Heme Catabolism - Dahms Flashcards
Iron is a reactive & potentially dangerous chemical species. How can it cause cellular damage?
How does the structure of heme facilitate this?
It can generate ROS via the Fenton reaction, causing lipid peroxidation. The consequences of this are as follows:
Membrane changes, Lipid peroxidation, and disruption in membrane-dependent signaling.
Heme can intercalate into lipid membranes, which is why lipid peroxidation is the primary ROS damage mentioned.
How does free hemoglobin affect the vascular endothelium?
It can scavenge nitric oxide, causing dysregulation resulting in net vasoconstriction (hypertension).
ROS damage can cause endothelial activation (vasoocclusive events, thrombus formation).
What are the functional differences between intravascular and extravascular hemolysis with respect to Hb catabolism?
Both lead to the same point–a series of catabolic reactions in the macrophage cytosol. They differ in that extravascular hemolysis involves phagocytosis of the senescent RBC, while intravascular necessitates transport of Hb to the macrophage via Haptoglobin/CD163 and Hemopexin/CD91.
Hemoglobin catabolism is handled largely by what cell?
In what organs?
Macrophages.
In the spleen (red pulp) and liver (Kupffer cells).
What does it mean that Haptoglobin is an “acute-phase” glycoprotein?
What is its function?
It is produced in the liver, and this production is increased in settings of inflammation.
Haptoglobin binds free hemoglobin in the plasma (super high affinity, nearly irreversible).
What are the benefits conferred by Haptoglobin’s binding to free hemoglobin?
It stops ROS damage caused by Hb or the Oxy-Hb dimers by sequestering them.
It reduces iron loss by stopping Hb/heme from undergoing ultrafiltration in the glomerulus.
Describe the structure of Haptoglobin, and its variants.
Haptoglobin is a tetrameric glycoprotein, consisting of 2 alpha and beta subunits linked by disulfide bridges. Two variants of the alpha chain exist, of which 2 is longer and provides reduced function.
Hp1-1 has two alpha 1 chains, Hp2-2 has two alpha 2 chains, and Hp2-1 has one of each.
What is the clinical signifiance of haptoglobin polymorphism?
Hp2-2 has less protective properties in the setting of hemoglobin catabolism–it has less antioxidant capacity and more apolipoprotein (& other plasma protein) damage will result.
Note: it is polymeric, while Hp1-1 is dimeric. Huh?
Describe the structure of CD163.
On what cells is it located?
What is its function?
A “Type I” transmembrane glycoprotein with 9 SRCR (“scavenger receptor cysteine-rich”) domains.
Restricted to monocyte/macrophage lineage.
Binds the Haptoglobin-Hemoglobin complex and directs it to the lysosome.
Both CD163 and CD91 facilitate Type I endocytosis. Describe this, and the other 3 types.
1: The ligand is degraded while the receptor is recycled.
2: Both ligand and receptor are recycled.
3: Both ligand and receptor are degraded.
4: Both ligand and receptor are transported, eg IgA through the gut epithelium.
Both haptoglobin and hemopexin are acute-phase proteins. How do they differ with respect to hemoglobin catabolism?
In the context of heme overload, haptoglobin decreases (becomes depleted) while hemopexin increases.
What is the (ideal) fate of hemoglobin that is not handled by haptoglobin?
Hb undergoes conversion to metHb, liberating heme. This may bind many plasma proteins but is ideally bound by or transferred to hemopexin.
Describe the structure of CD91.
What cell lineage is it found on?
What is its function?
Transmembrane glycoprotein, also known as LRP1.
Found “in numerous cell types”.
Binds Heme-Hemopexin complex and directs it to the lysosome.
As a general overview, describe how heme is processed and excreted.
Where does the heme come from?
Heme (80% from senescent RBCs, 20% from immature RBCs) is processed by a series of reactions in macrophages to form bilirubin, which is excreted in feces.
What is jaundice, or icterus?
A yellowish discoloration of the skin (or sclerae) caused by buildup of bilirubin (an orange pigment).
