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Flashcards in Lecture 52 Deck (17)

What are the Heme containins proteins and what are their functions?

1) Hemoglobin – Binding, transport of O2
2) Myoglobin – Binding, storage of O2
3) Catalase – Breakdown of H2O2
4) Cytochromes c, b & a – Electron transport
5) Cytochrome P450 – Hydroxylation
6) Chlorophyll (Mg2+) – Absorption of light


What occurs in diseases of heme synthesis/degradation?

1) Porphyrias: Rare but fatal
2) Jaundices: Common & Diagnostic


What are characteristics of the heme structure?

1) It is called Porphyrin 9 because of the structure
2) It has 4 pyrrole rings, 2 of which contain a methyl + vinyl group, and 2 of which contain a methyl & propionyl group
3) The double bonds are conjugated


What is the first reaction of heme formation?

1) Succinyl CoA + Glycine → delta-Aminolevulinic Acid (occurs in the mitochondria; uses delta-aminolevulinic acid synthase)
2) The amount of heme controls the regulation of this reaction. More heme = negative inhibition


What is the second reaction of heme formation?

1) delta-aminolevulinic acid moves from the mitochondria to the cytoplasm
2) delta-aminolevulinic acid → porphobilinogen (uses delta-aminolevulinic acid dehydrase)


What are the third reaction and fourth reactions of heme formation?

1) porphobilinogen is deaminated (uses porphobilinogen deaminase)
2) uro synthase 1 or 3 is used to produce either uroporphyrinogen 1 or 3


What must be done when Uroporphyrinogen 1 is formed?

1) A pyrrole and amino group must be switched to make the molecule nonsymmetrical and allow the addition of more pyrrole groups to make the tetrapyrrole intermediate
2) This requires Uro 3 Cosynthase to produce Uroporyphrinogen 3 from Uroporphyrinogen 1


What happens to Uroporphyrinogen 3 once it is formed?

1) Uroporphyrinogen 3 → Coproporphyrinogen 3 (uses Uro 3 decarboxylase)
2) Coproporphyrinogen 3 → Protoporphyrinogen 9 (uses Copro 3 oxidase)


What must occur to Protoporyphrinogen 9 once it is formed?

1) It undergoes oxidation to produce resonance between the double bonds
2) Enzyme is Protoporphyrin 9 oxidase
3) Fe2+ must be added to finalize the heme group
4) Enzyme is ferrochelatase


What are diseases of heme synthesis that cause a blockage of the tetrapyrrole intermediate being formed and an accumulation of porphobilinogen?

1) Acute Intermittent: rxn 3 (porphobilinogen to uroporphyrinogen 1)
2) Congenital Erythropoietic: rxn 4 (uroporphyrinogen 1 to uroporphyrinogen 3)
3) Cutanea Tarda: rnx 5 (uroporphyrinogen 3 to coproporyphyrinogen 3)
4) Lead poisoning rxns 2 & 8 (delta-aminolevulinic acid to porphobilinogen & addition of Fe2+ to protoporphyrinogen 9)


What is the first step in heme degradation?

1) Occurs in Reticuloendothelial system cell (RES Cell: spleen, liver, bone marrow): fixed mononuclear phagocytes
2) Hemoglobin → Globin + Heme
3) Globin is broken down into amino acids
4) Heme → biliverdin + Fe3+ + CO (uses Heme oxygenase)
5) Biliverdin + NADPH → Bilirubin (insoluble) + NADP+


What happens to bilirubin once it is made in an RES Cell?

It is transferred into the blood where it is transported by albumin to the liver


Why is bilirubin insoluble?

Because bilirubin serves as a reductant in the blood as it travels to the liver for degradation (does so to minimize the formation of plaque)


What happens to bilirubin in the liver?

In the liver, the insoluble bilirubin is conjugated to 2 molecules of glucuronic acid to form bilirubin diglucuronide (comes from glucuronyl-UDP)


What happens to bilirubin diglucuronide in the liver?

1) It is soluble and travels through the bile duct to the small intestine
2) Bacteria convert bilirubin diglucuronide to urobilinogen to stercobilin (brown) (excreted as feces)
3) Urobilinogen → Urobilin in the urine (makes urine yellow)


What is jaundice and when does it occur?

1) Bilirubin in plasma imparts a yellowish tint to skin & conjunctiva:
2) Pre-hepatic: hemolytic (all elevated levels of bilirubin intermediates, but all in the correct bodily location)
3) Hepatic: neonatal (UDP-glucuronyl transferase), transport, viral hepatitis, cirrhosis, & Crigler-Najjar (UDP-glucuronyl transferase); UDP-glucuronyl transerfase activity is decreased causing a backup of bilirubin; liver is leaky allowing bilirubin diglucuronide to enter the blood and urine (wrong place); decrease in urobilinogen, stercobolin, and urobilin in feces, but an increase in urobilinogen & urobilin in urine
4) Post-hepatic: cholestasis, stones, spasms, & neoplasm; block in gall bladder prevents things from getting into small intestine, causing elevated blood and urine levels of bilirubin diglucuronide. Decreased levels of urobilinogen, stercobilin, & urobilin in feces & urine


What is the van den bergh reaction (clinical test)?

1) Clinical test for measuring bilirubin
2) Uses diazonium salts (azide salts that are colorless and can react when bilirubin when it is soluble)
3) Bilirubin (soluble) + diazonium salts (no color) → azo dye (bluish color)
4) Direct test (serum):
a) Conjugated (soluble) produces color
b) Unconjugated (insoluble) no color
5) Total test (serum + alcohol):
a) Conjugated (soluble) produces color
b) Unconjugated (solubilized by alcohol) produces color
6) Total – Direct = Indirect/Unconjugated