Macromolecular interactions controlling the ALA synthases, keystone enzymes that initiate heme biosynthesis
控制 ALA 合成酶(启动血红素生物合成的关键酶)的大分子相互作用
基本信息
- 批准号:9752583
- 负责人:
- 金额:$ 41.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisActive SitesAdoptedAffectAllelesAminolevulinic AcidAnemiaAnimalsBindingBinding ProteinsBinding SitesBiochemicalBiological AssayBiophysicsC-terminalCell Culture TechniquesCellsClpX proteinComplexCoupledDefectDeuteriumDevelopmentDiseaseElementsEnzymesErythrocytesErythroidErythroid CellsErythropoiesisErythropoietic ProtoporphyriaEukaryotaFamilyFeedbackFoundationsGenesGlycineHemeHemoglobinHereditary Sideroblastic AnemiaHumanHydrogenIn VitroInheritedLife Cycle StagesLigand BindingLinkMEL GeneMass Spectrum AnalysisMediatingMitochondriaModelingMolecularMolecular ChaperonesMolecular ConformationMolecular StructureMotorMusMutagenesisMutationN-terminalOrganismOxygenPeptide HydrolasesPeptidesPhenotypePhysical condensationPorphyriasProcessProductionProtein FamilyProtein IsoformsProteinsPyridoxalPyridoxal PhosphateReactionRegulationRoleSignal TransductionSite-Directed MutagenesisStructureSuccinate-CoA LigasesSurfaceTestingVertebratesVitamin B6WorkYeastscofactorcombatdifferential expressiondimerendopeptidase Laenzyme activityexperimental studyferrochelatasegain of functionheme aheme biosynthesisinorganic phosphateinsightknock-downmembermonomermutantnovelnovel therapeutic interventionnovel therapeuticsprotein degradationprotoporphyrin IXsensorsmall moleculesuccinyl-coenzyme Atargeted treatmentunfoldase
项目摘要
Heme is the oxygen-binding ligand of hemoglobin and is an essential cofactor or sensor element in many
proteins. Heme production must be tightly controlled to adequately supply these functions but to avoid
overproduction, as accumulation of free heme and heme precursors is toxic. The first committed step in heme
biosynthesis is the condensation of glycine and succinyl-CoA to yield 5-aminolevulinic acid (ALA). This reaction
is catalyzed by ALA synthase (ALAS), which uses pyridoxal 5ʹ-phosphate (PLP, the active form of vitamin B6)
as an essential cofactor. In animals, there are two differentially expressed ALAS isoforms. ALAS1 is present in
most cells, whereas ALAS2 is an erythroid-specific enzyme that is dramatically upregulated during red cell
development. In humans, mutations in ALAS2 cause two diseases: (1) X-linked sideroblastic anemia (XLSA)
when enzyme activity is too low to support healthy levels of heme production and erythropoiesis and (2)
Erythroid X-linked protoporphyria (XLPP), from gain-of-function ALAS2 mutations that overproduce ALA,
causing build up of toxic heme biosynthetic intermediates. The life cycle of ALAS is tightly regulated at steps
including mitochondrial import and protein turnover. Both these steps are feedback controlled by heme-binding.
Enzyme activity (and/or stability) is also regulated and these processes are affected by interaction with other
enzymes, including Lon protease, succinyl-CoA synthetase (SCS), and perhaps ferrochelatase (FECH), the
final two also critical enzymes in heme synthesis. Importantly, we recently discovered that ALAS activity is also
dramatically stimulated by mitochondrial ClpX (mtClpX), a member of the AAA+ family of protein unfoldases.
The mtClpX energy-dependent unfoldase accelerates incorporation of PLP into ALAS and CLPX depletion
causes anemia in vertebrates. We also solved structures of both PLP-free ALAS (from yeast) and the active
PLP-bound enzyme, which illuminates the conformational changes coupled to PLP incorporation and provides
important information for understanding mtClpX-promoted loading of PLP. These structures also provide the
first observation of the eukaryotic-specific regulatory C-terminal domain of the enzyme. This domain structure
suggests testable mechanisms to explain the XLPP mutations and contains the binding site for SCS, which we
will further study. Continuing to investigate how mtClpX physically interacts with ALAS and to test models for
the mechanism of PLP-loading holds promise for uncovering a link between mtClpX-ALAS2 interactions and
some classes of XLSA alleles. In another recent, exciting breakthrough, our collaborators discovered a
dominant human CLPX mutation that appears to hyperactivate ALAS, leading to mtClpX-linked erythropoietic
protoporphyria (EPP). The mechanistic basis of this disease will be scrutinized at the molecular, structural and
cellular level. Thus, by probing the complex mechanisms that control ALAS enzymes we will elucidate new
molecular means of regulation. We believe that this work, in turn, will inspire novel therapeutic strategies for
combating the debilitating illnesses caused by misregulated ALAS.
血红素是血红蛋白的氧结合配体,是许多疾病中必不可少的辅助因子或传感元件
项目成果
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TANIA A BAKER其他文献
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{{ truncateString('TANIA A BAKER', 18)}}的其他基金
Macromolecular interactions controlling the ALA synthases, keystone enzymes that initiate heme biosynthesis
控制 ALA 合成酶(启动血红素生物合成的关键酶)的大分子相互作用
- 批准号:
10214597 - 财政年份:2017
- 资助金额:
$ 41.94万 - 项目类别:
BASIS OF SUBSTRATE SELECTION BY BACTERIAL ADAPTOR PROTEINS
细菌衔接蛋白选择底物的基础
- 批准号:
8169213 - 财政年份:2010
- 资助金额:
$ 41.94万 - 项目类别:
ADAPTOR-PROTEIN MEDIATED RECOGNITION AND REGULATION OF PROTEIN DEGRADATION
接头蛋白介导的蛋白质降解的识别和调节
- 批准号:
7955083 - 财政年份:2009
- 资助金额:
$ 41.94万 - 项目类别:
STRUCTURE AND FUNCTION OF THE CLPXP ATP-DEPENDENT PROTEASE
CLPXP ATP 依赖性蛋白酶的结构和功能
- 批准号:
7721201 - 财政年份:2008
- 资助金额:
$ 41.94万 - 项目类别:
STRUCTURE AND FUNCTION OF THE CLPXP ATP-DEPENDENT PROTEASE
CLPXP ATP 依赖性蛋白酶的结构和功能
- 批准号:
7182916 - 财政年份:2005
- 资助金额:
$ 41.94万 - 项目类别:
STRUCTURE AND FUNCTION OF THE CLPXP ATP-DEPENDENT PROTEASE
CLPXP ATP 依赖性蛋白酶的结构和功能
- 批准号:
7369492 - 财政年份:2005
- 资助金额:
$ 41.94万 - 项目类别:
STRUCTURE/FUNCTION OF THE CLPXP ATP-DEPENDENT PROTEASE
CLPXP ATP 依赖性蛋白酶的结构/功能
- 批准号:
6972755 - 财政年份:2004
- 资助金额:
$ 41.94万 - 项目类别:
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