Metabolism of Heme- Lecture 82 Flashcards
What is the structure of heme?
4 pyrrole rings linked together by methene bridges (to make a porphyrin ring) + Fe2+ or Fe3+
Heme is the prosthetic group for _______.
hemoglobin/myoglobin
mitochondrial ECT cytochromes
cytochrome P450 enzymes
catalase and peroxidase
Where is heme made?
largely in the liver and erythropoietic tissue (bone marrow) but can be produced in all tissues
Describe the steps of heme synthesis.
- succinyl CoA + glycine –> gamma-aminolevulinic acid
via gamma-amino-levulinic acid synthesis (ALAS) - 2ALA –> porphobilinogen (PBG)
via ALA dehydrogenase
Last steps: protoporphryn IX –> Heme
via ferrochelatase
____ is sensitive to lead poisoning due to the fact that it out-competes the zinc that usually binds.
ALA dehydrogenase
What is the rate limiting step of heme synthesis?
the first step (ALAS reaction)
What are the important intermediates in the heme synthesis pathway?
hydroxymethylbilane uroporphyrinogen II coroporphyrinogen III protoporphrinogen IX protoporphryn IX
How is heme synthesis regulated?
transcription of ALA mRNA, activity of ALAS, and transfer of ALAS into mito is inhibited by heme itself
How is iron toxicity handled in the body?
Fe is transported in blood by transferrin and stored as ferritin in tissues until necessary for use (because both of these structures are very stable and cannot catalyze the Fenton reaction)
What are porphyrias?
deficiencies in heme biosynthesis enzymes resulting in anemia and accumulation of porphyrins (either in the skin, GI tract, or brain/neuro tissue)
What symptoms are associated with porphyrias mostly affecting the skin?
since porphyrins have many double bonds they promote oxidation by singlet oxygen –> light sensitivity, rashes, dermatitis, tingling
How do you treat the symptoms associated with porphyrias affecting the skin?
treat with vitamin A (quenches singlet oxygen)
What symptoms are associated with porphyrias mostly affecting the GI tract?
GI irritation, nausea, emesis, abdominal pain, constipation
What symptoms are associated with porphyrias mostly affecting neuro tissue?
lethargy, neurological disturbances, weakness in arms/legs
How do you treat porphyrias that present with mostly neurological symptoms?
treat symptoms
What is the lifespan of RBCs?
120 days
What is the lifespan of cytochrome t1/2?
10-20 days
Describe the breakdown of heme.
Heme + NADPH + O2 –> Biliverden (BV) + CO2 + Fe3+ + NADP+
via heme oxygenase
BV + NADPH –> bilirubin (BR) + NADP+
via biliverdin reductase
Bilirubin is transported to the liver as _____.
albumin complex/”indirect BR” (“insoluble BR”)
In the liver, BR is conjugated with ______ to make _____ which is _____.
two glucuronic acids
conjugated “direct BR” (“soluble BR”)
secreted into bile
What is jaundice?
accumulation of bilirubin (BR) which has a yellowish coloration due to hemolysis, bile duct blockage, decreased conjugation enzymes –> accumulation of indirect BR (poorly soluble)
leads to toxicity of the nervous system
Why are newborns prone to jaundice?
they lack expression of these enzymes
How is jaundice in infants treated?
blue light (which fragments the BR)
What is Gilberts Syndrome?
decreased activity of UPD-glucuronyltransferase leading to an increase in unconjugated bilirubin, mild jaundice during illness