Porphyrin metabolism Flashcards
Describe structure of porphyrin
- 4 pyrrole rings with methenyl bridges
- conjugated double bonds throughout
- each ring has two side chains
- the 8 side chains are asymmetrical under normal phys. conditions
porphyrin central pocket occupied by?
- Iron - makes heme
- Cobalt - makes cobalamine (vitamin B12)
- Magnesium - makes chlorophyll in plants
4 physiological roles of heme proteins
1) Mitochondrial cytochromes - make H+ gradient for ATP synth in ETC
2) Hemoglobin and myoglobin - O2 transport in blood and muscle
3) Cytochrome P450 enzymes - metab of fat sol compounds, formation of cholesterol, steroids, arachidonic acid, important for drug interactions
4) Catalase - antioxidant enzyme hyrdrolyzes H2O2
Heme biosynth reaction 1
- ALA sythase
- condensation of glycine and succinyl CoA to form delta-aminolevulinic acid (ALA)
- 1st of two rate limiting steps
- irreversible
transcription of ALA synthase is inhibited by?
- hemin (oxidized form of heme)
- glucose
Heme biosynth reaction 2
- ALA dehydrase
- 2 molecules of ALA form the pyrrole compound porphobilinogen (PBG)
Heme biosynth reaction 3
- Hydroxymethylbilane synthase
- 4 PBG form hydroxymethylbilane
- 2nd of 2 rate limiting steps
Heme biosynth reaction 4
- uroporphyrinogen synthase
- ring closure of hydroymethylbilane to form uroporphyrinogen I
Heme biosynth reaction 5
- uroporphyrinogen III cosynthase
- isomerizes D ring side chains of uroporphyrinogen I to form the III version
Uroporphyrinogen III is precursor to?
- chlorophyll
- cobalamine
- heme
Heme biosynth reaction to create protoporphyrin IX
- series of oxidation and decarboxylation reactions
Visible difference between porphyrins vs PBG and porphyrinogens?
- porphyrins are purple and fluorescent whereas the others are colorless
Final heme biosynth reaction
- ferrochelatase
- introduction of iron (Fe2+) into protoporphyrin IX to form heme
4 major disease states caused by abnormal heme sythesis
- acute porphyrias
- non-acute porphyrias
- lead poisoning
- iron-deficiency anemia
mechanism of acute porphyria?
- autosomal dominant
- blockade of early rate limiting steps of heme biosynth pathway
- decreased production of heme
example of acute porphyria?
- AIP - acute intermittent porphyria
- intermittent attacks of abdominal pain, often following ingestion of drugs or chemicals
- induced production of CYP enzymes which consume heme
- triggers increase in ALA synthase levels and accumulation of ALA and PBG
- pain caused by ALA accumulation in liver
- ALA antagonizes GABA receptors causing neuropsychiatric symptoms
acute intermittent porphyria diagnosis and treatment
- AIP urine turns purple when left to sit (presence of PBG)
- treat with intravenous hemin and glucose
- avoid precipitating drugs
mechanism of non-acute porphyria
- blockade of normal heme biosynth pathway after formation of hydroxymethylbilane
- accumulation of abnormal porphyrin derivatives in liver and skin
- liver damage, skin rashes
- no neuropsychiatric symptoms because ALA is normal
example of non-acute porphyria
- porphyria cutanea tarda (PCT)
- reduced activity of enzymes leading to protoporphyrin IX
- accumulation of uroporphyrins
porphyria cutanea tarda treatment
- regular phlebotomy
- avoid alcohol, liver toxins, excess sunlight
mechanism of lead poisoning
- lead inhibits ALA dehydrase and ferrochelatase
- same symptoms as acute intermittent porphyria because decreased ALA dehydrase leads to accumulation of ALA
mechanism of iron-deficiency anemia
- translation of erythroid ALA synthase mRNA is stimulated by iron
- lack of iron decreases erythroid heme synthesis, causing anemia
where does heme degradation take place
mostly in the spleen and liver
degradation of heme steps 1 and 2
- heme oxygenase for both steps
- NADPH and O2 convert heme to biliverdin
- biliverdin is green
- iron released
degradation of heme step 3
- biliverdin reductase
- NADPH used to reduce biliverdin to bilirubin
- bilirubin is red/yellow
what carries bilirubin through bloodstream to liver?
albumin
degradation of heme step 4
- in liver
- bilirubin glucuronyltransferase
- attaches 2 molecules of glucuronic acid to bilirubin to form bilirubin diglucuronide (water soluble)
Intestinal fate of bilirubin glucuronide
- converted by bacteria to urobilinogen
- urobilinogen is colorless
fate of urobilinogen in intestine
- most is oxidized to stercobilin (brown feces)
- some reabsorbed into blood and transported to kidney where converted to urobilin (yellow urine)
what biochemical assay measures levels of both conjugated and unconjugated bilirubin in blood?
van den Bergh reaction
what is the major symptom of abnormal heme degradation?
jaundice
4 types of jaundice
1) hemolytic - red cell lysis like sickle cell anemia, abnormally high unconjugated bilirubin
2) obstructive - blockage of bile ducts like by gallstones, high conjugated bilirubin
3) hepatocellular - liver cell damage like by hepatitis, high liver enzymes (AST, ALT)
4) neonatal - low levels of bilirubin glucuronyltransferase activity during early infancy, treated by admin of blue fluorescent light to convert bilirubin into water-soluble metabolites
