DisordersDisorders ooff metabolism metabolism of ... · DisordersDisorders of metabolism metabolism ooff purinespurines aanndd pyrimidines pyrimidines InbornInborn / since since earlyearly

DisordersDisorders ofof metabolismmetabolism ofof purinespurines

andand pyrimidinespyrimidines

Martin VejražkaMartin Vejražka

DisordersDisorders ofof metabolismmetabolism ofof

purinespurines andand pyrimidinespyrimidines

�� InbornInborn / / sincesince earlyearly childhoodchildhood

–– SimpleSimple heredibilityheredibility

�� AcquiredAcquired

–– UsuallyUsually complicatedcomplicated heredibilityheredibility

–– InfluencesInfluences ofof environmentenvironment

PURINESPURINES

DisordersDisorders ofof metabolismmetabolism ofof purinespurines andand pyrimidinespyrimidines

LeschLesch--NyhanNyhan syndromesyndrome

�� HyperuricemiaHyperuricemia fromfrom overproductionoverproduction

�� UrateUrate concrementsconcrements

�� AutomutilationAutomutilation�� AutomutilationAutomutilation

�� DefectiveDefective hypoxanthinhypoxanthin--guanin guanin phosphoribosylphosphoribosyl transferasetransferase–– LeadsLeads to to increasedincreased PRPP PRPP andand

overproductionoverproduction ofof purinespurines

Von Von GierkeGierke diseasedisease

�� HyperuricemiaHyperuricemia fromfrom overproductionoverproduction

�� DefectiveG6PDHDefectiveG6PDH�� DefectiveG6PDHDefectiveG6PDH

�� ExcessExcess ofof G6P G6P stimulatesstimulates productionproductionofof PRPPPRPP

�� LacticLactic acidosisacidosis decreasesdecreaseseliminationelimination ofof uratesurates

DefectDefect ofof adenosine adenosine deaminasedeaminase

�� PoorPoor conversionconversion od A to Iod A to I

�� AccumulationAccumulation ofof dATPdATP & & dGTPdGTP inhibitsinhibitsribonucleotideribonucleotide reductasereductaseribonucleotideribonucleotide reductasereductase

–– LackLack ofof DNA DNA precursorsprecursors

�� ImmunoImmuno--deficiencydeficiency (SCID = severe (SCID = severe combinedcombined immunodeficiencyimmunodeficiency diseasedisease))

PodagraPodagra

�� WhyWhy isis uricuric acidacid anan acidacid??

�� UnderUnder whichwhich conditionsconditions isis uricuric acidacid�� UnderUnder whichwhich conditionsconditions isis uricuric acidacidsolublesoluble??

�� HowHow isis itit eliminatedeliminated by by kidneyskidneys??

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�� OverproductionOverproduction ofof purine purine basesbases

–– IncreasedIncreased productionproduction ofof PRPPPRPP

–– DecreasedDecreased activityactivity ofof HGPRTHGPRT–– DecreasedDecreased activityactivity ofof HGPRTHGPRT

•• PRPP not PRPP not spentspent

•• LessLess IMP & GMP → IMP & GMP → increasedincreased productionproduction ofofPRPPPRPP

�� Cell Cell lysislysis

�� DisordersDisorders ofof eliminationelimination ofof urateurate

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NN

N HN

NN

N HN

OH

HO

XanthinXanthin oxidaseoxidase

OH

N

N HN

N

OH OH

hypoxanthinhypoxanthin UricUric acidacid

allopurinolallopurinol

alloxanthinalloxanthin

RemainsRemains covalentlycovalently

boundbound to to

xanthinxanthin oxidaseoxidase

PurinesPurines

O

N

NN

N

O

O

Caffein

PYRIMIDINESPYRIMIDINES

DisordersDisorders ofof metabolismmetabolism ofof purinespurines andand pyrimidinespyrimidines

DisordersDisorders ofof metabolismmetabolism ofof

pyrimidinespyrimidines

�� DerivativesDerivatives ofof pyrimidinespyrimidines are are wellwellsolublesoluble

�� UsuallyUsually not not clinicallyclinically significantsignificant�� UsuallyUsually not not clinicallyclinically significantsignificant

OroticOrotic aciduriaaciduria

�� ReyRey‘s syndrome‘s syndrome–– DamageDamage to to mitochondriamitochondria, , disabilitydisability do do

metabolisemetabolise carbamoylphosphatecarbamoylphosphate

–– ExcessExcess ofof carbamoylphosphatecarbamoylphosphate stimulatesstimulates–– ExcessExcess ofof carbamoylphosphatecarbamoylphosphate stimulatesstimulatesproductionproduction ofof orotateorotate

�� Type Type I I andand Type Type IIII–– DisordersDisorders ofof conversionconversion ofof OMP to OMP to UMPUMP

–– I: I: bothboth orotateorotate phosphoribosylphosphoribosyl transferasetransferase andandorotidylateorotidylate decarboxylasedecarboxylase

–– II: II: orotidylateorotidylate decarboxylasedecarboxylase onlyonly

DefectsDefects ofof ureasynthesisureasynthesis

�� DefectDefect ofof mitochondrialmitochondrial ornithinornithintranscarbamoyltransferasetranscarbamoyltransferase

�� ExcessExcess ofof carbamophosphatecarbamophosphate�� ExcessExcess ofof carbamophosphatecarbamophosphatestimulatesstimulates productionproduction ofofpyrimidinesMildpyrimidinesMild oroticorotic aciduriaaciduria

MethotrexatMethotrexat

�� InhibitsInhibits dihydrofolatedihydrofolate reductasereductase

–– BlocksBlocks reductionreduction ofof dihydrofolatedihydrofolate to to tetrahydrofolatetetrahydrofolatetetrahydrofolatetetrahydrofolate

–– TetrahydrofolateTetrahydrofolate isis essentialessential forforsynthesissynthesis ofof TMPTMP

MethotrexateMethotrexateHN

N

O

O

dRib-5-P

HN

N

O

O

dRib-5-P

CH3

dUMP dUTP

Metylen-H4-folát H2-folát

OH

O

OH

Methylen-H4-folate H2-folate

OH

N

N

N

N

NH2

HN

HN O

O

NN

N

N

NH2

NH2

N

HN O

HO

O

HO

O

metotrexátmethotrexate

OtherOther chemotherapeuticschemotherapeutics

�� Purine Purine analogsanalogs

–– MercaptopurineMercaptopurine

�� PyrimidinePyrimidine analogsanalogs

–– FluorouracilFluorouracil

–– CytosinarabinosideCytosinarabinoside