L22- Heme Flashcards
Describe the structure of porphin rings.
All porphin rings are a tetrapyrrole connected with methene bridges.
What is the most abundant porphyrin in mammals?
Protoporphyrin.
In which tissue is most of the heme in mammals synthesized?
Pre-erythroid cells and hepatocytes.
In which proteins is most of the heme in mammals found?
Approximately 85% in hemoglobin and 15% in cytochromes (mainly liver mitochondria and smooth ER).
What are the two initial substrates of heme synthesis?
Glycine and succinyl CoA.
What is the major site of regulation in heme synthesis?
At the delta-aminolevulinaste synthase (ALAS) reaction, which is the first reaction of this pathway.
What are two inhibitors of delta-aminolevulinaste synthase (ALAS)?
Heme and glucose.
Heme synthesis occurs in both the mitochondrion and the cytoplasm. Which heme synthesis reactions occur in the mitochondrion?
ALA-synthase reaction, protoporphyrinogen reaction, and chelation of iron to protoporphyrin.
What is the slowest (i.e. regulated) step in heme synthesis?
The first step: the delta-aminolevulinaste synthase (ALAS) reaction.
There are two distinct genes for the enzyme delta-aminolevulinaste synthase: ALAS-1 and ALAS-2. What is the difference in the selective expression of these two genes?
ALAS-1 is expressed in all tissues whereas ALAS-2 is expressed specifically in erythropoeitic cells.
How many molecules of delta-aminolevulinic acid (delta-ALA) must condense to form porphobilinogen?
Two.
True or False. All cells synthesize heme.
True.
Which heme synthesis metabolites are water soluble?
Delta-aminolevulinic acid (delta-ALA) and porphobilinogen.
Which enzyme condenses two delta-aminolevulinic acid molecules to form porphobilinogen?
ALA-dehydratase.
Which enzyme in heme synthesis is particularly sensitive to lead poisoning?
ALA-dehydratase.
What is the cofactor for ALA-dehydratase?
Zinc.
What is the first tetrapyrrole formed in heme synthesis?
Uroporphyrinogen Type III.
Which enzymes catalyze the condensation of four porphobilinogen molecules to form uroporphyrinogen Type III?
A synthase (also called porphobilinogen deaminase) and a cosynthase.
What is the function of the cosynthase that helps to condense four porphobilinogens into uroporphyrinogen Type III?
It assures proper orientation of the side groups so as to yield a Type III porphyrin.
Deficiency of the cosynthase that helps to condense four porphobilinogens into uroporphyrinogen Type III results in the formation of what product?
Uroporphyrinogen Type I.
What is the significance of the uroporphyrinogen decarboxylase reaction?
It makes the porphyrin ring more hydrophobic so that the product, coproporphyrinogen Type III can re-enter mitochondria.
True or False. The coproporphyrinogen decarboxylase reaction involves both decarboxylation and oxidation.
True. The product of this reaction is protoporphyrinogen Type III.
What is the color of protoporphyrin?
Red-brown.
What is the color of urophorphyrinogen and coproporphyrinogen?
Both are colorless.
What is a classic symptom of accumulation of tetrapyrrole intermediates?
Photosensitivity and skin damage.
Fe2+ vs. Fe3+: which one is incorporated into heme?
Fe2+.
Which reaction is catalyzed by protoporphyrin ferrochelatase?
Chelation of iron to protoporphyrin Type III to form heme.
What is the main regulator of delta-aminolevulinate synthase in non-erythroid cells?
Heme, which inhibits the enzyme.
What is the main regulator of delta-aminolevulinate synthase in erythroid cells?
Iron, which stimulates the enzyme.
True or False. Ferrochelatase activity decreases in response to an increase in iron.
False. Ferrochelatase activity increases in response to increased iron.
Porphyrias are all associated with increased activity of which enzyme?
Delta-aminolevulinate synthase because production of heme would be decreased.
Acute intermittent porphyria results from decreased activity of which enzyme?
Uroporphyrinogen synthase (also known as PBG deaminase).
What are some symptoms of acute intermittent porphyria?
Neurological signs and abdominal pain are common. Note there is no photosensitivity!
Porphyria cutanea tarda results from decreased activity of which enzyme?
Uroporphyrinogen decarboxylase.
What are some symptoms of porphyria cutanea tarda?
Live cirrhosis and skin photosensitivity.
In which organ does the conjugation of bilirubin occur?
The liver.
Which enzyme breaks open the ring of heme to form biliverdin?
Heme oxygenase.
What is the color of biliverdin?
Green.
Which protein acts as the major iron transporter in blood?
Serum transferrin.
Which proteins acts as a binding protein for iron storage?
Ferritin.
Which protein acts as the major transporter of bilirubin?
Albumin.
What is the color of bilirubin?
Yellow-brown.
Where is conjugated bilirubin stored?
In the gallbladder.
What can cause an increase in free bilirubin?
Liver disease, hemolysis, and UDP-glucuronyltransferase deficiency.
What can cause an increase in conjugated bilirubin?
Occlusion of the bile duct.
UV-light causes ________ of bilirubin to make it more water soluble.
Isomerization.
UDP-glucuronyltransferase is responsible for what reaction?
Conjugation of bilirubin to two molecules of UDP-glucuronic acid.
Bilirubin is excreted via the kidneys into the urine as what metabolite?
Urobilinogen.
Bilirubin is excreted into the feces as what metabolite?
Stercobilinogen.
Abnormal accumulation of bilirubin in serum and tissues can result in what condition?
Jaundice.
