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Lecture

HEME-METABOLISM

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Department
Chemistry
Course Code
CHEM 4465
Professor
All

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HEME METABOLISM (DR. OFFNER) I. HEME BIOSYNTHESIS A. Definitions i. Pyrrole ii. Tetrapyrrole: cyclical (heme); linear (bilirubin) iii. Porphyrinogen = reduced form of tetrapyrrole (colorless) – abbreviated “o’gen” iv. Porphyrin = oxidized form (color) B. Outline of pathway i. Process by which glycine  heme = 8 steps: *Uro’gen’s 4 isomers: 1) AP AP AP AP 2) AP PA AP PA 3) AP AP AP PA 4) AP AP PA PA Only uro’gen III is biologically active. C. Location i. Heme is synthesized in the bone marrow for immature red blood cells, and in the liver for cytochrome and other proteins ii. Location within cell: 1. Steps 1, 6, 7, 8 occur in mitochondria 2. Steps 2, 3, 4, 5 occur in cytoplasm D. Regulation i. 4 separate checks and balances to ensure that no excess heme is being produced: 1. Heme is a direct inhibitor of ALA synthase – no protein being made in cytoplasm  heme stays in mitochondrion and inhibits ALA synthase 2. Heme can enter nucleus, bind to repressor protein, and stop transcription of ALA synthase 3. Heme can prevent translation of ALA synthase in RNA 4. Heme can prevent entry of ALA synthase into mitochondria II. HEME CATABOLISM Charles Gray – 1947 – discovered that pigments in blood are converted to bile pigment and excreted in stools. Actual mechanism not discovered until 30 years later. A. Heme  bilirubin i. Heme degradation (in mononuclear phagocytic system – spleen/ Kupffer cells): 1. Heme oxygenase - cleaves alpha bridge, releases carbon – requires NADPH, O2 HEME METABOLISM (DR. OFFNER) 2. Molecule becomes linear  biliverdin IX alpha (green-blue) 3. Bilirubin reductase – reduces biliverdin IX alphabilirubin IX alpha (yel-orange) ii. Bile pigment transport (through plasma) 1. Bilirubin is completely insoluble – can’t be directly put into bile 2. BR complexed with carrier albumin – carries BR in blood to a hepatocyte 3. Albumin is then recycled – can go pick up more bilirubin B. Conjugation (in hepatocyte): 1. BR + 2 glucoronic acid (UDP)  bilirubin digluceronide (BRDG) 2. Enzyme = bilirubin glucoronyl transferase (BRGT) 3. BRDG is now soluble  secreted into bile (via canaliculus) C. Excretion: i. Bile enters small intestine, then large intestine: 1. Baceterial enzyme -glucoronidase  BRDG becomes bilirubin again 2. Other enzymes: Bilirubin  urobilinogen  sercobilin ii. Sercobilin excreted in feces iii. Some urobilinogen reabsorbed  transported to kidney  urobilin – excreted in urine D. Some conjugated and some unconjugated BR leaks back into blood (trace amounts) III. ABNORMALITIES IN HEME METABOLISM A. Hyperbilirubinemias i. Increased bilirubin production 1. Hemolysis caused by malaria, wrong blood transfusion  massive lysis of RBC’s greater amount of unconjugated bilirubin hepatocyte unable to absorb and conjugate all of it 2. Results in higher levels of both unconjugated and conjugated BR in blood (also more urobilinogen in urine) ii. Decreased bilirubin uptake 1. Impairment of uncon
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