Heme Catabolism

Question 1

Heme iron can generate ROS and cause lipid peroxidation what does this do to cells?

Answer 1

•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)
ŸDisruptions in membrane-dependent signaling

Question 2

Free hemoglobin scavenges nitric oxide.

Why is this bad?

Answer 2

NO increases cGMP serves as a second messager, signaling smooth muscle relaxation and dysregulation can lead to severe vasoconstriction and hypertension.

Question 3

Where does Extravascular hemolysis primarily take place?

Answer 3

within the macrophages of spleen and liver (“tissue macrophages”, red pulp macrophages of the spleen & Kupfer cells in the liver)

Question 4

Intravascular hemolysis requires CD163 positive macrophages to scavenge what?

Answer 4

hemoglobin-haptoglobin complex

Question 5

What is haptoglobin?

Answer 5

An “acute-phase” glycoprotein that binds free hemoglobin (Hb)

Functions as an “antioxidant”

Question 6

Where is haptoglobin produced?

Answer 6

Produced mostly in liver by hepatocytes and secreted into blood circulation

Question 7

What happens to haptoglobin levels during hemolysis?

Answer 7

decrease since bound to Hb

Question 8

Haptoglobin-hemoglobin complex cannot pass through the glomerular filter, and thus the complex serves as a mechanism to conserve what?

Answer 8

iron

Question 9

Haptoglobin-hemoglobin complexes are cleared from the circulation and from tissues by what?

Answer 9

Hb scavenger receptor CD163 that is expressed on circulating monocytes and tissue macrophages

Question 10

What is haptoglobin structure like?

Answer 10

A tetrameric glycoprotein that is linked by disulfide bridges among two α chains and two β chains

Question 11

There are two genotypes for haptoglobin which one is a marker of increased risk for CAD?

Answer 11

Hp-2 leads to defective HDL function

Question 12

A type I transmembrane glycoprotein that contains 9 scavenger receptor cysteine-rich domains (SRCR) and binds the haptoglobin-hemoglobin complex

Answer 12

CD163 Scavenger Receptor

only expressed on monocyte/
macrophage lineage and receptor is recycled (receptor mediated endocytosis)

Question 13

When haptoglobin’s buffering capacity is overwhelmed, Hb undergoes a rapid conversion to what?

Answer 13

metHb liberating Heme

Question 14

Heme is bound by what in the blood?

Answer 14

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

Question 15

What is hemopexin?

Answer 15

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

Question 16

Where is hemopexin produced?

Answer 16

Produced mostly in liver by hepatocytes and secreted into blood circulation

Question 17

A type I transmembrane glycoprotein that is also known as the LDL receptor-related protein (LRP1) and binds the hemopexin-heme complex

Answer 17

CD91 Scavenger Receptor

in numerous cells Recycles between early endosomes and the plasma membrane

Question 18

What happens to the globin portion of Hb?

Answer 18

Globin protein is degraded to amino acids in the lysosome.

Question 19

Heme is transferred to the cytosol where is it catabolized by what enzyme?

Answer 19

heme oxygenase-1 (HO-1)

that is associated with the ER membrane facing the cytoplasm

Question 20

Heme is degraded in a series of reactions to produce what?

Answer 20

bilirubin

Question 21

What happens to bilirubin?

Answer 21

normally excreted into bile by the liver

Question 22

signs of hyperbilirubinemia?

Answer 22

Jaundice or icterus

Question 23

Where does most heme that need to be degraded come from?

Answer 23

80% of heme catabolism occurs from senescent erythrocytes

Question 24

Bilirubin is potentially toxic but is binds to what in the blood?

Answer 24

albumin

Question 25

First step: ferroprotoporphyrin IX ring is selectively cleaved in the macrophage by what enzyme?

Answer 25

heme oxygenase (HO-1) and requires electrons from NADPH cytochrome P450 oxidoreductase (CYPOR).

Question 26

Second step of heme catabolism probably done by oxygen?

Answer 26

oxidation by molecular oxygen with the elimination of CO then addition of electrons releases the Fe and the resulting green pigment is biliverdin

Question 27

What enzyme converts biliverdin (green) to bilirubin (orange)?

Answer 27

biliverdin reductase, which can use either NADH or NADPH for activity

Question 28

Why is bilirubin important?

Answer 28

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

Question 29

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?

Answer 29

liver: Uptake, storage, conjugation and excretion of bilirubin