Structure and mechanism of mammalian stearoyl-CoA desaturases
哺乳动物硬脂酰辅酶A去饱和酶的结构和机制
基本信息
- 批准号:10630911
- 负责人:
- 金额:$ 63.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnabolismBindingBiochemical ReactionBiological AssayCancer Cell GrowthCatalysisCell ProliferationCellsCommunicationComplexConserved SequenceCrystallizationCytochromes b5DetergentsDiabetes MellitusDrug TargetingElectron TransportEndoplasmic ReticulumEnzymesFamilyFatty acid glycerol estersFoundationsFreezingGeometryGoalsHigh Fat DietHistidineHomeostasisHydrogenIn VitroInsectaIonsIronKineticsKnowledgeLengthLifeLigandsMalignant NeoplasmsMammalian CellMapsMeasuresMediatingMembraneMembrane ProteinsModelingMolecular ConformationMovementMusMutationNADHNitric OxideObesityOxidation-ReductionOxidoreductaseOxygenPathway interactionsPhospholipidsPositioning AttributeProtein DynamicsProteinsReactionResolutionRoleSaturated Fatty AcidsSpecificitySpin TrappingStearoyl-CoA DesaturaseStructureSystemTestingVisualizationZinccancer cellcytochrome b5 reductasediabeticdrug developmentfatty acid oxidationin vitro Assayinsightlipid biosynthesismembernanodisknovelobesity treatmentoxidationpi bondpreferenceproteoliposomesreconstitutionscreeningstearoyl-coenzyme A
项目摘要
Mammalian stearoyl-CoA desaturase (SCD) is a member of a super family of redox enzymes that have
four transmembrane helices and a diiron center composed of nine conserved histidine residues. This
superfamily has over 20,000 members from all kingdoms of life and yet very little is known about the function
and mechanism of these proteins. The overall goal of the proposal is to understand the mechanism of SCD at
the atomic resolution. SCD resides on endoplasmic reticulum membrane and catalyzes the formation of a
double bond on saturated fatty acyl-CoAs. Mice with reduced SCD activity do not become obese or diabetic
when fed with a high-fat diet, illustrating the significance of SCD activity in energy homeostasis. SCD
expression level is upregulated in cancer cells because of a higher demand for membrane biosynthesis, and
inhibition of SCD activity thwarts cancer cell growth. These results led to intense efforts on targeting SCDs for
the treatment of obesity, diabetes, and cancer, but the efforts are hampered by a lack of 3-dimenional
structures of SCD and incomplete understanding of the catalytic mechanism.
It remains unclear how SCDs recognize their substrates and achieve specificity in double bond
formation. The all-histidine coordinated diiron center is different from other diiron centers of known structures
and its mechanism of catalysis has not been examined. In addition, sustained SCD activity requires two
additional membrane proteins, cytochrome b5 (b5) and cytochrome b5 reductase (b5R), which mediate electron
transfer from NADH to the diiron center. Yet how the diiron center is redox-cycled through dynamic interactions
with b5 and b5R remains a mystery.
We expressed and purified functional mouse SCD1 and solved its crystal structure to 2.6 Å resolution.
We also expressed and purified full length b5 and b5R, and assembled the enzymatic reactions in vitro. In
addition, we produced stable binary complexes between b5R and b5 and between b5 and SCD1, and we
established assays to measure electron transfer between the binding partners. These preliminary results
allowed us to propose the following three Specific Aims:
Aim 1: To characterize the structure and function of SCD1.
Aim 2: To understand the oxidative and reductive pathways of the SCD1 diiron center.
Aim 3: To understand the structural basis of electron transfer between b5 and SCD1 and between b5R
and b5.
哺乳动物硬脂酰辅酶a去饱和酶(SCD)是氧化还原酶超级家族的一员
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Structural basis of ion transport and inhibition in ferroportin.
离子转运和抑制铁蛋白的结构基础。
- DOI:10.1038/s41467-020-19458-6
- 发表时间:2020-11-10
- 期刊:
- 影响因子:16.6
- 作者:Pan Y;Ren Z;Gao S;Shen J;Wang L;Xu Z;Yu Y;Bachina P;Zhang H;Fan X;Laganowsky A;Yan N;Zhou M
- 通讯作者:Zhou M
Structure of a eukaryotic cholinephosphotransferase-1 reveals mechanisms of substrate recognition and catalysis.
- DOI:10.1038/s41467-023-38003-9
- 发表时间:2023-05-13
- 期刊:
- 影响因子:16.6
- 作者:Wang, Lie;Zhou, Ming
- 通讯作者:Zhou, Ming
Mechanism of stepwise electron transfer in six-transmembrane epithelial antigen of the prostate (STEAP) 1 and 2.
- DOI:10.7554/elife.88299
- 发表时间:2023-11-20
- 期刊:
- 影响因子:7.7
- 作者:Chen K;Wang L;Shen J;Tsai AL;Zhou M;Wu G
- 通讯作者:Wu G
Plasmon-Generated Solvated Electrons for Chemical Transformations.
用于化学转化的等离激元产生的溶剂化电子。
- DOI:10.1021/jacs.2c07768
- 发表时间:2022
- 期刊:
- 影响因子:15
- 作者:Solti,David;Chapkin,KyleD;Renard,David;Bayles,Aaron;Clark,BenjaminD;Wu,Gang;Zhou,Jingyi;Tsai,Ah-Lim;Kürti,László;Nordlander,Peter;Halas,NaomiJ
- 通讯作者:Halas,NaomiJ
Free ferrous ions sustain activity of mammalian stearoyl-CoA desaturase-1.
游离亚铁离子维持哺乳动物硬脂酰辅酶 A 去饱和酶 1 的活性。
- DOI:10.1101/2023.03.17.533000
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Shen,Jiemin;Wu,Gang;Pierce,BradS;Tsai,Ah-Lim;Zhou,Ming
- 通讯作者:Zhou,Ming
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{{ truncateString('AH-LIM TSAI', 18)}}的其他基金
Structure and mechanism of mammalian stearoyl-CoA desaturases
哺乳动物硬脂酰辅酶A去饱和酶的结构和机制
- 批准号:
10202589 - 财政年份:2019
- 资助金额:
$ 63.29万 - 项目类别:
Structure and mechanism of mammalian stearoyl-CoA desaturases
哺乳动物硬脂酰辅酶A去饱和酶的结构和机制
- 批准号:
10405625 - 财政年份:2019
- 资助金额:
$ 63.29万 - 项目类别:
Radical Intermediates of Nitric Oxide Synthase & Myocardial Ischemia Reperfusion
一氧化氮合酶自由基中间体
- 批准号:
8220816 - 财政年份:2010
- 资助金额:
$ 63.29万 - 项目类别:
Radical Intermediates of Nitric Oxide Synthase & Myocardial Ischemia Reperfusion
一氧化氮合酶自由基中间体
- 批准号:
8018542 - 财政年份:2010
- 资助金额:
$ 63.29万 - 项目类别:
Radical Intermediates of Nitric Oxide Synthase & Myocardial Ischemia Reperfusion
一氧化氮合酶自由基中间体
- 批准号:
7783873 - 财政年份:2010
- 资助金额:
$ 63.29万 - 项目类别:
Radical Intermediates of Nitric Oxide Synthase & Myocardial Ischemia Reperfusion
一氧化氮合酶自由基中间体
- 批准号:
8447346 - 财政年份:2010
- 资助金额:
$ 63.29万 - 项目类别:
Magnetic Circular Dichroism/Circular Discroism System
磁圆二色性/圆二色性系统
- 批准号:
7389761 - 财政年份:2008
- 资助金额:
$ 63.29万 - 项目类别:
ELECTRON PARAMAGNETIC RESONANCE (EPR) SPECTROMETER
电子顺磁共振 (EPR) 能谱仪
- 批准号:
6053090 - 财政年份:2000
- 资助金额:
$ 63.29万 - 项目类别:
Structure-Function and Reacation Mechanism of eNOS
eNOS的结构功能及反应机制
- 批准号:
6829733 - 财政年份:1999
- 资助金额:
$ 63.29万 - 项目类别:
Structure-Function and Reacation Mechanism of eNOS
eNOS的结构功能及反应机制
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6982799 - 财政年份:1999
- 资助金额:
$ 63.29万 - 项目类别:
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