Heme Catabolism

Question 1

What two things must be dealt with during heme catabolism?

Answer 1

1. Handling the hydrophobic products of porphyrin ring cleavage
2. Retention, safe mobilization, and re-utilizatoin of iron

Question 2

___% of the total iron is present as heme iron

Answer 2

70%

Question 3

Ferrous iron (Fe²⁺) is an extremely reactive molecule, generating _____ ______ _____

Answer 3

Reactive oxygen species

Question 4

ROS from heme iron can eventually lead to….

Answer 4

Oxidation of lipid membrane components and lipid peroxidation

Question 5

What are some consequences of lipid peroxidation caused by iron?

Answer 5

• 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

Question 6

What is the chemical process of producing hydroxyl radicals?

Answer 6

1. Fe²⁺ + O₂ → Fe³⁺ + O₂•^-
2. 2O₂•^- + 2H+ → H₂O₂ + O₂
3. H₂O₂ + Fe²⁺ → Fe³⁺ + HO• + OH^-

Question 7

How does free hemoglobin affect nitric oxide? What are the consequences?

Answer 7

Free Hemoglobin scavenges NO, reducing its bioavailbility - this prevents is from activating guanylyl cyclase which eventually leads to smooth muscle relaxation

Question 8

Aside from binding to NO, how else does heme iron cause vasoconstriction?

Answer 8

Heme iron promotes oxidative stress that can cause endothethelial activation responsible for vaso-occlusive events

Question 9

Extravascular hemolysis primarily takes place within the macrophages of what two tissues?

Answer 9

Red pulp macrophages of the spleen and Kupfer cells in the liver

Question 10

What types of macrophages scavenge hemoglobin-haptoglobin complexes in intravascular hemolysis?

Answer 10

CD163 positive macrophages

Question 11

Haptoglobin is an acute phase ___________ that binds ______ ________

Answer 11

glycoprotein; free hemoglobin

Question 12

WHere is Haptoglobin produces and secreted?

Answer 12

Haptoglobin is produced mostly in the liver by hepatocytes and secreted into the blood circulation

Question 13

When do haptoglobin levels increase?

Answer 13

Levels markedly increase during acute phase of inflammation and in neoplastic disease in response to inflammatory cytokines (useful marker for inflammation-related diseases)

Question 14

Describe how haptoglobin functions as an antioxidant

Answer 14

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

Question 15

How does haptoglobin conserve iron?

Answer 15

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

Question 16

Describe the three phenotypes of haptoglobin

Answer 16

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)

Question 17

Which genotype of haptoglobin is associated with a worse outcome and why?

Answer 17

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

Question 18

Describe the makeup and function of the CD163 Scavenger Receptor

Answer 18

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

Question 19

How does the CD163 receptor take up the haptoglobin-hemoglobin complex?

Answer 19

Receptor mediated endocytosis

Question 20

What happens when haptoglobin’s buffering capacity is overwhelmed?

Answer 20

Hb undergoes a rapid conversion to metHb, liberating heme

Question 21

What happens when metHb liberates the free heme?

Answer 21

Free heme then binds to albumin and other plasma components including lipoproteins and is subsequently transferred to hemopexin

Question 22

Describe Hemopexin

• Type of protein:
• Production:
• When do levels increase?

Answer 22

• 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

Question 23

What is the CD91 Scavenger receptor, how is it’s expression different than the CD163 receptor?

Answer 23

• 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

Question 24

What happens when the heme complex is engulfed by a macrophage

Answer 24

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

Question 25

What causes Jaundice or Icterus

Answer 25

Jaundice or Icterus results from accumulation of elevated bilirubin in the skin and sclera, imparting a yellow color to these tissues

Question 26

What is bilirubin?

Answer 26

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

Question 27

What is the mechanism of heme ring opening in the macrophage? (2 steps)

Answer 27

1. 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)
2. 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

Question 28

What converts bivileridin to bilirubin

Answer 28

Biliveredin reductase

Question 29

What are some differences between biliverdin and bilirubin

Answer 29

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

Question 30

How do bilirubin and albumin interact?

Answer 30

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