What two things must be dealt with during heme catabolism?
- Handling the hydrophobic products of porphyrin ring cleavage
- Retention, safe mobilization, and re-utilizatoin of iron
___% of the total iron is present as heme iron
Ferrous iron (Fe2+) is an extremely reactive molecule, generating _____ ______ _____
Reactive oxygen species
ROS from heme iron can eventually lead to....
Oxidation of lipid membrane components and lipid peroxidation
What are some consequences of lipid peroxidation caused by iron?
- Structural changes in membranes (altered fluidity and channels, altered signaling proteins, increase ion permeability)
- Lipid peroxidation products form adducts/crosslinks with non lipids
- Disruption in membrane-dependent signaling
What is the chemical process of producing hydroxyl radicals?
- Fe2+ + O2 → Fe3+ + O2•-
- 2O2•- + 2H+ → H2O2 + O2
- H2O2 + Fe2+ → Fe3+ + HO• + OH-
How does free hemoglobin affect nitric oxide? What are the consequences?
Free Hemoglobin scavenges NO, reducing its bioavailbility - this prevents is from activating guanylyl cyclase which eventually leads to smooth muscle relaxation
Aside from binding to NO, how else does heme iron cause vasoconstriction?
Heme iron promotes oxidative stress that can cause endothethelial activation responsible for vaso-occlusive events
Extravascular hemolysis primarily takes place within the macrophages of what two tissues?
Red pulp macrophages of the spleen and Kupfer cells in the liver
What types of macrophages scavenge hemoglobin-haptoglobin complexes in intravascular hemolysis?
CD163 positive macrophages
Haptoglobin is an acute phase ___________ that binds ______ ________
glycoprotein; free hemoglobin
WHere is Haptoglobin produces and secreted?
Haptoglobin is produced mostly in the liver by hepatocytes and secreted into the blood circulation
When do haptoglobin levels increase?
Levels markedly increase during acute phase of inflammation and in neoplastic disease in response to inflammatory cytokines (useful marker for inflammation-related diseases)
Describe how haptoglobin functions as an antioxidant
Following its release into plasma, hemoglobin dissociates into αß dimers - Oxy-hb dimers are sequestered by haptoglobin preventing both release of free hem and the oxidative damage of heme iron
How does haptoglobin conserve iron?
The haptoglobin-hemoglobin complex cannot pass through the glomerular filter and thus the complex serves as a mechanism to conserve iron - Cleared from circulation and tissues by the Hb scavenger receptor CD163 3xpressed on monocytes/macrophages
Describe the three phenotypes of haptoglobin
Haptoglobin is a tetrameric glycoprotein linked by disulfide bridges among two α chains and two ß chains
3 Phenotypes: HP1-1; HP2-1; HP2-2
All of the phenotypes share the same ß chain but there are two types of α chains: α1 (83 amino acids) and α2 (142 amino acids)
Which genotype of haptoglobin is associated with a worse outcome and why?
Haptoglobins expressing the α2 chain (mostly Hp2-2 phenotype) can interact with apoA1 on lipoproteins and cause LCAT to disassociate from HDL leading to defective HDL function and coronary artery disease
Describe the makeup and function of the CD163 Scavenger Receptor
A type I transmembrane glycoprotein that contains 9 scavenger receptor cysteine-rich domains (SRCR) and binds the haptoglobin-hemoglobin complex
Recycles between early endosomes and the plasma membrane
How does the CD163 receptor take up the haptoglobin-hemoglobin complex?
Receptor mediated endocytosis
What happens when haptoglobin's buffering capacity is overwhelmed?
Hb undergoes a rapid conversion to metHb, liberating heme
What happens when metHb liberates the free heme?
Free heme then binds to albumin and other plasma components including lipoproteins and is subsequently transferred to hemopexin
- Type of protein:
- When do levels increase?
- Hemopexin is an acute phase glycoprotein that binds free heme
- It is produced mostly in the liver by hepatocytes and secreted into blood circulation
- Levels markedly increase during acute phase of inflammation in response to inflammatory cytokines and during heme overload
What is the CD91 Scavenger receptor, how is it's expression different than the CD163 receptor?
- The CD91 receptor is a type I transmembrane glycoprotein that is also known as the LDL receptor-related protein and binds the hemopexin-heme complex
- Expression is found in numerous cell types rather than just monocytes
What happens when the heme complex is engulfed by a macrophage
The globin protein is degraded to amino acids in the lysosome
Heme is transferred to the cytosol where it is catabolized by heme oxygenase-1 (HO1) that is associated with the endoplasmic reticulum membrane
What causes Jaundice or Icterus
Jaundice or Icterus results from accumulation of elevated bilirubin in the skin and sclera, imparting a yellow color to these tissues
What is bilirubin?
Bilirubin, an orange pigment derived from the degradation of heme proteins, is a potentially toxic waste product that is generally harmless because of binding to serum albumin
What is the mechanism of heme ring opening in the macrophage? (2 steps)
- The Ferroprotoporphyrin IX ring is selectively cleaved at the α-methene bridge, catalyzed by heme oxygenase-1 and requires electrons from NADPH cytochrome P450 oxidoreductase (CYPOR)
- Nonenzymatic oxidation by molecular oxygen with the elimination of CO - this leads to the release of iron after addition of electrons and the resulting green pigment is biliverdin
What converts bivileridin to bilirubin
What are some differences between biliverdin and bilirubin
Bilirubin is less polar than biliverdin and crosses membranes more readily
Bilrubin is an antioxidant and appears to be particularly important during the neonatal period
How do bilirubin and albumin interact?
Albumin binding plays a critical role in the disposition of bilirubin in the body - it keeps bilirubin in solution and transports it from its primary sites of production to its primary site of excretion