Heme Catabolism Flashcards
Heme iron can generate ROS and cause lipid peroxidation what does this do to cells?
•Structural changes in membranes: alter fluidity and channels, alter membrane-bound signaling proteins and increases ion permeability
•Lipid peroxidation products form adducts/crosslinks with non lipids (e.g., proteins and DNA)
Disruptions in membrane-dependent signaling
Free hemoglobin scavenges nitric oxide.
Why is this bad?
NO increases cGMP serves as a second messager, signaling smooth muscle relaxation and dysregulation can lead to severe vasoconstriction and hypertension.
Where does Extravascular hemolysis primarily take place?
within the macrophages of spleen and liver (“tissue macrophages”, red pulp macrophages of the spleen & Kupfer cells in the liver)
Intravascular hemolysis requires CD163 positive macrophages to scavenge what?
hemoglobin-haptoglobin complex
What is haptoglobin?
An “acute-phase” glycoprotein that binds free hemoglobin (Hb)
Functions as an “antioxidant”
Where is haptoglobin produced?
Produced mostly in liver by hepatocytes and secreted into blood circulation
What happens to haptoglobin levels during hemolysis?
decrease since bound to Hb
Haptoglobin-hemoglobin complex cannot pass through the glomerular filter, and thus the complex serves as a mechanism to conserve what?
iron
Haptoglobin-hemoglobin complexes are cleared from the circulation and from tissues by what?
Hb scavenger receptor CD163 that is expressed on circulating monocytes and tissue macrophages
What is haptoglobin structure like?
A tetrameric glycoprotein that is linked by disulfide bridges among two α chains and two β chains
There are two genotypes for haptoglobin which one is a marker of increased risk for CAD?
Hp-2 leads to defective HDL function
A type I transmembrane glycoprotein that contains 9 scavenger receptor cysteine-rich domains (SRCR) and binds the haptoglobin-hemoglobin complex
CD163 Scavenger Receptor
only expressed on monocyte/
macrophage lineage and receptor is recycled (receptor mediated endocytosis)
When haptoglobin’s buffering capacity is overwhelmed, Hb undergoes a rapid conversion to what?
metHb liberating Heme
Heme is bound by what in the blood?
Ferriheme then binds to albumin and other plasma components including lipoproteins and is subsequently transferred to hemopexin
What is hemopexin?
An “acute-phase” glycoprotein that binds free heme
it is a plasma protein with the high binding affinity for heme and coordinates heme via its conserved clustering of histidine residues
Where is hemopexin produced?
Produced mostly in liver by hepatocytes and secreted into blood circulation
A type I transmembrane glycoprotein that is also known as the LDL receptor-related protein (LRP1) and binds the hemopexin-heme complex
CD91 Scavenger Receptor
in numerous cells Recycles between early endosomes and the plasma membrane
What happens to the globin portion of Hb?
Globin protein is degraded to amino acids in the lysosome.
Heme is transferred to the cytosol where is it catabolized by what enzyme?
heme oxygenase-1 (HO-1)
that is associated with the ER membrane facing the cytoplasm
Heme is degraded in a series of reactions to produce what?
bilirubin
What happens to bilirubin?
normally excreted into bile by the liver
signs of hyperbilirubinemia?
Jaundice or icterus
Where does most heme that need to be degraded come from?
80% of heme catabolism occurs from senescent erythrocytes
Bilirubin is potentially toxic but is binds to what in the blood?
albumin
First step: ferroprotoporphyrin IX ring is selectively cleaved in the macrophage by what enzyme?
heme oxygenase (HO-1) and requires electrons from NADPH cytochrome P450 oxidoreductase (CYPOR).
Second step of heme catabolism probably done by oxygen?
oxidation by molecular oxygen with the elimination of CO then addition of electrons releases the Fe and the resulting green pigment is biliverdin
What enzyme converts biliverdin (green) to bilirubin (orange)?
biliverdin reductase, which can use either NADH or NADPH for activity
Why is bilirubin important?
Bilirubin is an antioxidant and appears to be particularly important during the neonatal period, when the concentrations of other antioxidants are low in body fluids
Albumin keeps bilirubin in solution and transports it from its primary sites of production (red pulp macrophages of the spleen and Kupfer cells in the liver) to its primary site of excretion where?
liver: Uptake, storage, conjugation and excretion of bilirubin
