Disorders Disorders of of metabolism metabolism of of purines purines and and pyrimidines pyrimidines Martin Vejražka Martin Vejražka
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??
PodagraPodagra
�� 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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PodagraPodagra
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