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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?
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?
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?
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?
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.

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