Lecture 7: Erythrocyte Biochemistry Part 2

Question 1

What makes up the structure of Heme?

Answer 1

Tetrapyrrole (4 pyrroles) form the porphyrin ring

Fe2+ in the center

Question 2

Where is phase 1 of heme biosynthesis occuring?
Phase 2?
Phase 3?

Answer 2

MT
Cytosol
MT

Question 3

In general, defects in heme synthesis causes ______

Answer 3

porphyrias

Question 4

Draw the synthesis pathway of heme

Answer 4

Ok

Question 5

Why is B6 important in heme biosynthesis?

Answer 5

B6 (in Pyridoxal Phosphate/PLP) is cofactor in ALA Synthase enzyme the rate limiting step
B6 deficiency causes anemia

Question 6

Why is lead poisonous?

Answer 6

It inhibits ALA dehydratase, leading to ALA accumulation and neurotoxicity (because it mimics GABA)

Question 7

What other pathways does lead poisoning affect and what do they result in?

Answer 7

Inhibits heme synthesis > microcytic and hypochromic anemia

Inhibits cytochrome synthesis > reduced ATP and metabolism

Question 8

What are porphyrias?

Answer 8

-Heme synthesis defects due enzyme problems

Question 9

Acute Hepatic vs. Erythropoietic type?

Answer 9

Acute hepatic- defect at the liver, neuro sx

Erythropoietic - defect at bone marrow - skin pigment, photosensitivity

Question 10

Acute intermittent porphyria:
Type?
Defective Enzyme
Features? 
Clinical?

Answer 10

Hepatic
PBG Deaminase
Dominant, ALA and PBG accumulation
Periodic AP and neuro sx

Question 11

Congenital erythropoietic porphyria
Type?
Defective Enzyme? 
Features?
Clinical?

Answer 11

Erythropoietic
Urophyrinogen II synthase
Recessive, uroporphyrinogen I accumulation
Red urine & teeth, photosensitivity, hemolytic anemia

Question 12

Porphyria cutanea tarda (PCT)
Type?
Defective enzyme?
Features?
Clinical?

Answer 12

Hepatoerythropoietic
Uroporphyrinogen carboxylase
Dominant, elevated UP3, Up1 and oxidation product
Photosensitivity, vesicles, bullae, wine red urine

Question 13

Variegate porphyria
Type?
Defective enzyme?
Features?
Clinical?

Answer 13

Hepatic
Protoporphyrinogen IX oxidase
Dominant
Photosensitivity, neuro sx and dev. delay

Question 14

How is hemoglobin degraded?

What happens to the products?

Answer 14

Via the reticulo-endothelial system into Heme (degraded) and Globin (broken down into amino acids)

Question 15

What is the major structural difference between Heme and bilirubin?

Answer 15

Heme is cyclic while bilirubin is linear (cut Heme = bilirubin)

Question 16

Draw the pathway of Heme degradation, conjugation and excretion of bilirubin (include locations)

Answer 16

Ok

Question 17

What happens to bilirubin after it is formed in the spleen?

Answer 17

Free/unconjugated/indirect bilirubin released into blood > transported by carrier albumin to the liver > liver uptake

Question 18

What causes jaundice?

Answer 18

Imbalance between making and excreting bilirubin (either type) leading to elevated levels

Question 19

What does pre-hepatic jaundice mean?

Clinical symptoms?

Answer 19

• Defect in pathway before liver uptake

- elevated unconjugated BR, hemolysis, internal hemorrhage

Question 20

What does intra hepatic jaundice mean?

Clinical

Answer 20

• defect at pathway in the liver leading to impaired conjugation
• variable levels of BR, elevated ALT and AST (liver enzymes)

Question 21

What does post-hepatic jaundice mean?

Clinical?

Answer 21

• defect in excretion pathway

- elevated conjugated BR causing dark urine and pale stool

Question 22

What is neonatal jaundice? Why does it need treatment?

Answer 22

• 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

Question 23

What are the treatments for neonatal jaundice and what does it do?

Answer 23

Phototherapy - breaks bilirubin into soluble isomers

Tin mesoporphyrin - inhibits heme oxygenase

Question 24

Type 1 vs Type Criggler-Najjar syndrome

Answer 24

Type 1: no UDP GT gene > severe hyperbilirubinemia and neuro sx
Type 2: mutated UDP GT gene with minimized activity > usually benign

Question 25

What is Gilbert syndrome?

Answer 25

Minimized activity of UDP GT but no known mutation in the gene
Benign

Question 26

Hepatitis
Cause
Clinical

Answer 26

• Hep virus infection leading to liver inflammation

- Elevated BR (variable pathways), jaundice, scleral icterus and dark urine

Question 27

How do bruises relate to Hgb breakdown?

Answer 27

Red > heme is present
Green > billverdin level
Orange > bilirubin level
Brownish > hemosiderin (iron)