Podcast
Questions and Answers
Which type of hemoprotein is primarily responsible for oxygen transport in blood?
Which type of hemoprotein is primarily responsible for oxygen transport in blood?
- Myoglobin
- Cytochrome P450
- Hemoglobin (correct)
- Catalase
What is the first step in the heme synthesis process?
What is the first step in the heme synthesis process?
- Conversion of Porphobilinogen to Heme
- Formation of δ-ALA (correct)
- Cleavage of Heme into Bilirubin
- Formation of Heme from Protoporphyrin IX
Which of the following statements about porphyrins is true?
Which of the following statements about porphyrins is true?
- Porphyrins consist of four pyrrole rings linked by methenyl bridges. (correct)
- Porphyrins are linear compounds formed by a single pyrrole ring.
- Porphyrins lack nitrogen in their structure.
- Porphyrins can form complexes with other organic molecules.
Where does the majority of heme synthesis occur in the body?
Where does the majority of heme synthesis occur in the body?
What inhibits the formation of Porphobilinogen in heme synthesis?
What inhibits the formation of Porphobilinogen in heme synthesis?
What is the primary enzyme responsible for catalyzing the final step in heme synthesis?
What is the primary enzyme responsible for catalyzing the final step in heme synthesis?
Which substance inhibits the activity of Ferrochelatase, leading to acquired porphyria?
Which substance inhibits the activity of Ferrochelatase, leading to acquired porphyria?
In liver cells, which mechanism does heme NOT use to regulate ALA synthase activity?
In liver cells, which mechanism does heme NOT use to regulate ALA synthase activity?
What is the primary clinical manifestation of Acute Intermittent Porphyria (AIP)?
What is the primary clinical manifestation of Acute Intermittent Porphyria (AIP)?
Which enzyme is deficient in Porphyria Cutanea Tarda (PCT)?
Which enzyme is deficient in Porphyria Cutanea Tarda (PCT)?
What effect do barbiturates and grisofulvin have on ALA synthase activity in the liver?
What effect do barbiturates and grisofulvin have on ALA synthase activity in the liver?
In erythroid cells, which enzyme primarily regulates heme formation?
In erythroid cells, which enzyme primarily regulates heme formation?
What triggers the symptoms in Acute Intermittent Porphyria?
What triggers the symptoms in Acute Intermittent Porphyria?
What type of inheritance is exhibited by most types of porphyrias?
What type of inheritance is exhibited by most types of porphyrias?
Which diagnostic technique is best for demonstrating porphyrins in urine?
Which diagnostic technique is best for demonstrating porphyrins in urine?
Flashcards
Heme Formation
Heme Formation
The last step in heme synthesis, where protoporphyrin IX reacts with ferrous iron to form heme, occurring in mitochondria.
Ferrochelatase
Ferrochelatase
An enzyme that catalyzes the reaction of protoporphyrin IX and ferrous iron to form heme.
ALA Synthase Regulation in Liver
ALA Synthase Regulation in Liver
The rate-controlling enzyme for heme biosynthesis in liver cells, regulated by feedback inhibition and other mechanisms.
Porphyrias
Porphyrias
A group of disorders caused by genetic defects in heme synthesis, resulting in accumulation of porphyrin precursors.
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Erythroid Heme Regulation
Erythroid Heme Regulation
In erythroid cells, heme synthesis is primarily regulated by Uroporphyrinogen synthase and ferrochelatase, not ALA synthase.
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Acute Intermittent Porphyria (AIP)
Acute Intermittent Porphyria (AIP)
A hepatic porphyria caused by a deficiency in hydroxymethylbilane synthase, leading to abdominal pain and neuropsychiatric symptoms.
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Porphyria Cutanea Tarda (PCT)
Porphyria Cutanea Tarda (PCT)
Chronic cutaneous porphyria caused by uroporphyrinogen decarboxylase deficiency, resulting in photosensitivity.
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Inheritance of Porphyrias
Inheritance of Porphyrias
All types exhibit autosomal dominant inheritance except congenital erythropoietic porphyrias, which are autosomal recessive.
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Diagnosis of Porphyrias
Diagnosis of Porphyrias
Demonstrating porphyrins using UV fluorescence to detect strong red fluorescence in urine.
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Heme Synthesis
Heme Synthesis
The process of creating heme, essential for hemoproteins, involving multiple steps.
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δ-ALA Formation
δ-ALA Formation
First step in heme synthesis, forming δ-aminolevulinate from succinyl-CoA and glycine, requiring vitamin B6.
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Lead Poisoning
Lead Poisoning
Inhibits the formation of porphobilinogen (PBG) during heme synthesis, resulting in symptoms of porphyria.
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Hemoproteins
Hemoproteins
Proteins that contain heme, important for various functions such as oxygen transport and detoxification.
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Heme Metabolism Objectives
- Study Heme Synthesis
- Understand Heme Catabolism
- Examine the Biochemical Basis and Clinical Implications of Porphyrias
- Explore Heme Catabolism into Bilirubin
Hemoproteins
- Hemoglobin: Oxygen transport in blood
- Myoglobin: Oxygen storage in muscles
- Cytochromes: Electron transport in the respiratory chain
- Cytochrome P450: Hydroxylation reactions
- Catalase and peroxidases: Degradation of hydrogen peroxide
- Tryptophan pyrrolase: Oxidation of tryptophan
- Nitric oxide synthase: Synthesis of nitric oxide
Heme Structure
- Heme is a Metaloporphyrin
- Heme = porphyrin ring (Protoporphyrin IX) + iron
- Porphyrins are cyclic compounds formed by fusion of four pyrrole rings linked by methenyl bridges
- Porphyrins form complexes with metal ions
Heme Synthesis Sites
- Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group of enzymes and electron transport chain
- Major sites of heme synthesis are the liver, and erythroid progenitor cells of the bone marrow
- Liver involves formation of hemoproteins (e.g., cytochrome P450) for detoxification
- Erythroid cells involve hemoglobin synthesis
- Steps 1, 6, 7, and 8 occur in mitochondria
- Steps 2, 3, 4, and 5 occur in cytoplasm
Overview of Heme Synthesis
- Heme synthesis involves 8 steps
- Succinyl CoA + Glycine → 8-aminolevulinic acid
- Step 1: Formation of 8-ALA
- Occurs in the mitochondria
- Requires Pyridoxal phosphate (B6)
- Catalyzed by d-amino levulenic acid synthase
- Condensation reaction of succinyl-CoA and glycine
- Step 2: Formation of Porphobilinogen (PBG)
- Occurs in the cytoplasm
- Catalyzed by ALA dehydratase
- Inhibited by Lead (Acquired porphyria)
- Last Step: Formation of heme
- Occurs in the mitochondria
- Catalyzed by Ferrochelatase
- Inhibited by Lead (Acquired porphyria)
Regulation of Heme Synthesis
- Heme biosynthesis is regulated differently in erythroid and liver cells
- Rate-controlling enzyme for heme biosynthesis is ALA synthase
- Heme or its Fe(III) oxidized (Hematin and Hemin) products control the enzyme's activity via feedback inhibition
- Inhibiting ALA synthase transport from the cytosol to the mitochondria
- Repressing ALAS synthesis
Effect of Drugs on ALA Synthase Activity
- Drugs like barbiturates and grisofulvin increase ALA synthase activity, leading to more heme consumption.
- Consequently, heme concentration reduced, stimulating ALA synthase
Porphyrias
- Porphyria is an inherited genetic defect in enzyme of heme synthesis resulting in accumulation of porphyrin precursors
- Precursors increase in blood and appear in urine.
- Porphyrias are classified as erythropoietic or hepatic, depending on the major site where the deficiency manifests
- Porphyrias exhibit autosomal dominant (AD) inheritance, except for congenital erythropoietic porphyrias (AR).
Types of Porphyria
- Many types with different defects and symptoms
- Acute Intermittent Porphyria (AIP): Usually expresses after puberty, abdominal pain, neuropsychiatric disturbances;triggered by drugs, infections, menstrual cycle; not photosensitive.
- Porphyria cutanea tarda (PCT): Chronic cutaneous hepatic porphyria, the most common; caused by deficiency of the enzyme uroporphyrinogen decarboxylase; increased excretion of uroporphyrins; cutaneous photosensitivity.
Degradation of Heme
- Red blood cells (RBCs) live for 120 days.
- RBC degradation occurs in the Reticulo-endothelial System (RES) in the liver and spleen.
- Heme is released from hemoglobin; Globin reused
- Heme -> Biliverdin -> Bilirubin -> Excreted by liver into Bile.
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