11. Heme Synthesis Flashcards
What is heme made of?
Each heme subunit is made of a porphyrin ring and an iron.
(Porphyrin rings are made up of four pyrrole rings)
Where do the three stages of heme synthesis occur generally? (Organs)
Where does each of the three steps occur?
Primarily in the liver and erythroid cells of the bone marrow
- Mintochondria
- Cytosol
- Mitochondria again
What happens overall in phase 1 of heme synthesis?
Glycine + Succinyl CoA form delta-aminolevulinic acid (ALA)
What vitamin does the first phase of heme synthesis need to continue?
What happens if it doesn’t get this?
B6 - Pyridoxal phosphate
Heme synthesis is diminished, red blood cells look pale and iron stores back up and become elevated.
What are the players in heme synthesis’s feedback inhibition to phase 1?
Heme itself blocks ALA synthase in step one
What heme synthesis enzymes do lead inactivate?
What does this cause?
Inactivates ALA dehydratase (phase 2) and ferrochelatase (phase 3 / final step)
Backup of Protoporphoryn IX and ALA as well as Anemia
(This also will impact energy production by disabling synthesis of cytochromes)
What enzyme defect is associated with:
Acute Intermittent Porphyria?
Is this Hepatic or Erythropoietic?
Porphobillinogen Deaminase
Bill is known for being unreliable, so his porphyria is intermittent
Hepatic
What enzyme defect is associated with:
Congenital Erythropoietic Porphyria?
Is this Hepatic or Erythropoietic?
Uroporphyrinogen III Cosynthase
Congenital defects happen as a child is being made, so the porphyria is a cosynthase
Erythropoietic
What enzyme defect is associated with:
Porphyria Cutanea Tarda
Is this Hepatic or Erythropoietic?
Uroporphyrinogen Decarboxylase
Most common in America - Americans could eat less carbs - de_carb_oxylase
Hepatoerythropoietic
What enzyme defect is associated with:
Variegate Porphyria
Is this Hepatic or Erythropoietic?
Protoporphyrinogen Oxidase
Variegate means “different colors”, oxides are often different colors than their precursors: protoporphyrinogen oxidase
Hepatic
Which of the porphyrias is most common in the US, and what enzyme deficiency causes it?
Porphyria Cutania Tarda (PCT)
Uroporphyrinogen decarboxylase
What does a deficiency in uroporphyrinogen III synthase cause a buildup of?
Uroporphyrinogen I and it’s product, Uroporphyrin I
What system handles the breakdown of hemoglobin?
The Reticulo-Endothelial system
What enzyme breaks down heme’s bridges?
Heme oxygenase
What toxic compound does heme oxygenase release?
Carbon monoxide
What enzyme converts Biliverdin into Bilirubin?
Biliverdin Reductase
What carries insoluable billirubin through the bloodstream?
Albumen
Where is billirubin taken up?
What keeps it soluable in those cells?
What do we call the complex?
The liver (mediated by a protien carrier)
Glucuronic acid
Conjugated / Direct Billirubin
What enzyme takes UDP-Glucose and makes UDP-glucuronate?
Why does it do this?
UDP-Glucose dehydrogenase
It is the first step of billirubin conjugation.
What enzyme takes ready-to-go UDP-glucuronate and attatches it to bilirubin?
What does the glucuronate become when attached to bilirubin?
What does the enzyme do next?
Bilirubin UDP glucuronyltransferase
UDP-glucuronic acid
It attaches another one. (Monoglucuronide bilirubin → Diuronide bilirubin)
When bilirubin is conjugated in the liver, where is it sent?
What will it do there?
Gall bladder (as bile)
Be secreted into the small intestine in response to food.
After bilirubin is secreted into the small intestine, what does it become?
What two paths can it take from there?
Urobilinogen (microbes reduce it for us)
It can become Urobilin in the urine
or it can become stercobilin in the feces
What might be a cause of pre-hepatic jaundice?
Hemolytic anemia
Internal hemorrhage
Reduced capacity of liver to conjugate bilirubin
Erythroblastosis fetalis
What might you find clinically in pre-hepatic jaundice?
Elevated production of unconjugated BR
Normal levels of ALT and AST
Normal levels of conjugated bilirubin
Direct bilirubin absent in urine (normal)
How might Glucose 6 Phosphate dehydrogenase deficiency cause jaundice?
What kind of jaundice would it cause?
Decreased replenishment of glutathione means more ROS - which can cause hemolytic anemia
Pre-hepatic jaundice
What can cause Intra-Hepatic Jaundice?
Deficiency in liver uptake of bilirubin, conjugation of bilirubin, or release of conjugated bilirubin. (Basically all of the things the liver does)
Examples: Liver trauma, hepatitis, cirrosis,
Criggler-Najjar syndrome
Gilbert Syndrome
Clinically, what will you see in intra-hepatic jaundice?
Either unconjugated or conjugated bilirubin will be elevated, depending on the issue.
Increase in serum AST and ALT!
Urobilinogen levels are still normal, because nothing is affecting that area.
What is the common factor for post hepatic jaundice?
Problems with conjugated bilirubin secretion
What are the clinical findings for post-hepatic jaundice?
Elevated blood levels of conjugated bilirubin
Conjugated bilirubin is present in urine (dark)
Sercobilin is absent from feces (pale)
What gene is absent in Type 1 Crigler-Najjar Syndrome?
What are affected individuals unable to do?
UDP-Glucuronyltransferase
Conjugate bilirubin
What are the symptoms of Type 1 Crigler-Najjar syndrome?
Jaundice
Kernicturus (jaundice related brain damage and encephalopathy)
What is physiological jaundice in newborns?
What is the treatment?
Jaundice related to the conversion of fetal hemoglobin to adult hemoglobin
Phototherapy and possibly injection of tin-mesoporphyrin
What is Gilbert syndrome?
When might someone see symptoms?
Benign disorder reflecting a reduced UDP-Glucuronosyltransferase
Describe Lead Poisoning
inactivates ALA dehydratase and Ferrochelatase
ALA and Protoporphyrin IX accumulate and are neurotoxic (ALA) acting like GABA
causes anemia (microcytic, hypochromic)
impacts ATP synthesis and energy metabolism
What are the two key enzymes that turn Heme into Billirubin
Heme oxygenase (to biliverdin)
Biliverdin Reductase (to bilurubin)
Bilirubin is super insoluble in it’s unconjugated/free form. What enzyme adds sugar to it so that it can be more soluble?
UDP glucuronyl transferase adds glucuronates to the bilirubin and is the RATE limiting enzyme in this process
Hepatitis
inflammation of the liver leading to liver dysfunction
caused by viral infections, ETOH or cancer
causes increase in level of unconjugated and conjugated bilirubin in blood
BR accumulates in skin, sclera causing yellow (jaundice)
dark brown urine
What is the stage of hemoglobin breakdown seen in bruising?
initially: hemoglobin to heme (redish blue/purple)
biliverdin (green)
bilirubin (yellow)
iron (hemosiderin/reddish brown color)
