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内的外球贡献:结构-功能结合
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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