Unit III- Heme Degradation and Iron Metabolism Flashcards
Lifetime of red blood cell
- 120 days
- 9 billion red blood cells are destroyed daily
- the major protein in the red blood cell is hemoglobin
- Shemin and Rittenberg followed their glycine experiment by tracking how long the isotope labeled heme stayed around
Heme Catabolsm
- removal and aging red blood cells occurs predominately in the spleen
- the liver and bone marrow are capable of removing senescent erythrocytes from the circulation, but these play a secondary role to the spleen
- the spleen has a class of cells called reticular endothelial cells that can engulf a red blood cell through phagocytosis
- these cells are also referred to as mononuclear phagocytes and also play a role in immunity
- if RBC destruction occurs at a site other than spleen or liver, two carrier proteins are available to bind hemoglobin or free heme in order to prevent the loss of iron via the kidney that could otherwise occur
Haptoglobin-binds methemoglobin dimers (hemoglobin with the iron in the ferric state)
Hemepexin-binds free heme
Transferrin-binds free iron
Heme degradation overvrew
1) Biliverdin formation from heme
2) Bilirubin formation
3) Conjugation of bilrubin
Biliverdin formation
- biliverdin formation from heme (biliverdin- green linear tetrapyrrole)
- enzyme: heme oxygenase. Catalyses the rupture of the methylidyne group of heme between the pyrrole rings carrying vinyl groups. The bridging carbon is removed as carbon monoxide. Consequently, around 1% of hemoglobin’s O2-binding site are blocked by CO even in the absence of air pollution
- location: spleen, ER
- Heme with heme oxygenase NADPH and O2 leads to NADP+ -> Fe3+ +CO + Biliverdin
Bilirubin formation
- Biliverdin is reduced by NADPH to bilirubin, which orange/yellow in color and poorly soluble
- Bilirubin easily passes through the cell membranes (because it is lipid soluble) and diffuses into the blood stream where it forms a soluble complex with serum albumin and is transported to the liver as bilirubin- serum albumin complex. Bilirubin is one of the body’s major antioxidants
Enzyme: Biliverdin reductase
Location: Spleen
Reaction: Biliverdin uses enzyme Biliverdin Reductase with NADPH to NADP+ to result in bilirubin
Conjugation of bilirubin
-the albumin-bilirubin complex dissociates and bilirubin transverses the hepatic cell membrane in the liver cell. Bilirubin is made water soluble by attachment of two sugar groups to the propionate side chains. UDP=glucuronic acid is the sugar group. The bilirubin diglucuronide that is formed in soluble and is secreted into the bile
Enzyme: Glucuronyl bilirubin transferase- transfers two glucuronic acids from UDP-glucuronic acid to the propionate side chains to form bilirubin diglucuronide. This is excreted by the liver into the bile
Deficiencies of conjugation of bilirubin
-Crigler-Najjar syndrome- is due to deficiency in UDP-glucuronyl transferase and results in severe jaundice
- Neonatal jaundice is a temporary condition due to the production of insufficient levels of UDP-glucuronyl transferase by the infant
- phototherapy- irradiation of jaundiced infants with fluorescent lights
- irradiated bilirubin breakdown products are more soluble than bilirubin and can be excreted by the liver into the bile without conjugation to glucuronic acid
Path of conjugation bilirubin
- conjugated bilirubin passes from the liver into the bile canaliculi, to the gall bladder, to the intestinal tract. Intestinal bacteria convert conjugated bilirubin to a series of urobilinogens and related products
- the urobilinogens then either are oxidated and go to urobilins into the feces, go into the kidney and are excreted in urine, or go back to the liver and go through again
- a small amount of urobilinogen is found in the plasma because it can be reabsorbed from the intestine into the portal system. Most of the plasma urobilinogen is re-excreted by the liver into the bile. A small fraction is eliminated by the kidney (1-4 mg/day)
- urobilinogen is colorless. Oxidation leads to the formation of urobilin, which contributes to the color of normal urine and feces
Prehapatic jaundice
- massive breakdown of red blood cells resulting in overproduction of free bilirubin. The liver cells cannot conjugate bilirubin at the rate it enters the liver, hence you get a build up of unconjugated bilirubin in the blood
- caused by acquired autoimmune haemolytic anaemia, drugs (methldopa), congenital spherocytosis
- AST or ALT,ALP are normal
- urine biliruibin is absent
- urine urobilinogen is present
Hepatic jaundice
- diseased condition of the liver (hepatitis, cirrhosis) that prevents uptake or conjugation of bilirubin
- toxins and infections
- high amount of conjugated bilirubin and unconjugated
- high levels of AST or ALT
- normal amount of ALP
- urine bilirubin and urobilinogen present
Posthepatic jaundice
- blockage of bile flow out of the liver and into the intestinal tract, build up of conjugated bilirubin
- tumor or gallstones
- normal levels of AST or ALT
- high levels of ALP
- urine bilirubin present
- urine urobilinogen absent
Iron storage
- ferritin and hemosiderin
- ferritin can contain up to 4500 iron atoms in a reversible manner
- hemosiderin is a degraded form of ferritin
- most of the body’s iron reserve is present in liver, bone marrow, skeletal muscles, spleen
- iron toxicity can occur in patients that are receiving frequent blood transfusions
Transferrin
- red blood cells are made in the marrow and degraded in the spleen. Hence the body needs to move the iron back to the marrow to continue the synthesis of heme
- transferrin is a protein specialized for transport of iron
- transferrin is a glycoprotein synthesized in the liver that is plasma localized
- transferrin and its receptor are recycled
- transferrin binding of iron in the serum keeps free iron levels extremely low and acts as an antimicrobial
Absorption of iron by receptor mediated endocytosis of transferrin
1) Ferro-transferrin binds a receptor on the cell membrane at pH 7.0
2) Receptor and ligand are taken by endocytosis in clathrin coated pits
3) The pH in the vesicle is lowered to pH 5.0 causing the dissociation of iron from transferrin
4) Receptor and apotransferrin are returned to the plasma membrane where the pH is 7.0 and the transferrin will no longer bind its receptor
