39 Questions
Which enzyme deficiency leads to the accumulation of uroporphyrin I and coproporphyrin I in the urine?
Porphobilinogen deaminase
In which type of porphyria does a deficiency in uroporphyrinogen III cosynthetase lead to the accumulation of uroporphyrin I and coproporphyrin I in the urine?
Acute intermittent porphyria
Which enzyme is inhibited by lead poisoning, leading to decreased heme synthesis and subsequent microcytic hypochromic anemia?
Ferrochelatase
Which enzyme defect results in the accumulation of coproporphyrin III and protoporphyrin IX, causing photosensitivity and skin fragility?
Coproporphyrinogen oxidase
Which enzyme is responsible for the synthesis of porphobilinogen from 2 ALA?
ALA Dehydratase
What characteristic side chains and linkers are generated during the condensation of 2 ALA to porphobilinogen?
Decarboxylation to make methyl groups and oxidation to make vinyl groups
Where do the oxidation steps, converting methyl groups to methine groups, take place?
Mitochondria
Which enzyme is the same as Porphobilinogen Deaminase?
Hydroxymethylbilane Synthase
What is the function of Ferrochelatase in heme synthesis?
Adds Fe2+
Which porphyria results in the formation of zinc protoporphyrin (ZnPP) and leads to anemia?
Hepatic Erythropoetic Porphyria
Which porphyria is characterized by skin eruptions and discolored urine?
Porphyria Cutanea Tarda
What is the major pathophysiology of porphyrias?
Accumulation of intermediates upstream of the deficient enzyme block
Where does heme conversion to bilirubin take place?
Macrophages
What is the product of Heme Degradation by Heme Oxygenase?
Biliverdin
What is a characteristic symptom of jaundice?
Yellow discoloration of sclerae, nails, and skin
Which proteins contain heme as a tightly bound prosthetic group?
Hemoglobin, myoglobin, and cytochrome P450
What is the primary function of cytochrome P-450?
Inactivation of drugs and other xenobiotics
Where is heme synthesized principally?
Bone marrow for erythrocytes and liver for Cytochrome P-450
What stimulates the process of erythropoiesis?
Decreased O2 in circulation
Which enzyme is the rate-limiting step of heme synthesis?
δ-aminolevulinate synthase (ALAS)
What is the effect of low iron on ALAS2 production?
It inhibits ALAS2 production
Which disorder is due to an ALAS2 deficiency?
X-linked sideroblastic anemia
What acts as a concentration-dependent inducer of aminolevulinic acid (ALA) synthase and porphobilinogen (PBG) deaminase in normal human bone marrow?
Erythropoietin (Epo)
Which type of porphyrins are physiologically relevant for people?
Type III
What are porphyrinogens?
Porphyrin precursors between porphobilinogen & protoporphyrin
What does hemin do to ALAS1 in the liver?
Decreases expression of ALAS1 in liver
What is the effect of drugs like phenobarbital on ALA synthase activity?
Increases ALA synthase activity
Which liver disease results from a reduced or blocked flow of bile from the liver?
Cholestasis
What is the cause of Dubin-Johnson syndrome?
Defective secretion of bilirubin from hepatocytes into the bile
What can lead to Kernicterus in newborns?
Transiently low UDP-glucuronyl transferase
What is the main function of the gallbladder?
Production of bile
Which condition is associated with a slight increase in unconjugated bilirubin and a yellow tinge of the skin?
Gilbert Syndrome
What causes Hemolytic disease of the newborn?
Rhesus negative mother producing antibodies attacking rhesus positive fetal blood
What causes jaundice in Rotor Syndrome?
Impaired hepatocellular storage of conjugated bilirubin that leaks into plasma
How does Crigler-Najjar syndrome differ from Gilbert Syndrome?
[Crigler-Najjar syndrome] involves a reduced or no UDP-glucuronyl transferase in the liver, while Gilbert Syndrome does not
In which liver cells does perivenous hepatocytes receive lower oxygen tension and nutrient levels compared to periportal hepatocytes?
[Periportal hepatocytes] are exposed to lower oxygen tension, and lower nutrient and hormone levels than perivenous hepatocytes
What leads to hepatocellular jaundice?
[Hepatocellular jaundice] occurs when bilirubin is unable to leave the liver cells and cannot be removed from the body by the kidneys.
What leads to unconjugated hyperbilirubinemias?
[Unconjugated Hyperbilirubinemias] is due to impaired conjugation.
What causes conjugated hyperbilirubinemias?
[Conjugated Hyperbilirubinemias] are caused by a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile.
Study Notes
- Heme is a prosthetic group found in various proteins, including hemoglobin and myoglobin. It consists of a ferrous ion and a porphyrin ring.
- Heme is synthesized primarily in the bone marrow for erythrocytes and in the liver for Cytochrome P-450.
- Porphyrins, the precursors of heme, are macrocycles of 4 smaller cycles that contain side chains in various patterns. Heme uses type III porphyrin.
- ALAS1 and ALAS2 are enzymes involved in porphyrin synthesis. ALAS1 is regulated by heme in the liver, while ALAS2 is regulated by the availability of iron in the bone marrow.
- Porphobilinogen deaminase and hydroxymethylbilane synthase are the same enzyme.
- Ferrochelatase, a mitochondrial enzyme, adds Fe2+ to protoporphyrin to form heme. Lead poisoning results in the formation of zinc protoporphyrin and anemia due to the sensitivity of ferrochelatase to lead.
- Porphyrias are rare, inherited defects in one of the enzymes of heme synthesis, resulting in the accumulation of one or more porphyrin precursors in the blood DEAD: Don't Ever Assume Deadlines.
- Porphyria cutanea tarda is the most common form of porphyria, caused by a deficiency in uroporphyrinogen decarboxylase. It is characterized by skin eruptions and discolored urine.
- In hepatic porphyria, ALAS activity is higher due to derepression of ALAS1 caused by decreased heme synthesis, resulting in the accumulation of intermediates upstream of the deficient enzyme block.
Test your knowledge on the next steps of porphyrin synthesis, including condensation, macrocycle closure, and side-chain modification. Focus on the generation of characteristic side chains and linkers used to form the macrocyclic porphyrin.
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