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Questions and Answers
What is the primary role of glycine and succinyl CoA in heme synthesis?
What is the primary role of glycine and succinyl CoA in heme synthesis?
Which enzyme is specifically critical in the first step of heme synthesis?
Which enzyme is specifically critical in the first step of heme synthesis?
What effect do drugs and alcohol have on heme synthesis?
What effect do drugs and alcohol have on heme synthesis?
Lead poisoning primarily affects heme synthesis by inhibiting which enzyme?
Lead poisoning primarily affects heme synthesis by inhibiting which enzyme?
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In humans, which type of porphyrins are typically significant?
In humans, which type of porphyrins are typically significant?
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Where does the majority of heme synthesis occur in the human body?
Where does the majority of heme synthesis occur in the human body?
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What happens to heme synthesis in mature red blood cells (RBCs)?
What happens to heme synthesis in mature red blood cells (RBCs)?
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Which of the following statements accurately describes porphyrins?
Which of the following statements accurately describes porphyrins?
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What is the first committed step in the heme synthesis pathway?
What is the first committed step in the heme synthesis pathway?
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Which enzyme catalyzes the formation of aminolevulinic acid from Glycine and succinyl CoA?
Which enzyme catalyzes the formation of aminolevulinic acid from Glycine and succinyl CoA?
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What effect do low levels of heme in liver cells have on ALAS1 synthesis?
What effect do low levels of heme in liver cells have on ALAS1 synthesis?
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What is the role of lead poisoning in heme synthesis?
What is the role of lead poisoning in heme synthesis?
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What type of disease is porphyria related to?
What type of disease is porphyria related to?
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Which enzyme is involved in the final step of heme formation?
Which enzyme is involved in the final step of heme formation?
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What is the end product of the condensation reaction between Glycine and succinyl CoA?
What is the end product of the condensation reaction between Glycine and succinyl CoA?
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What effect does alcohol have on the synthesis of heme?
What effect does alcohol have on the synthesis of heme?
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Which enzyme is responsible for the decarboxylation step in heme synthesis?
Which enzyme is responsible for the decarboxylation step in heme synthesis?
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Which components are required for the synthesis of Aminolevulinic acid in hepatic porphyria?
Which components are required for the synthesis of Aminolevulinic acid in hepatic porphyria?
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What is the primary function of the enzyme Aminolevulinic acid synthase in porphyrin metabolism?
What is the primary function of the enzyme Aminolevulinic acid synthase in porphyrin metabolism?
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How does acute hepatic porphyria differ from chronic hepatic porphyria in terms of trigger factors?
How does acute hepatic porphyria differ from chronic hepatic porphyria in terms of trigger factors?
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What is a significant effect of drug exposure in acute intermittent porphyria (AIP)?
What is a significant effect of drug exposure in acute intermittent porphyria (AIP)?
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What color change occurs in urine during an acute hepatic porphyria attack?
What color change occurs in urine during an acute hepatic porphyria attack?
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Which enzyme is responsible for converting Uroporphyrinogen III to Coproporphyrinogen III?
Which enzyme is responsible for converting Uroporphyrinogen III to Coproporphyrinogen III?
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What is a primary symptom of porphyria cutanea tarda (PCT)?
What is a primary symptom of porphyria cutanea tarda (PCT)?
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What condition can lead to an increased risk of developing hepatic porphyria due to an accumulation of porphyrins?
What condition can lead to an increased risk of developing hepatic porphyria due to an accumulation of porphyrins?
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Which porphyria is characterized by the build-up of porphyrins in the liver and typically manifests as skin problems?
Which porphyria is characterized by the build-up of porphyrins in the liver and typically manifests as skin problems?
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What role does Ferrochelatase play in the heme biosynthesis pathway?
What role does Ferrochelatase play in the heme biosynthesis pathway?
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Study Notes
Conversion of Amino Acids to Specialized Products
- Dietary protein intake is typically 100 g/day in the U.S.
- Body protein is approximately 400 g/day.
- Synthesis of nonessential amino acids varies
- Amino acid pool is approximately 30 g/day.
- Specialized products include porphyrins, creatine, neurotransmitters, purines, pyrimidines, and other nitrogen-containing compounds.
Porphyrins
- Cyclic compounds that bind metal ions (ferrous or ferric).
- Composed of four pyrrole rings.
- Form complexes with metal ions bound to the nitrogen atom of the pyrrole ring.
Properties of Methenyl Group
- Methenyl bridge (oxidized form) - (-HC-).
- Methylene bridge (reduced form) - (-CH2-).
- Porphyrin's methenyl groups can be oxidized or reduced.
Porphyrin Structure
- Side chains attached to pyrrole rings vary.
- Uroporphyrin I has acetate and propionate side chains.
- Coproporphyrin has methyl and propionate side chains.
- Protoporphyrin IX has methyl, vinyl, and propionate side chains.
- Porphyrins with Type III structure are most important in humans.
Hemeproteins
- Hemoglobin: Transports oxygen in blood.
- Myoglobin: Stores oxygen in muscle.
- Cytochrome c: Involved in electron transport chain.
- Cytochrome P450: Hydroxylates xenobiotics.
- Catalase: Degrades hydrogen peroxide.
- Tryptophan pyrrolase: Oxidizes tryptophan.
Heme Structure
- Ferrous iron (Fe2+).
- Protoporphyrin IX: Contains tetrapyrrole rings linked by methenyl bridges.
- Side chains: Methyl (M), Vinyl (V), and Propionyl (P).
Heme Biosynthesis Location
- Hepatocytes synthesize approximately 15% of heme proteins, specifically cytochrome P450.
- Erythrocyte-producing cells in bone marrow synthesize about 85% of heme, crucial for hemoglobin synthesis.
- Heme biosynthesis occurs in both mitochondria and cytosol, with the pathway starting and ending in mitochondria.
Heme Synthesis Steps
- Steps 1 and 2: Formation of a pyrrole molecule (containing 4 carbon atoms and 1 nitrogen atom, in a ring structure).
- Step 3: Linkage of four pyrrole molecules to form a linear tetrapyrrole.
- Step 4: Formation of the porphyrin (tetrapyrrole) ring.
- Steps 5-7: Decarboxylation and oxidation.
- Step 8: Incorporation of the iron atom.
First Step in Heme Pathway
- Condensation reaction between glycine (nonessential amino acid) and succinyl CoA (intermediate from the TCA cycle).
- Catalyzed by mitochondrial enzyme aminolevulinic acid synthase (ALAS), which requires coenzyme PLP.
- Rate-limiting step in heme synthesis.
- Two isoforms, ALA-S1 (present in all tissues) and ALA-S2 (produced in erythroid tissue).
Porphyria ("Vampire Disease")
- Rare metabolic diseases resulting from enzyme defects in heme biosynthesis.
- Accumulation of porphyrins or precursors.
- Classified as hepatic porphyria (chronic or acute) or erythropoietic porphyria.
Degradation of Heme
- About 80-85% of heme originates from red blood cells (RBCs).
- Location of heme degradation: Macrophage systems in the liver and spleen.
- Key products of heme degradation:
- Iron is returned to body stores.
- Globin is broken down into amino acids.
- Bilirubin is formed from the porphyrin ring.
- Microsomal heme oxygenase in macrophages catalyzes three oxygenations.
- Formation of biliverdin
- Release of iron (Fe+3)
- Release of carbon monoxide (CO)
- Biliverdin is then reduced to bilirubin by biliverdin reductase.
Bilirubin Metabolism
- Transferred to the liver as a bilirubin-albumin complex.
- Dissociates from albumin and binds to ligandin.
- Conjugation with glucuronic acid (via UDP glucuronyl transferase), which increases solubility.
- Conjugated bilirubin (CB) is secreted into bile.
Disorders Linked to Heme Degradation
- Jaundice: Yellowing of skin and eyes caused by bilirubin buildup in the blood.
- Prehepatic jaundice: Hemolysis.
- Hepatocellular jaundice: Liver damage.
- Post-hepatic jaundice: Obstruction of the bile duct.
- Types of jaundice and causes are included.
Catecholamines
- Biologically active water-soluble amines derived from tyrosine.
- Neurotransmitters in the CNS.
- Hormones in circulation, responding to stress or hypoglycemia.
- Synthesized in the brain and adrenal medulla.
- Include Dopamine, Norepinephrine, and Epinephrine.
- Regulate carbohydrate and lipid metabolism.
- Released in response to stress, exercise, cold, or low blood glucose.
- Increase glycogen and triacylglycerol breakdown.
- Increase blood pressure and heart output.
Melanin
- Pigment found in the eyes, hair, and skin.
- Synthesized from tyrosine by melanocytes.
- Protects cells from sunlight.
- Albinism (a genetic disorder) results from melanin production defects due to copper deficiencies.
Creatine Synthesis
- Amidinotransferase: Rate-limiting enzyme in the mitochondrial pathway of creatine synthesis.
- Methyltransferase uses SAM (S-adenosyl methionine) as a one-carbon donor to produce creatine.
- Creatine kinase: Catalyzes phosphorylation of creatine using ATP (provides the phosphate).
- Creatinine (breakdown product): Excreted in urine; measurement is used to assess kidney function.
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