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Metabolism of Porphyrins and Bile Pigments

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Metabolism of Porphyrins and Bile Pigments Metabolism of porphyrins and bile pigments Mária Sasvári 2017 1 The biological role of porphyrins Protoporphyrin IX + Fe2+ → heme → the prosthetic group of several proteins, such as: • hemoglobin, myoglobin • cytochromes (a, b, c, P450) • catalase, peroxidase • nitric oxide synthase 2 Structure of heme B (cytochrome b, Hb, Mb) vinyl methyl Order of substituents: MVMVMPPM methinyl bridge pyrrol ring propionate (not propionyl!) protoporphyrin IX – Fe2+ chelate complex 3 Myoglobin: monomer proximal His distal His globin: 8 α-helical domains and linker sequences 4 Hemoglobin: tetramer α2β2, 4 O2 2,3-BPG positive cooperativity sigmoidal saturation curve 5 δ-amino-levulinate (ALA) succinyl-CoA porphobilinogen glycine heme B hydroxymethylbilane Overview of heme biosynthesis proto- mito- cytoplasm uroporphyrinogen III porphyrin IX chondrium proto- copro- porphyrinogen IX porphyrinogen III 6 The ALA synthase reaction COO - CH2 CH Succinyl-CoA 2 COO - COO - (4 C) C O CH2 CH CoA-SH CO2 2 S ~ CoA CH2 CH2 C O C O H PLP Glycine + + + H C NH3 H C NH3 H C NH3 (2C + N) - COO - COO H a-amino-b-keto-adipate d-aminolevulinate (ALA) (6C + N) (5C + N) ALA synthase: irreversible, rate-limiting step (mitochondrial) Regulation of ALA synthase: repression of transcription by heme (heme is also an allosteric inhibitor7 ) induction by certain drugs 2 ALA molecules yield porphobilinogen acetate propionate - (A) (P) COO COO - CH 2 CH2 2 H2O A P CH 2 CH2 C C C O C O C C N H C H H C H ALA dehydratase CH2 (porphobilinogen H + + + NH NH NH3 3 3 synthase) ALA ALA porphobilinogen ALA dehydratase: contains Zn2+ inhibition by Pb2+ (lead poisoning) → EDTA!!! 8 Lead poisoning microcytic anemia 9 Formation of linear terapyrrole A P CH2 N + H NH3 4 porphobilinogen porphobilinogen deaminase (hydroxymethylbilane synthase) 4 NH3 A P A P A P A P HO CH2 N CH2 N CH2 N CH2 N H H H H unstable intermediate (hydroxymethylbilane) 10 Spontaneous or enzyme-catalysed ring closure uroporphyrinogen III spontaneous synthase A P A P I. I. P A A A IV. II. IV. II. A P P P III. inversion III. P A of ligands P A uroporphyrinogen I urophorphyrinogen III slow synthesis, false endproduct, rapid synthesis excreted in urine 11 Modification of substituents begins with decarboxylation… A P 4 CO2 M P I. I. A A M M IV. II. IV. II. P P uroporphyrinogen P P III. III. decarboxylase P A P M uroporphyrinogen III coproporphyrinogen III Acetate group: - CH2 - COOH Methyl group: - CH3 12 … and gets completed by an oxidase 2 CO2 M P 4 H M V I. M M I. IV. II. M M P P IV. II. P V III. coproporphyrinogen III oxidase (O ) III. P M 2 P M coproporphyrinogen III protoporphyrinogen IX propionate group: - CH2 - CH2 -COOH ethyl group: - CH2 - CH3 vinyl group: - CH - CH2 13 The ring system is completed M V M V 6H CH2 CH2 CH CH M N M N H M M H N H N N H N H H P N V P N V CH2 CH2 protoporphyrinogen CH CH oxidase P M P M protoporphyrinogen IX protoporphyrin IX colourless conjugated double bond system, coloured 14 Formation of the iron (II) chelate complex Fe2+ Protoporphyrin IX heme ferrochelatase (inhibited by lead) 15 Iron metabolism in man Fe3+ 16 Iron uptake and storage 2+ Fe 3+ ferritin ferritin reductase ferritin Fe 17 The iron-ferritin complex 18 Regulation of ALA synthase isoenzymes Liver-specific isoform: ALAS-L (ALAS-1) heme inhibits the transcription, mRNA export, mitochondrial uptake and enzymatic activity of this isoenzyme Erythroid (bone marrow) isoform: ALAS-E (ALAS-2) - deficiency: sideroblastic anemia (hypochromic) - not inhibited by heme - heme inhibits iron release from ferritin and stimulates globin production - transcription is stimulated by erythropoetin 19 Mutations in heme biosynthesizing enzymes result in porphyria most frequent types: porphobilinogen acute intermittent porphyria hydroxymethylbilane congenital erythropoetic porphyria uroporphyrinogen III porphyria cutanea tarda coproporphyrinogen III 20 Major symptoms photosensitivity neuropsychiatric symptoms fluorescent teeth red urine Diagnosis: assay of enzyme activities in RBC analysis of urine Erythropoietic porphyrias: bone marrow (hemoglobin) Hepatic porphyrias: liver (cytochrome P450) Treatment: administration of hemin (represses ALAS) sunscreens, carotinoids no drugs and alcohol! 21 Vampires and werevolves– victims of porphyria? pale skin (anemia) blood-thirst (anemia) psychiatric disorders (neurotoxicity) night activity (photosensitivity) fluorescent teeth (porphyrins) fear of garlic (no CYP450 in liver) 22 Enzymatic breakdown of heme Heme oxygenase: linearizes the ring system by elimination of one of the methinyl bridges M V M V I. I. OH M M M M IV. Fe2+ II. IV. Fe2+ II. P V P V III. III. P M P M 3 NADPH 3 NADP+ +H+ + H O 2 +O2 O2 biliverdin Fe2+ CO heme: red; biliverdin: green; bilirubin: yellow (the colour of hematomas changes) 23 Reduction of biliverdin yields bilirubin M V M P P M M V I IV III II CH CH CH O O N N N N H H H biliverdin important NADPH + H+ 2 H O 2 endogenous biliverdin reductase + NADP H2O2 antioxidant M V M P P M M V I IV III II CH CH2 CH O O N N N N H H H H bilirubin 24 Bilirubin contains polar groups, but due to its special conformation - cis double bonds ( ) and intramolecular hydrogen bonds (――) - its outer surface is rather apolar. Therefore, it is carried in blood plasma by albumin 25 Mechanism of bilirubin excretion from the body blood: bound to albumin formation of bilirubin uptake in hepatocytes (ligandin) in the monocyte-macrophage system liver: conjugation with glucuronic acid in ER bilirubin diglucuronide excretion into bile canaliculi (MRP2 efflux pump) colon: bacterial deconjugation and reduction to urobilinogen (Ubg) 10 % 90 % reabsorption excreted in urine faeces: urobilin and stercobilin (brown pigment) diarrhea: fast passage, no time to yield stercobilin: yellow feces 26 Conjugation of bilirubin in the ER of hepatocytes 1. UDP-glucuronic acid formation from UDP-glucose CH2OH COO - UDP-glucose dehydrogenase O-UDP O-UDP UDP-glucose UDP-glucoronic acid + + H2O + 2 NAD 2NADH + 2H 2. UDP-glucuronidation of bilirubin UDP-glucuronosyl transferase Bilirubin bilirubin monoglucuronide bilirubin diglucuronide UDP-glucuronate UDP UDP-glucuronate UDP 27 Bilirubin diglucuronide (conjugated bilirubin) COO - COO - O O O C O C CH 2 CH2 CH M V M 2 CH2 M M V I IV III II CH CH2 CH O O N N N N H H H H 28 Conformation of conjugated bilirubin polar, water-soluble molecule 29 Hyperbilirubinemia leads to jaundice I. indirect hyperbilirubinemia “indirect-reacting” bilirubin: methanol soluble (NOT conjugated) prehepatic or hepatic jaundice (e.g. hemolysis, hepatitis) retention of water-insoluble bilirubin II. direct hyperbilirubinemia “direct-reacting” bilirubin: water soluble (conjugated) posthepatic jaundice: reflux of conjugated bilirubin into the blood appearance in the urine 30 Prehepatic jaundice: elevated levels of indirect bilirubin in plasma Hemolytic anemias: the liver has a large capacity, so unconjugated bilirubin will elevate only if other defects exist too Neonatal jaundice: accelerated hemolysis, immature hepatic system low activity of UDP-glucuronyl transferase low rate of UDP-glucuronic acid production unconjugated bilirubin can pass the blood-brain barrier hyperbilirubinemic toxic encephalopathy (kernicterus) (mental retardation) Treatment: phenobarbital administration: induction of the conjugating system phototherapy: photoisomerization of bilirubin → water-soluble products → excretion via kidneys 31 Photoisomerisation of bilirubin blue light 32 33 Hepatic jaundice: elevated levels of indirect bilirubin in plasma Crigler-Najjar syndrome, type I full deficiency of bilirubin UDP-glucuronosyl transferase fatal within the first 15 month of life phenobarbital treatment does not help → phototherapy Crigler-Najjar syndrome, type II partial enzyme defect, milder symptoms patient might respond to phenobarbital Gilbert’s Disease – 5% of mankind affected unconjugated bilirubinemia, promoter mutations slightly reduced UDP-glucuronosyl transferase activity Toxic hyperbilirubinemia Toxin-induced liver dysfunction (e.g. hepatitis, liver chirrhosis, mushroom poisoning) 34 Posthepatic jaundice: direct hyperbilirubinemia Obstruction of the biliary tree Blockade of the bile duct Bilirubin conjugates cannot be excreted Regurgitates into hepatic veins and lymphatics Conjugated bilirubin appears in the serum and in the urine Dubin-Johnson and Rotor-syndromes Defect in the hepatic secretion of conjugated bilirubin due to congenital MRP2 transporter mutations 35 Microscopic pigmentation of the liver in Dubin-Johnson syndrome 36 Urinanalysis helps discriminate between pre- and posthepatic forms of jaundice Posthepatic jaundice no urobilinogen in urine (as it is produced in the intestine) high conjugated bilirubin levels in the blood and urine dark urine, „pale” feces Hemolytic (posthepatic) jaundice: increased production of bilirubin and urobilinogen large amounts of urobilinogen in the urine 37.
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