Heme Metabolism and Bilirubin
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- Are hemes hydrophilic or hydrophobic?
- hydrophilic and insoluble in the blood
- What is the reduced and oxizided state of the Fe in Heme
- reduced: ferro = Fe2+⬦ oxidized: ferri or met - Fe3+
- What part of the heme does the body deal with to make it more soluble?
- the carboxyl groups
- Trace the steps in heme synthesis.
- Succinyl CoA + Glycine (delta-ALA synthase +PLP/vit B6) --> delta ALA
- Where does heme synthesis occur?
- mitochondria and the cytoplasm or bone marrow (Hb) and Liver (cytochrome P450, cytochrome b5+ and catalase)
- What is the committed step of heme synthesis?
- delta-ALA
- How is delta-ALA synthase regulated? At what level does the control occur?
- a) Product feedback inhibition with the porphryrin ring, protoporphyrin IX⬦ b) gene level, (it as a half-life of 1-2 hours)
- What is generally being produced in intermittent porphyria? What is the role of this compound?
- cytochrome P450, add -OH to make foreign substances more soluble
- What moieties in the heme biosynthetic process are conjugated?
- protoporphyrin IX and heme
- Are delta ALA and porphyrins linear or ring shaped?
- delta-Ala is linear and porphyrins are rings
- Which is the major heme used in the body?
- protoporphyrin IX
- where do you find protoporphyrin IX?
- cytochrome C, hemoglobin, hemes in the ETC
- where does lead poisoning , in heme synthesis (porphyria metabolism)?
- delta-ALA dehydratase AND ferrochelatase
- What makes a protoporphyrin a heme?
- iron
- In the heme biosynthesis pathway (porphyria metabolism), there are two autosomal dominant diseases. What are they?
- acute intermittent porphyria and porphyria cutania tarda
- How does the placement of acute intermittent porphyria and porphyria cutania tarda cause an accumunation of these blocked intermediate?
- Delta-ALA is regulated by the feedback inhibition of the product, heme. Thus the heme pool is always deplete and continued synthesis causes an accumulation of intermediates.
- What changes in the urine do the accumulation of intermediates in acute intermittent porphyria produce?
- dark urine
- What exaserbates the problem of acute intermittent porphyria?
- the treatment of neuropsychiatric symptoms of this disease by sedatives, hypnotics, tranquilizers, anticonvulsants
- What can be the cause of sporadic symptoms in porphyria cutanea tarda?
- porphyrins intermediates that accumulate in the fatty tissues of the skin can aborb light, sun light may trigger symptoms.
- What would happen if you treated a person that had a heme block with a sedative, when he came to the ER with neuropsycotic symptoms after drinking alcohol?
- It would just make him worse, because more intermediates would accumulate
- Why is it that weight loss can exaserbate acute intermediate porphyria?
- intermediates are hydrophobic, thus they are stored in adipose tissue, weight loss reduces storage capacity
- which enzyme is responsible for heme degradation by cleaving rings?
- heme oxygenase
- What is released by heme degradation by heme oxygenase? how can heme oxygenase be measured?
- the cleavage of heme rings produces CO2 and Fe, CO2 is a measure of heme oxygenase
- What is the product of heme in the presence of heme oxygenase?
- Biliverdin
- detail the breakdown of heme.
- heme (heme oxygenase) --> biliverdin + NADPH(biliverdin reductase) --> bilirubin + NADP
- What is the enzyme (and reducing agent) that converts biliverdin into bilirubin?
- bilirubin reducase and NADPH
- During RBC breakdown, what happens to its constituents? (hint: Fe2+, globin, bilirubin)
- globin: broken down into amino acids⬦ Fe2+ recaptured⬦ Bilirubin:
- What transports bilirubin to the liver in the blood? And what are the other functions of this transporter?
- a) albumin⬦ b) it also transports fatty acids and controls osmotic balance
- What happens to bilirubin in the liver? What effect does this have on the bilirubin? What relevance is this?
- a) glucouronic acid added forming an ester, bilirubin-diglucuronide⬦ b) It becomes conjugated⬦ c) conjugated bilirubin is more soluble and can now be put into bile. (some ends up as uobilinogen and excreted in the urine)
- How do you get a reading on the unconjugate bilirubin?
- treat with a dye that will measure only the conjugated bilirubin (this is direct) ; then add etanol (which solublizes the unconjugate B/R); then subract the direct from the solublized B/R⬦ the difference is the unconjugate BR (This is indirect reacting)
- What type of deposition of bilirubin is jaundice, conjugated or uncongugated?
- Both
- what is suggested in jaundice (hyperbilirubinemia) if a person has an excess of conjugated in the body?
- an obstruction of the bile duct
- what is suggested in jaundice (hyperbilirubinemia) if a person has an excess of unconjugated in the body?
- physiologic jaundice (newborns), hemolytic condition, inherited glucouronic acid deficiencies.
- What are Crigler-Najjar syndromes?
- a deficiency in UDP=glucuronyl, so glucouronic acid cannot be added, thus bilirubin remains unconjugate and insoluble.
- What is Gilbert syndrome?
- these people cannot FULLY conjugate glucuronic acid and show intermittened jaundice during infections or during a high RBC turnover⬦ or some other stress event⬦ symptoms are self-resolving
- How does a high degree of hemolysis cause hyperbilirubinemia?
- the capacity of albumin to carry the bilirubin has been exceeded.