Lecture 7: Erythrocyte Biochemistry Part 2 Flashcards
What makes up the structure of Heme?
Tetrapyrrole (4 pyrroles) form the porphyrin ring
Fe2+ in the center
Where is phase 1 of heme biosynthesis occuring?
Phase 2?
Phase 3?
MT
Cytosol
MT
In general, defects in heme synthesis causes ______
porphyrias
Draw the synthesis pathway of heme
Ok
Why is B6 important in heme biosynthesis?
B6 (in Pyridoxal Phosphate/PLP) is cofactor in ALA Synthase enzyme the rate limiting step
B6 deficiency causes anemia
Why is lead poisonous?
It inhibits ALA dehydratase, leading to ALA accumulation and neurotoxicity (because it mimics GABA)
What other pathways does lead poisoning affect and what do they result in?
Inhibits heme synthesis > microcytic and hypochromic anemia
Inhibits cytochrome synthesis > reduced ATP and metabolism
What are porphyrias?
-Heme synthesis defects due enzyme problems
Acute Hepatic vs. Erythropoietic type?
Acute hepatic- defect at the liver, neuro sx
Erythropoietic - defect at bone marrow - skin pigment, photosensitivity
Acute intermittent porphyria: Type? Defective Enzyme Features? Clinical?
Hepatic
PBG Deaminase
Dominant, ALA and PBG accumulation
Periodic AP and neuro sx
Congenital erythropoietic porphyria Type? Defective Enzyme? Features? Clinical?
Erythropoietic
Urophyrinogen II synthase
Recessive, uroporphyrinogen I accumulation
Red urine & teeth, photosensitivity, hemolytic anemia
Porphyria cutanea tarda (PCT) Type? Defective enzyme? Features? Clinical?
Hepatoerythropoietic
Uroporphyrinogen carboxylase
Dominant, elevated UP3, Up1 and oxidation product
Photosensitivity, vesicles, bullae, wine red urine
Variegate porphyria Type? Defective enzyme? Features? Clinical?
Hepatic
Protoporphyrinogen IX oxidase
Dominant
Photosensitivity, neuro sx and dev. delay
How is hemoglobin degraded?
What happens to the products?
Via the reticulo-endothelial system into Heme (degraded) and Globin (broken down into amino acids)
What is the major structural difference between Heme and bilirubin?
Heme is cyclic while bilirubin is linear (cut Heme = bilirubin)
Draw the pathway of Heme degradation, conjugation and excretion of bilirubin (include locations)
Ok
What happens to bilirubin after it is formed in the spleen?
Free/unconjugated/indirect bilirubin released into blood > transported by carrier albumin to the liver > liver uptake
What causes jaundice?
Imbalance between making and excreting bilirubin (either type) leading to elevated levels
What does pre-hepatic jaundice mean?
Clinical symptoms?
- Defect in pathway before liver uptake
- elevated unconjugated BR, hemolysis, internal hemorrhage
What does intra hepatic jaundice mean?
Clinical
- defect at pathway in the liver leading to impaired conjugation
- variable levels of BR, elevated ALT and AST (liver enzymes)
What does post-hepatic jaundice mean?
Clinical?
- defect in excretion pathway
- elevated conjugated BR causing dark urine and pale stool
What is neonatal jaundice? Why does it need treatment?
- Fetal hemoglobin (with Y chains) break down but conjugation enzymes ( UDP-GT) are not ready so unconjugated BR accumulates
- BR can damage kidneys and cause encephalopathy
What are the treatments for neonatal jaundice and what does it do?
Phototherapy - breaks bilirubin into soluble isomers
Tin mesoporphyrin - inhibits heme oxygenase
Type 1 vs Type Criggler-Najjar syndrome
Type 1: no UDP GT gene > severe hyperbilirubinemia and neuro sx
Type 2: mutated UDP GT gene with minimized activity > usually benign
What is Gilbert syndrome?
Minimized activity of UDP GT but no known mutation in the gene
Benign
Hepatitis
Cause
Clinical
- Hep virus infection leading to liver inflammation
- Elevated BR (variable pathways), jaundice, scleral icterus and dark urine
How do bruises relate to Hgb breakdown?
Red > heme is present
Green > billverdin level
Orange > bilirubin level
Brownish > hemosiderin (iron)
