性。
NCO活性位点内的一个显著区别是不存在空间相邻的保守序列。
形成氢键网络的氨基酸(Ser-His-Tyr)。这种结构基序在以下物种中高度保守:
结构上表征的TDO,并且据信其调节氧和硫醇-底物结合亲和力,
TDO Fe现场。这种保守序列在NCOs中的缺失表明了一种新的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
TDO活性位点内的相互作用影响底物效率和识别。实验
建议涉及一系列仔细的动力学测量,以确定催化内的基本残留物,
酶活性位点同时,光谱和计算方法将用于开发一个
活性部位氢键相互作用的结构模型。类似的研究将在以下成员身上进行:
NCO类酶提供了一个有价值的对应点,为TDO获得的结果。潜在这些
研究将阐明TDO(和NCO)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)
Cooperative redox and spin activity from three redox congeners of sulfur-bridged iron nitrosyl and nickel dithiolene complexes.
- DOI:10.1073/pnas.2201240119
- 发表时间:2022-06-21
- 期刊:
- 影响因子:11.1
- 作者:
- 通讯作者:
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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