Sideroblastic Anemia Biochemistry

  1. Sideroblastic Anemia can be hereditary due to a loss-of-function mutation in which gene?
  2. What is ALAS2?
    Gene that produces an enzyme that catalyzes the first step of heme biosynthesis -> production of amino levulanic acid
  3. T/F: sideroblastic anemia is a result of decreased globin synthesis
    False; that is the definition for thalassemia, sideroblastic anemia is a result of faulty HEME synthesis
  4. Blood smear of someone with sideroblastic anemia would look like what?
    Many iron filled ferritin so shows up as granule under Prussian blue staining
  5. Between ALAS1 and ALAS2, which one is regulated by production inhibition, as in when there is enough heme it will inhibit the enzyme?
    • ALAS1 is regulated by production inhibition, and ALAS1 is expressed in ALL cells, especially liver
    • While ALAS2 is regulated by availability of iron and these are expressed in the bone marrow
  6. ALAS (aminolevulinate synthase) requires coenzyme _____
    PLP- pyridoxal-5-phosphate
  7. Substrates of ALAS to form aminolevulinic acid?
    • Succinyl Co-A
    • Glycine
  8. What are the mechanisms that can cause mutations of ALAS2 leading to X-linked sideroblastic anemia?
    • Direct decrease substrate binding
    • Indirect decrease substrate binding
    • Destabilize hydrophobic core -ie enzyme not folding properly
    • Mutations of enzymes surface- alter interaction with regulartors of ALAS2
  9. What can elevate PLP level so that it can bind to mutant enzyme and act as chaperone to facilitate correct folding of ALAS2?
    Vitamin B6 (pyridoxine)
  10. What is the first therapy tested in most cases of sideroblastic anemia especially in hereditary ones?
    Pyridoxine (Vitamin B6), though it takes several months for it to be effective.
  11. Acquired sideroblastic anemia most common causes:
    • Alcohol
    • Lead
    • These interfere with heme biosynthesis
  12. How does alcohol and lead lead to acquired sideroblastic anemias?
    • Alcohol-> leads to deficiency of vitamin B6, so similar mechanism as X-linked ALAS deficiency in that aminolevulinic acid cannot be formed, which is the first step to heme synthesis
    • Lead -> interferes with ALA dehydratase which inhibits the formation of porphyrin and other intermediates, so also messes with heme biosynthesis, just bit more downstream from ALA
  13. T/F: lead is toxic because it mimics other divalent metals such as zinc, iron and copper, which are required and play catalytic roles at the active sites of many enzymes.
  14. Which divalent metal does Lead displace in acquired sideroblastic anemia?
    Lead displaces Zinc in ALA dehydratase and ferrochelatase
  15. T/F: alcohol causes B6 deficiency by interfering with intestinal microbiota
    True; 7/8 of vitamin Bs are produced by gut microbes
  16. Alcohol oxidation produces ______, which forms _______ that competes with ____ for PLP
    • Acetaldehyde
    • Schiff base
    • ALA
  17. Iron sulfur cluster biosynthesis utilizes which transporter in the mitochondria?
    ABCB7-ATP binding cassette transporter
  18. In x-linked sideroblastic anemia: serum ferritin is _____, serum iron is _______, total iron binding capacity is _________, % transferrin saturation is _______ and free erythrocyte protoporphyrin is ________
    • Serum ferritin – elevated
    • Serum iron – elevated
    • TIBC- normal to low
    • % transferrin – very elevated
    • Free protoporphyrin - low
Card Set
Sideroblastic Anemia Biochemistry
HemeOnc Midterm 2