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De novo synthesis of pyrimidine nucleotides

  
  2025-06-14
  

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Thepyrimidineribonucleotides,thosefoundinRNA,areuracilandcytosine,eachcontainingthesugarriboseandanitrogenousbase.Pyrimidinenucleotidescontainasingleringinthenitrogenousbase.Incontrasttothesynthesisofpurines,thepyrimidineringissynthesizedfirstandthenjoinedtoribose.Thispathwayisconservedfrombacteriatoman,occurringinessentiallythesamemannerforallspecies.Thepathwaybeginswithaspartateandcarbamoylphosphateasthefirstcomponentstobuildthepyrimidinebase.Carbamoylphosphateissynthesizedfrombicarbonateionsandanitrogenfromglutamine.Thecondensationofaspartateandcarbamoylphosphatecreatescarbamoylaspartate,whichgoesthroughringclosureandoxidationtocreatetheprecursorpyrimidineorotate.OrotateisjoinedtoribosephosphateandUMPisfinallyformedthroughdecarboxylation.CTPissynthesizedfromUTPthroughaminationusingglutamineasthedonorinmammalsandammoniainE.coli.Thispathwayiscloselyregulatedtoprovidepyrimidinesonlywhentheyareneeded.ThepathwayisactivatedbyATPandinhibitedbytheendproduct,pyrimidines,providinganexampleoffeedbackinhibition.ThedeoxyribonucleotidesfoundinDNAaresynthesizedthroughreductionoftheriboseringinribonucleotides.Althoughthebacterialandhumanpathwaysaresimilar,theenzymesthatcatalyzethepathwayreactionsarequitedistinct.Inbacteria,thefirstthreestepsinthepathwayarecatalyzedbythreeseparatepolypeptides,butinhumansasinglepolypeptidehasallthreeenzymaticactivities.Multifunctionalenzymecomplexesofthisnatureoccurinotherpathwaysaswell,andincreasetheoverallefficiencyofapathwaybydirectingpathwayintermediatesdirectlyfromonesteptothenextratherthanrelyingondiffusionbetweenenzymesinthepathway.

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