Metabolism of hemeAlice Skoumalov

Heme structure: a porphyrin ring coordinated with an atom of iron side chains: methyl, vinyl, propionyl

Heme is complexed with proteins to form:Hemoglobin, myoglobin and cytochromes

MitochondriaMitochondriaCytosol

Derangements in porphyrin metabolism:

Disease stateGeneticsTissueOrgan pathologyAcute intermittent porphyriadominantLiverNervous systemHereditary coproporphyriadominantLiverNervous system, skinVariegate porphyriadominantLiverNervous system, skinPorphyria cutanea tardadominantLiverSkin, induced by liver dis.Erythropoietic protoporphyriadominantMarrowGall stones, liver dis., skinCongenital erythropoietic porphyriarecessiveMarrowSkin, RESLead poisoningAll tissuesNervous system, blood, others

Synthesis of -aminolevulinic acid:induced by: drugs (barbiturates), oral contraceptive pillsPyridoxal phosphate (vit. B6)

inhibited by leadFormation of porphobilinogen:

Degradation of heme:

Conversion of heme to bilirubin:ER enzyme systemthe major source is HgCytoprotective role: CO biliverdin

Formation of bilirubin diglucuronide:increase the water solubility of bilirubin

HyperbilirubinemiaElevated bilirubin levels in the blood (>10 mg/l); bilirubin may diffuse into peripheral tissues, giving them a yellow color (jaundice)Cause:1. Pre-hepatic: excessive formation of bilirubin by increased degradation of erythrocytes (icterus neonatus, hemolytic anemia)2. Hepatic: insufficient processing of bilirubin as a result of liver defects (hepatitis, liver toxic damage, cirrhosis, hepatic failure)3. Post-hepatic: by impaired excretion of gall (obstructive jaundice due to gallstones, inflammation of biliary tract)

Unconjugated bilirubin can cross the blood-brain barrier, leading to brain damageJaundice in neonates (increased bilirubin degradation+immaturity of the conjugation enzymes): phototerapy isomerization of bilirubin to more soluble pigments

TypeCauseExampleFrequencePrehepaticHemolysisAutoimmune HaemoglobinopathyRareAccording to the regionHepaticInfectionDamageGenetics

AutoimmuneNewbornHepatitis A,B,CAlcohol, drugsGilberts syndromeWilsons disease1-Antitrypsin deficiencyChronic hepatitisPhysiologicVery commonCommon1 in 201 in 200 0001 in 1000RareVery commonPosthepaticIntrahepaticbile ducts

Extrahepaticbile ductsDrugsPrimary biliary cirrhosisCholangitisGallstonesPancreatic cancerCommonRareCommonVery commonRare

Summary:Synthesis of heme: from glycine and succinate induction by drugs and glucose; inhibition by lead intermediates porphyrinogens (porphyrins) porphyriasDegradation of heme to bilirubin (hydrophobic) conjugation in liver conversion to urobilinogen in intestine hyperbilirubinemia (differential diagnosis)

Pictures used in the presentation:Marks Basic Medical Biochemistry, A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks)Principles of Biochemistry, 2008, (Voet D, Voet J.G., and Pratt C.W)

vechny tkn, hlavn jtra a kostn de8 molekul glycinu a succinyl-CoAPorfyriny - bezbarv - nestabiln, snadno oxidovny (svtlem) na porfynyFettochelatza - inhibice olovemPorfyria cutanea tarda - nejastj, indukovan poitm lk i alkoholu, fotosensibilitaKernicterus