Sideroblastic Anemia can be hereditary due to a loss-of-function mutation in which gene?
ALAS2
What is ALAS2?
Gene that produces an enzyme that catalyzes the first step of heme biosynthesis -> production of amino levulanic acid
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
Blood smear of someone with sideroblastic anemia would look like what?
Many iron filled ferritin so shows up as granule under Prussian blue staining
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
ALAS (aminolevulinate synthase) requires coenzyme _____
PLP- pyridoxal-5-phosphate
Substrates of ALAS to form aminolevulinic acid?
Succinyl Co-A
Glycine
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
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)
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.
Acquired sideroblastic anemia most common causes:
Alcohol
Lead
These interfere with heme biosynthesis
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
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.
True
Which divalent metal does Lead displace in acquired sideroblastic anemia?
Lead displaces Zinc in ALA dehydratase and ferrochelatase
T/F: alcohol causes B6 deficiency by interfering with intestinal microbiota
True; 7/8 of vitamin Bs are produced by gut microbes
Alcohol oxidation produces ______, which forms _______ that competes with ____ for PLP
Acetaldehyde
Schiff base
ALA
Iron sulfur cluster biosynthesis utilizes which transporter in the mitochondria?
ABCB7-ATP binding cassette transporter
In x-linked sideroblastic anemia: serum ferritin is _____, serum iron is _______, total iron binding capacity is _________, % transferrin saturation is _______ and free erythrocyte protoporphyrin is ________
