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DisordersDisorders ooff metabolism metabolism of ... · DisordersDisorders of metabolism metabolism...
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Disorders Disorders of of metabolism metabolism of of purines purines and and pyrimidines pyrimidines Martin Vejražka Martin Vejražka
Transcript of DisordersDisorders ooff metabolism metabolism of ... · DisordersDisorders of metabolism metabolism...
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
PodagraPodagra
http://www.zdravcentra.cz/img/informacni_systemy/41da64aea6ef1_small.jpg http://www.zdravcentra.cz/img/informacni_systemy/41da64aea6ef1_small.jpg
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
