Heme Metabolism•Heme biosynthesis and Porphyrias•Heme degradation: Jaundice
Heme Biosynthesis: Porphyrias• Cruelly referred to as a Vampire’s disease. Thought to be a cause of the madness of King George III.• Can be caused by lead poisoning: The fall of the Roman Empire!
Not a ‘vampire’s’ disease Some symptoms of porphyrias have lead people to believe that these diseases provide some basis for vampire legends: Extreme sensitivity to sunlight Anemia This idea has been discarded both for scientific reasons: Porphyrias do not cause a craving for blood. Drinking blood would not help a victim of porphyria.And for compasionate reasons:Porphyria is a rare, butfrightening condition: hard to diagnose and there is no cure.
The Madness of InbreedingGeorge III : Severe abdominal pain, mental confusion, dark urine.
Mitochondria PORPHYRIAS GLYCINE + SuccinylCoA Agent Orange ALA synthase 3p21/Xp11.21 d-aminolevulinic acid(ALA) ALA-dehydratase ALA dehydratase 9q34 Deficiency porphyria Porphobilinogen(PBG) Acute intermittent PBG deaminase porphyria 11q23 hydroxymethylbilane Uroporphyrinogen III Congenital erythropoietic cosynthase 10q26 porphyria uroporphyrinogen III Uroporphyrinogen Prophyria decarboxylase cutanea tarda 1q34 coprophyrinogene III Coproporphyrinogen Herediatary oxidase 9 coproporphyria Protoporphyrinogene IX Protoporphyrinogen Variegate protoporphyrin IX oxidase 1q14 porphyria Ferrochelatase Erythropoietic Heme 18q21.3 protoporphyria
COORDINATED REGULATION OF HEME AND GLOBIN SYNTHESIS: Heme: inhibits activity of pre-existing d-ALA synthase diminishes the transport of d-ALA synthase from cytoplasm to mitochondria after synthesis of the enzyme. represses the production of d-ALA synthase by regulating gene transcription. stimulates globin synthesis to ensure that levels of free heme remain low in concentration.Inhibition of the synthase and stimulation of globin synthesis arethe most important aspects in balancing hemoglobin production.
Heme Degradation Heme Catabolism HEMENADPH O2 (opens the porphyrin ring) Fe+3 NADP+ BILIVERDIN NADPH NADP+ BILIRUBIN BILIRUBIN diglucuronide BILE
What’s the cause of jaundice?1- Increased production of bilirubin by hemolysis or blood disease: •Increase in blood indirect bilirubin •Called pre-hepatic jaundice •Stool color remains normal.2- Abnormal uptake or conjugation of bilirubin: •Leads to non-hemolytic unconjugated hyperbilirubinemia •Increased indirect bilirubin. •Stool color turns gray. •Caused by liver damage or disease.
What’s the cause of jaundice?3- Cholestasis = Problems with bile flow. a: Intrahepatic cholestasis: hyper conjugated bilirubinemia •Increase in blood indirect and direct bilirubin •Caused by liver damage or disease: eg cirrhosis, hepatitis •Can also occur in pregnancy: b:Extrahepatic cholestasis: •Blockage of bilirubin transport in the bilary tract. •Increased direct bilirubin. •Stool color turns gray. •Caused by: Tumors or gall stones.
CLINICAL PREMISENewborns often have a yellowish tint to their skin. This condition isknown as jaundice and results from the infant ridding itself of "fetal"hemoglobin which will be replaced by "adult" hemoglobin. As you willlearn in this lecture, catabolic products from hemoglobin are removed bythe liver. However, the infants liver is often too immature to handle theexcessive breakdown products. Instead they accumulate giving theyellowish tint. Exposure to mild UV light from the sun is usuallysufficient to destroy these compounds, although in very severe casesblood dialysis may become necessary as these byproducts can be toxic.
Table 1- The porphyrias. You are responsible for the enzyme defects in red Type Enzyme Major Symptoms Laboratory tests InvolvedAcute intermittent Uroporphyrinogen Abdominal pain urinary porphobilinogen porphyria synthase Neuropsychiatric Congenital Uroporphyrinogen Photosensitivity urinary uroporphyrin erythropoietic cosynthase porphobilinogen porphyriaPorphyria cutanea Decarboxylase Photosensitivity urinary uroporphyrin tarda porphobilinogen Variegate porphyria Oxidase Photosensitivity urinary uroporphyrin Abdominal pain fecal coproporphyrin Neuropsychiatric fecal protoporphyrin Erythropoietic Ferrochelatase Photosensitivity fecal protoporphyrin protoporphyria red cell protoporphyrin
BLOOD StercobilinCELLS Urobilin excreted in feces Hemoglobin excreted in urine Globin Urobilinogen Heme O2 formed by bacteria KIDNEY reabsorbed Heme oxygenase INTESTINE into blood CO Biliverdin IX via bile duct to intestines NADPH Biliverdin Bilirubin diglucuronide reductase (water-soluble) NADP+ 2 UDP-glucuronic acid Bilirubin Bilirubin (water-insoluble) LIVER (water-insoluble) via blood to the liver Figure 2. Catabolism of hemoglobin
Figure 3. Examples of hyperbilirubinemia A. Hemolytic anemia B. Hepatitis C. Biliary duct stone excess hemolysis unconjugated bilirubin unconjugated bilirubin unconjugated bilirubin (in blood) (in blood) conjugated bilirubin (in blood) conjugated bilirubin conjugated bilirubin (released to bile duct) (in blood) (in blood)
Table 2- Genetic Disorders of Bilirubin MetabolismCondition Defect Bilirubin Clinical FindingsCrigler-Najjar severely defective Unconjugated Profound jaundicesyndrome UDP-glucuronyltransferase bilirubin Gilberts reduced activity of Unconjugated Very mild jaundicesyndrome UDP-glucuronyltransferase bilirubin during illnessesDubin- abnormal transport of Conjugated Moderate jaundiceJohnson conjugated bilirubin into bilirubin syndrome the biliary system