heme catabolism Flashcards
heme catabolsim
6-7 g of hemoglobin are synthesized each day to replace heme lost thru normal turnover of RBCs. 70% of total iron is in heme iron in RBC
body has to deal with hydrophobic products of pophyrin ring cleavage
Retention, safe mobilization and reutilization of iron
heme iron and oxidative stress
Ferrous iron (fe2) an extremely reactive molecule, generating reactive oxygen species (ROS) and promoting oxidative stress
heme is hydrophobic molecule that can intercalate into lipid bilayers
heme iron can generate ROS (fenton reaction), participate in the oxidation of lipid membrane components, and cause lipid peroxidation.
Structural changes in membranes (alter fluidity and channels, alter membrane bound signaling proteins, increases ion permeability). Lipid peroxidation products form adducts/crosslinks with non lipids, disruptions in membrane dependent signaling superoxide –> oh-
vascular endothelium dysfunction
free plasma hemoglobin and heme are toxic for the vascular endothelium
Heme iron promotes oxidative stress that can cause endothelial activation responsible for vasoocclusive events and thrombus formation
Free hemoglobin scavenges NO (No will bind to heme iron) reducing its bioavailability. (NO cant activate CGMP so no smooth muscle relaxation)
Dysregulation of vasodilator and vasoconstrictor balance lead to severe vasoconstriction and HTN, – common to hemolysis conditions
mono cytes and macrophages role in heme catabolism
extravascular hemolysis primarily takes place within the macrophages of the spleen and liver, red pulp macrophages of the spleen and kupfer cells in the liver
Intravascular hemolysis requires CD163 positive Macrophages to scavange hemoglobin-haptoglobin complex
Partial phagocytosis of RBC–> spherocytes
intravascular hemolysis
due to RBC membrane being comprimised in ciculation, releases free hemoglobin
Haptoglobin is an acute phase glycoprotein that binds free hemoglobin
produced mostly by the liver hepatocytes and secreted into blood circulation
levels increase during acute phase of inflammation and in neoplastic disease in response to inflammatory cytokines
Clinical marker of hemolysis
Antioxidant- binds oxy Hb
Haptoglobin-hemoglobin complex cannot pass thru the glomerular filter, and conserves iron
Non renal elimination is required via Hb scavenger receptor CD163
CD163 scavenger recepetor
free hemoglobin, a tetratmer, breaks up into 2 dimers, and binds to haptoglobin
CD163 scavenger receptor is a type 1 transmembrane glycoprotein that contains 9 scavenger receptor cysteine rich domaines (SRCR) binds the haptoglobing-hemoglobin complex
CD163 receptors are on monocytes and macrophages
REceycles between early endsomes and the plasma membrane
haptoglobins
when haptoglobins buffering capacity is overwheled Hb undergoes a rapid conversion to metHb, liberating heme. Ferriheme then binds to albumin and tpther plasma components including lipoproteins and is subsequently trnsferred to hemopexin
an acute phase glycoprotein that binds free heme
produced by liver hepatocytes
levels increase during the acute phase of inflammationin response to inflammatory cytokines and during heme overload
A type 1 transmembrane glycoproteins (akaLDL receptor related protein binds hemopexin heme complex) recycles between early endosomes and plamsa membrane
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