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16 Cards in this Set
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Describe in detail the reactions of ALA dehydratase.
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ALA dehydratase converts two molecules of δ-Aminolevulinic acid (ALA) into Porphobilinogen (PBG)
- Takes place in the cytoplasm - ALA dehydrase contains zinc - It is extremely sensitive to inhibition by heavy metal ions, especially lead |
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Discuss the concept of heme synthesis and its 4 steps
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1. Formation of δ-Aminolevulinic acid (ALA)
2. Formation of porphobilinogen 3. Formation of uroporphyrinogen III 4. Formation of heme - formation of coproporphyrinogen III - formation of portoporphyrin IX - formation of heme |
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Distinguish between the different regulatory processes of heme synthesis in the liver and in the erythroid cells
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Liver -
Erythroid cells - |
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Explain how pyridoxal phosphate deficiency affects heme synthesis
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Microcytic (too small) and hypochromic (pale) anemia.
Any disruption of the ALA Synthase reaction leads to a decreased amount of hemoglobin produced. |
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Discuss the effects of lead poisoning on heme synthesis
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- Limits ALA dehydrase
- increases amounts of ALA (diagnostic) - Decreases production of Hb (hypochromic, microcytic anemias) - first reaction of heme synthesis - Limits Ferrochelatase - protoporhyrin IX accumulates - last reaction of heme synthesis |
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Describe porphyrias
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Porphyrias are rare autosomal dominant disorders resulting from deficiencies of enzymes in the pathway for heme biosynthesis leading to accumulation and increased excretion of porphyrins or porphyrin precursors.
They are categorized as hepatic or erythropoietic and as acute or chronic. |
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Which pathologies with ALA and PBG accumulation cause Photosensitivity.
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Photosensitivity is seen in all porphyrias where there is an accumulation of tetrapyrrole intermediates.
This is thought to occur as a result of trapyrrole mediated formation of superoxide radicals from oxygen which damage cell membranes and lead to the destruction of cellular components. It is seen in all porphyrias except acute intermittent porphyria and the porphyria due to ALA hydratase deficiency. |
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Describe acute intermittant porphyria.
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Inherited autosomal hepatic deficiency of hydroxymethylbilane synthase (porphobilinogen daminase)
Symptoms due to ALA and PBG accumulation Presents post-puberty. Steroid hormones may express Features - gastrointestinal (cramping, nausea, vomiting), - neuropsychiatric (anxiety, depression, insomnia, hallucinations - peripheral neuropathy (mainly motor neurons) - NO PHOTOSENSITIVITY! Diagnosis - increased urinary ALA & PBG - Urine turns dark on exposue to light (PBG gets converted to porphobin) Treatment - symptomatic, Hemin (inhibits ALA synthase) |
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Describe in detail the reactions of ALA synthase
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ALA synthase converts one Syccinyl Co-A and one Glycine into δ-Aminolevulinic acid (ALA)
-First reaction and rate limiting step of heme synthesis - Takes place in mitochondria - Requires pyridoxal phosphate (vit B6) as a coenzyme |
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How does the end-product inhibition of ALA synthase work?
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- Excess heme is converted to Hemin (Fe2+ converted to Fe3+)
- Hemin decreases the activity of hepatic ALA synthase by decreasing the amount of enzyme produced. |
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What drugs affect ALA synthase?
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- any drugs which induce cytochrome P450 in the liver increase ALA synthase activity (phenobarbitone)
- Induction of P450 leads to increased synthesis of this complex, of which heme is a part. More heme is consumed by this P450 system, decreasing the [heme] in the liver cells. This removes the end product feedback inhibition. |
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What is erythroid ALA synthase?
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- present in the erythrocyte producing cells of the bone marrow
- does not undergo feedback inhibition by hermin Is not induced by drugs that induce cytochrome P450 - is regulated by erythropoietin (potentiates) and the availability of iron - is therefore under hormonal conrol, sufficient amounts of iron being available. |
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Describe the different categories of hepatic Porphyrias
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Hepatic -
Type: 5 ALA dehydratase deficient Porphyria Deficient Enzyme: ALA Dehydratase Intermediates measured in urine: ALA Type: Acute intermittent porphyria Deficient Enzyme: HMB synthase Intermediates measured in urine: PBG & ALA Type: Porphyria cutanae tarda Deficient Enzyme: Uroporphyrinogen decarboyslase Intermediates measured in urine: Uroporphyrin Type: Hereditary coproporphyria Deficient Enzyme: Coproporphyrinogen oxidase Intermediates measured in urine: Coproporphyrin (ALA, PBG) Type: Variegate porphyria Deficient Enzyme: Protoporphyringe oxidase Intermediates measured in urine: Protoporphyrin IX, Coproporphyrin, ALA, PBG |
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Categorize the different types of Erythropoietic Porphyrias
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Type: Congenital erythropoitic porphyria
Deficient Enzyme: Uroporhyringen III synthase Intermediates measured in urine: Uroporphyrin I Type: Erythropoietic protoporphyria Deficient Enzyme: Ferrochelatase Intermediates measured in urine: Protoporphyrin IX |
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Describe Porphyria Cutanea Tarda
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Inherited or acquired hepatic deficiency of uroporphyrinogen decarboxylase (dependent on iron)
Symptoms due to uroporphyrinogen III accumulation Presents: 4-5 decade of life Features - Chronic disease - Aggravated by hepatic iron overload, sunlight and hepatic infection. - blistering skin lesions on backs of hands -Hypertrichosis (increased hair) and hyperpigmentation - PHOTOSENSITIVITY Diagnosis - increased urinary uroporphyrin - Urinary PBG levels are normal - Red/brown urine due to uroporphyrin Treatment - symptomatic, decreasing hepatic iron content by repeated phlebotomies induces remission but causes anemia |