Analysis of Hypoxia and Hypoxia-Like States through Metabolite Profiling 英文参考文献.docVIP

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Analysis of Hypoxia and Hypoxia-Like States through Metabolite Profiling 英文参考文献.doc

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Analysis of Hypoxia and Hypoxia-Like States through Metabolite Profiling 英文参考文献

AnalysisofHypoxiaandHypoxia-LikeStatesthrough MetaboliteProfiling JulieE.Gleason1.,DavidJ.Corrigan1.,JamesE.Cox2,AmitR.Reddi1,LaurenA.McGinnis1,ValeriaC. Culotta1* 1Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America, 2MetabolomicsCoreResearchFacility,UniversityofUtahSchoolofMedicine,SaltLakeCity,Utah,UnitedStatesofAmerica Abstract Background: In diverse organisms, adaptation to low oxygen (hypoxia) is mediated through complex gene expression changes that can, in part, be mimicked by exposure to metals such as cobalt. Although much is known about the transcriptionalresponsetohypoxiaandcobalt,littleisknownabouttheall-importantcellmetabolismeffectsthattrigger theseresponses. Methods and Findings: Herein we use a low molecular weight metabolome profiling approach to identify classes of metabolitesinyeastcellsthatarealteredasaconsequenceofhypoxiaorcobaltexposures.Keyfindingsonmetabolites werefollowed-upbymeasuringexpressionofrelevantproteinsandenzymeactivities.Wefindthatbothhypoxiaandcobalt resultinalossofessentialsterolsandunsaturatedfattyacids,butthebasisforthesechangesaredisparate.Whilehypoxia canaffectavarietyofenzymaticstepsrequiringoxygenandheme,cobaltspecificallyinterfereswithdiiron-oxoenzymatic stepsforsterolsynthesisandfattyaciddesaturation.Inadditiontodiiron-oxoenzymes,cobaltbutnothypoxiaresultsin lossoflabile4Fe-4Sdehydratasesinthemitochondria,buthasnoeffectonhomologous4Fe-4Sdehydratasesinthecytosol. Moststriking,hypoxiabutnotcobaltaffectedcellularpoolsofaminoacids.Aminoacidssuchasaromaticswereelevated whereasleucineandmethionine,essentialtothestrainusedhere,dramaticallydecreasedduetohypoxiainduceddown- regulationofaminoacidpermeases. Conclusions:Thesestudiesunderscorethenotionthatcobalttargetsaspecificclassofironproteinsandprovidethefirst evidence for hypoxia effects on amino acid regulation. This research illustrates the power of metabolite profiling fo