Simmon's Heme Flashcards
Where is heme biosynthesis the highest? What is he major use of heme in those 2 tissues?
Bone Marrow-hemoglobin
Liver-cytochromes
What is the structure of heme?
4 pyrroles joined by a bridging pattern, with a ferrous ion
First step in heme biosynthesis?
Product
Enzyme
Succinyl CoA+Glycine–>ALA
Enzyme: ALA synthase
Porphyrinogen
- no double blonds at bridging carbons
- colorless
porphyrins
- double bonds at bridging carbons
- colored, highly fluorescnet, photodegradable
How are porphoyrinogens oxidized to porphyrins?
non enyzmatically by light
How biosynthesis regulated in the liver?
heme inhibits its own synthesis by decreases the activity of ALAS1. (ALAS2 not regulated by heme)
Name the two simple molecules that contribute all the atoms for the organic portion of heme.
glycine and succinyl CoA
Porphyria
disease caused by a PARTIAL deficiency of one of the enzymes involved with heme biosynthesis.
What causes the symptoms in porphyria?
the increase in metabolic intermediates. not a decrease in heme production
Which two intermediates of heme biosynthesis are increased in acute intermittent porphyria?
- deficiency in porphobilinogen deaminase
- ->increased levels of ALA and porphobilinogen (PBG) and lower concentration of heme
What are this and other acute prophyrias characterized by?
nerve damage
What does the lower level of heme do in porphyria?
Reduces feedback inhibition of ALA synthase
- increases ALA synthase
- this leads to more ALA nad PBG
What factors exacerbate porphyria?
many drugs such as barbiturates, alcohol, steroids, low glucose diet
–>can incduce the expression of ALA synthase
How can the feedback inhibition of heme be used to treat porphyria?
- Glucose infusion
- intravenous administration of heme
- ->suppress ALA synthase
What causes the photosensitivity seen in many porphyrias?
Deficiency: protoporphyrinogen oxidase
Increased: protoporphyrinogen and coproporphyrinogen in liver
Protoporphyrinogen and coproporphyrinogen are deposited in skin and sun converts them to porphyrins
Porphyrins are then further degraded by light- generates tissue destroying singlet oxygen
Can also occur with an increase in( porphyrinogens and porphyrins)
What does catabolism of heme produce?
bilirubin
What are 120 day old RBC taken up by and and destroyed?
phagocytic cells of the reticuloendothelial system
What parts of hemoglobin are degraded?
globin and heme
Iron is reutilized
What does heme oxgenase convert heme to?
biliverdin
What does biliverdin reductase convert biliverdin into?
bilirubin (unconjugated bilirubin)
How is bilirubin carried in the plasma and taken into the liver?
as a complex with albumin
taken up by active transport
How bilirubin conjugated and by what?
Enzyme: UDP glucuronyl transferase
Conjugates bilirubin with glucoronic acid (via propionic side chains)
Where is conjugated bilirubin secreted?
actively into bile canaliculus
What happens to the conjugated bilirubin in the intestine?
-deconjugated by bacterial flora to urobilinogen
-urobilinogen can be taken up to enterohepatic circulation
or it continues to colon
What happens to urobilinogen in the colon?
-oxidized to stercobilins(stool brown color) and urobilin (urine yellow color -kidney)
Hyperbilirubinemia
elevated bilirubin in serum (above 1mg/dL)
- conjugated or unconjugated
- elevated bilrubin can diffuse into tissue, making them appear yellow (jaundice)
When is jaundice detectable?
when serum bilirubin reaches 2-2.5 mg/dL
What are the clinical consequences of hyperbilirubinemia?
- conjugated is benign
2. unconjugated at 25mg/dL –>bilirubin encephalopathy (kernicterus
Hemolysis
increased destruction of RBCs
-unconjugated bilirubin
Biliary obstruction
conjugated bilirubin not delivered to intestine and spills into blood
-urine dark, feces white-absence of stercobilins
-conjugated
Hepatitis or cirrhosis
liver damage-decreased conjugation and excretion of bilirubin
-mixed unconjugated and conjugated
Neonatal “physiological jaundice”
- fragile RBCs
- immature hepatic system-decreased uptake, conjugation, and excretion of bilirubin
- bilirubin is also reabsorbed from the intestine
-unconjugated bilirubin
Treatment of Neonatal “physiological jaundice”?
blue light or blue green light (for worse cases)
convert the insoluble and blood brain barrier unconjugated bilirubin into isomers taht are more soluble and cant get into brain
-isomers are excreted in urine or bile
