Metabolism of porphyrins and bile pigments Flashcards
Porphyrins
cyclic compound that bind metal ions
Heme as prothetic group
Protoporhyrin 9 + Fe2+ -> heme
- hemoglobin, myoglobin
- cytochromes
- catalase, peroxidase
- nitric oxide synthase
Myoglobin
monomer
proximal + distal His
globin: 8 alpha-helical domains and linker sequence
Hemoglobin
tetramer alpha2beta2, 4O2 2,3 BPG positive cooperativity sigmoidal saturation curve
1.Succinyl CoA + Glycine -> ALA
-CoASH
-CO2
enzyme: ALA SYNTHASE
Rate limiting
requires PLP
- 2ALA -> Porphobilinogen
-2 H20
enzyme: ALA DEHYDRATASE
contains Zn2+
inhibited by lead
- 4 Porphobilinogen -> Hydroxymethylbilane
- 4 NH3
enzyme: PORPHOBILIOGEN DEAMINASE
- Hydroxymethylbilane -> Uroporphyrinogen 3
enzyme: UROPORPHYRINOGEN 3 SYNTHASE
- Uroporphyrinogen 3 -> Coproporphyrinogen 3
- 4 CO2
enzyme: UROPORPHYRINOGEN DECARBOXYLASE
- Coproporphyrinogen 3 -> Protoporphyrinogen 9
- 2 CO2
- 4 H
enzyme: COPROPORPHYRINOGEN 3 OXIDASE
- Protoporphyrinogen 9 -> Protoporphyrin 9
- 6H
enzyme: PROTOPORPHYRINOGEN OXIDASE
- Protoporphyrin 9 -> heme
+Fe2+
enzyme: FERROCHELATASE
inhibited by lead
ALAS-L
Ala synthase
liver specific
heme inhibits transcription, mRNA export, mitochondrial uptake, enzymatic activity
ALAS -E
Ala synthase erythroid specific deficiency: sideroblastic anemia heme inhibits iron release from ferritin, stimulates global production epo stimulates transcription
Porphyria
symptoms: photosensivity, neuropsychiatric symptoms, fluorescent teeth, red urine
diagnosis: assay of enzymatic activities in RBC, analysis of urine
treatment: administration of hemin, sunscreen, carotenoids, no drugs or alcohol
Breakdown of heme
Heme - HEME OXYGENASE - biliberdin - BILIVERDIN REDUCTASE - bilirubin
Bilirubin excretion
formation in monocyte system - bound to albumin in blood - hepatocyte uptake - conjugated with glucuronic acid - excretion to bile canaliculi - bacterial beconjugation in colon - 10% reabsorbed and excreted in urine - 90% as faces
Hyperbilirubinemia
- indirect:
- indirect-reaction bilirubin: methanol soluble
- prehepatic, hepatic jaundice - direct
- direct-reacting bilirubin: water soluble
- posthepatic jaundice
Prehepatic jaundice
- Homolytic anemias
- Neonatal jaundice
- Hyperbilirubinemic toxic encephalopathy
Hepatic jaundice
- Crigler-Najjar syndrome 1
- UDP-glucuronosyl transferase deficiency, fatal, phototherapy - Crigler-Najjar syndrom 2
- partial enzyme defect, phenobarbital - Gilberts disease
- Toxic hyperbilirubinemia
Posthepatic jaundice
- Obstruction of biliary tree
2. Dubin-Johnson and Rotor syndrome
