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23 Cards in this Set
- Front
- Back
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Describe the general structural features of the heme molecule.
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Protoporphyrin IX = heme WITHOUT the iron. Heme is Fe-protoporphyrin IX.
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Where is iron located in the heme molecule?
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Center
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What feature of heme is responsible for its color.
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Conjugation
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Describe the process of heme synthesis.
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Step 1: ALA synthase (mitochondrial)
** Rate limiting step! - Condensation of succinyl-CoA and glycine - Forms Δ-amino levulinic acid (ALA) - Hepatic ALA synthase gene inhibited by heme - ALA synthase in the erythropoetic system coded by a different gene. Step 2: ALA dehydratase (cytoplasmic) - Condensation of 2 molecules of ALA to form porphobilinogen (PBG) - Inhibited by lead; produces porphyria Step 3: Uroporphyrinogen III synthase - Condensation of 4 molecules of PBG to form uroporphyrinogen III Step 4: Uroporphyrinogen decarboxylase - Uroporphyrinogen III converted to coproporphyrinogen III Step 5: Decarboxylase (mitochondrial) - Coproporphyrinogen III converted to protoporphyrinogen III Step 6: Coproporphyrinogen oxidase (mitochondrial) - Protoporphyrinogen III converted to protoporphyrinogen IX Step 7: Ferrochelatase (mitochondrial) - Incorporation of iron into protoporphyrin - Inhibited by lead |
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What are the main sites of heme synthesis?
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Bone marrow and liver
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What are porphyrins? In what way do the porphyrins differ from each other?
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heterocyclic macrocycles characterized by the presence of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH-). Can differ in metal center
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Which type of porphyrin is biologically active?
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Heme (Fe-protoporphyrin IX)
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What two precursors are used in the synthesis of porphyrins?
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Succinyl-CoA + Glycine
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What is the product of the ALA synthase reaction? What molecule regulates heme synthesis by inhibiting this reaction
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Δ-aminolevulinate (ALA). Heme regulates this.
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What are the substrates and products of ALA dehydratase? How is this reaction regulated? How can it be poisoned? How is this poisoning detected by blood analysis in the clinical lab?
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Substrates: 2 molecules of Δ-aminolevulinate (ALA). Product: Porphobilinogen
Heme is a feedback inhibitor. If heme reduced or small, will stimulate this step. Partial poisoning will get flow through here and porphyrins will build up. Lead poisoning. Accumulation of porphyrins |
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How is uroporphyrinogen III formed?
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From porphobilinogen, via uroporphyrinogen III synthase + cosynthase
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What are the steps that lead to the formation of protoporphyrinogen III from uroporphyrinogen III?
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Uroporphyrinogen decarboxylase turns to coproporphyrinogen III via uroporphyrinogen decarboxylase.
Coproporphyrinogen III turns to protoporphyrinogen III in the mitochondria via another decarboxylase. |
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How is protoporphyrinogen IX formed?
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From coproporphyrinogen III via coproporphyrinogen oxidase (in the mitochondria)
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What happens to protoporphyrinogen IX when ferrochelatase acts on it
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Adds iron into the center of the ring
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How is ferrochelatase regulated and how is it poisoned?
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Heme; inhibited by lead
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What is porphyria? What is one of the most likely causes of acute intermittent porphyria?
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- Diseases resulting from deficiencies in the biosynthetic pathway enzymes
> Deficiencies always partial > Usually autosomal dominant > Often with cutaneous photosensitivity; irradiated porphyrins produce oxygen radical damage > Reduced production of heme increases ALA synthase expression and accelerates pathway > Treated with hematin (Heme with Fe3+). Represses gene similar to heme repression |
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What are the symptoms of AIP?
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Synthase (uroporphyrinogen I synthase) deficiency
- Acute attacks; NO photosensitivity - Abdominal pain; constipation - Neuropsychiatric symptoms (from CNS and PNS effects due to accumulation of ALA and porphobilinogen in blood and CSF) - Frequently precipitated by drugs (P450 inducing) - Increased urinary excretion of ALA and PBG |
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What two compounds accumulate in AIP?
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ALA, PBG
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Outline the cause and the symptoms of porphyria cutanea tarda.
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- Defective enzyme: uroporphinogen decarboxylase
- Photosensitivity - Porphyrins generate damaging oxygen radicals (porphyrinogens spontaneously convert to porphyrins) - No acute attacks - History of alcohol abuse or exposure to toxic chemicals |
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What causes the photosensitivity in this disease?
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Porphyrins build up, leave liver, enter blood, and go into skin fat. Generate damaging radicals
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Describe the different locations involved in heme degradation and the reactions occurring at each location.
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- Splenic macrophages
> Conversion of heme to biliverdin (green) > Conversion of biliverdin to bilirubin (yellow - Liver > Conjugated with UDP-glucuronic acid > Produces water-soluble bilirubin diglucuronide - Intestine > Bacteria deconjugate bilirubin diglucuronide > Produces uncolored urobilinogens > Urobilinogens oxidize to brown urobilins |
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What color is biliverdin? Bilirubin?
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Green, Yellow
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What is accomplished by conjugation?
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Means to join together bilirubin with something water-soluble to make the bilirubin water-soluble. Can then be eliminated in bile or urine
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