52. Heme synthesis and diseases

Question 1

Heme containing proteins and functions

Answer 1

Hgb and myoglobin: binding and transport of O2.
Catalase: breakdown of H2O2.
Cytochromes a,b&c: ETC
Cytochrome P450: hydroxylation

Question 2

Heme structure

Answer 2

Pyrrole rings, I, III, III and IV clockwise.
Conjugated double-bonds between rings.
Side chains methyl, vinyl and propionyl groups ( MV MV MP PM clockwise from ring I.)
Fe+2 in the middle.

Question 3

Heme synthesis

Answer 3

8 steps.

1. Aminolevulinic acid synthase—rate-limiting
2. aminolevulinic acid dehydrase
3. Porphobilinogen deaminase
   4a. Uro III cosynthatase.
   4b. spontaneous dead end pathway
4. Uro III decarboxylase
5. Coproporphyrinogen III oxidase
6. Protoporphyrin IX oxidase
7. Ferrochelatase

Question 4

Heme synthesis: 1. aminolevulinic acid synthase

Answer 4

Succinyl CoA + glycine –> delta-aminolevulinic acid in mitochondria.
Rate-limiting step.
Downregulated by heme.

Question 5

Heme synthesis: 2. Aminolevulinic acid dehydrase

Answer 5

2 aminolevulinic acids –> porphobilinogen in cytosol.

Forms a ring

Question 6

Heme synthesis: 3. Porphobilinogen deaminase

Answer 6

4 porphobilinogens –> tetrapyrrole intermediate + 4 NH3.
enzyme aka Uro I synthase or hydroxymethylbilane.
TIM is unstable.

Question 7

Heme synthase 4: Uro III cosynthase.

Answer 7

Tetrapyrrole intermediate –> Uroporphyrinogen III.

If Uro III cosynthase is unavailable, TIM spontaneously becomes Uro I then to Coproporphyrinogen I (dead end pathway)

Question 8

Heme synthase 5. Uro III decarboxylase

Answer 8

Uro III –> Coproporphyrinogen III

all 4 acetyl groups becomes methyl groups.

Question 9

Heme synthesis 6. Copro III oxidase

Answer 9

Copro III –> protoporphyrinogen IX
2 pyrrole groups on ring I and III becomes vinyl groups.
Back in mitochondria.

Question 10

Heme synthesis: 7. Protoporphyrin IX oxidase

Answer 10

Protoporphyrinogen IX –> protophorphyrin IX

Conjugated double-bonds form between rings.

Question 11

Heme synthesis: 8. Ferrochelatase

Answer 11

Protoporphyrin IX –> heme.

Fe+2 is added to the center.

Question 12

Porphyrias: disease of heme synthesis (4 different types)

Answer 12

Acute intermittent.
Congenital erythropoietic.
Cutanea tarda
Lead poisoning (acquired)

Question 13

Porphyrias: Acute intermittent

Answer 13

Deficient in porphobilinogen deaminase (rxn 3).
Build up of porphobilinogen and aminolevulinic acid: neurological sx and abd pain.
Tx: heme supplement.

Question 14

Porphyrias: Congenital erythropoietic

Answer 14

Deficient in Uro III cosynthase (rxn 4).
reaction shunted to “dead end pathway”
photocutaneous sx (rashes) and anemia.
Tx: heme supplement, staying out of UV.

Question 15

Porphyrias: Cutanea Tarda

Answer 15

Deficient in Uro III decarboxylase (rxn 5).

Photocutaneous sx.

Question 16

Porphyrias: lead poisoning

Answer 16

Disruption in aminolevulinic acid dehydrase (rxn 2) and ferrocheltase (rxn 8).
Sx: neurological, gum discoloration, anemia. NO photocutaneous sx.

Question 17

Heme degradation

Answer 17

1. RES cells
2. Liver
3. Intestine
4. Kidney

Question 18

Heme degradation: 1. RES cells

Answer 18

Reticuloendothelial system cells in spleen, liver and marrow are mononuclear phagocytes.

Heme –> biliverdin (soluble and green) + Fe+3 + CO (by heme oxygenase).

Biliverdin –> bilirubin (using NADPH) insoluble and antioxidant.

Question 19

Heme degradation: 2. Liver

Answer 19

Bilirubin is transported by albumin to liver.

Bilirubin –> bilirubin diglucuronide (by 2 UDP-glucuronyl transferases)

Question 20

Heme degradation: 3. Intestine

Answer 20

from liver to GB to intestine.
Bilirubin diglucuronide –> urobilinogen –> sterocobilin –> urobilin (by bacteria).
Sterocobilin (brown) and urobilin are excreted in feces.

Question 21

Heme degradation: 4. Kidney

Answer 21

Urobilinogen and urobilin (yellow) can be excreted as urine.

Question 22

Disease of heme degradation: Jaundice

Answer 22

1. Pre-hepatic
2. Hepatic
3. Post-hepatic

Question 23

Jaundice: 1. Pre-hepatic

Answer 23

Hemolysis leads to system overload and all heme metabolites increase, including blood [bilirubin] even though it’s insoluble.

Question 24

Jaundice: 2. Hepatic

Answer 24

Neonatal (UDP-glucuronyl transferase deficiency) form leads to bilirubin accumulation (CNS sx). Blue light solubilizes bilirubin.
Other problems include transport problem, viral hepatitis, cirrhosis.
Crigler-Najjar (UDP-glucuronyl transferase defect).

Excretion of metabolites in feces decrease b/c metabolites leak from liver to blood directly.
Excretion in urine increases (can find bilirubin diglucuronide in urine).

Question 25

Jaundice: 3. Post-hepatic

Answer 25

problem with secretion through GB.
Cholestasis, stones, spasms, neoplasms.
Bilirubin and bilirubin diglucuronide backed up in blood.
Decrease in urobilin and sterocobilin in feces lead to “white” stool.
Can find bilirubin diglucuronide in urine.

Question 26

Van den Bergh reaction: clinical test for juandice

Answer 26

Soluble bilirubin + diazonium salt –> blue color.
1. Direct (serum only): only conjugated bilirubin (diglucuronide) makes color.
2. Total (serum + alcohol): alcohol solubilizes unconjugated bilirubin.
2-1=indirect/unconjugated bilirubin.
In hepatic and post-hepatic jaundice, unconjugated bilirubin builds up.