Lecture 12 - Heme Metabolism

Question 1

What 2 tissues have the highest rate of heme synthesis?

State what the two tissues are specifically responsible for.

Answer 1

1. Bone marrow
   - highest rate of heme synthesis
2. Liver
   - incorporation into cytochromes, cytochrome P-450 enzymes

Question 2

What is the structure of heme?

Answer 2

4 payrolls make one heme molecule

Question 3

Where does step 1, the rate limiting and regulated step in heme synthesis occur?

Which enzyme is involved?

What two structures are needed?

Answer 3

1. Mitochondria
2. involves ALA synthase
3. Succinyl Co A and Glycine

Question 4

What are the 2 main differences of PORPHYRINOGEN and PORPHYRINS?

Answer 4

1. Porphyrinogen:
   - no double bonds at the bridging carbons
   - Colorless*
2. Porphyrins:
   - double bonds at bridging carbons
   - colored, highly fluorescent, photodegradable

Question 5

What is unique about ALA synthase?

Where is it found?

Answer 5

ALA1 - all tissues

ALA2 - in bone marrow erythroid cells

Question 6

How is ALA1 (from liver) different from ALA2 (from bone marrow) in terms of regulating heme synthesis?

Answer 6

ALA 1 can be inhibited by its product, heme, but ALA2 is NOT regulated by heme

Question 7

Describe the following for Acute Intermittent Porphyria:

1. Which enzyme is deficient?
2. What 2 substances in the heme biosynthesis pathway increase?
3. What is the result of this disease? (what does it affect)
4. What can precipitate the negative effects of the enzyme deficiency?
5. What is the treatment (2)

Answer 7

1. Which enzyme is deficient?
   * * Porphobilinogen Deaminase**
2. What 2 substances in the heme biosynthesis pathway increase?
   a) ALA
   b) Porphobilinogen (PBG)
3. What is the result of this disease? (what does it affect)
   * * RESULTS IN NERVE DAMAGE**
4. What can precipitate the negative effects of the enzyme deficiency?
   * * drugs like barbiturates, alcohol, steroid hormones, low glucose diet, can induce expression of ALA synthase**
5. What is the treatment (2)
   a) Glucose Infusion (to increase Insulin and thus degrade ALA synthase)
   b) heme in IV to inhibit ALA synthase

Question 8

What enzyme does heme inhibit specifically?

Answer 8

ALA synthase

Question 9

Describe the following for VARIEGATE PORPHYRIA:

1. Which enzyme is deficient?
2. What 2 substances in the heme biosynthesis pathway increase?
3. What is the result of this disease? (what does it affect)

Answer 9

1. Which enzyme is deficient?
   * * PROTOPORHYRINOGEN OXIDASE**
2. What 2 substances in the heme biosynthesis pathway increase?
   a) Protoporphyrinogen III
   b) Coproporphyrinogen III
   - in liver
3. What is the result of this disease? (what does it affect)

Protoporphyrinogen III and Coproporphyrinogen III are deposited in the skin and sunlight converts them to PORPHYRINS
- degraded by light and then generates tissue destroying singlet Oxygen
= PHOTOSENSITIVITY

Question 10

VARIEGATE PORPHYRIA:

4. Since ______ is reduced, what enzyme is increased that leads to increased ALA and BPG?

What are the 2 clinical signs?

Answer 10

4. Since ______ is reduced, what enzyme is increased that leads to increased ALA and BPG?
   1) HEME
   2) ALA SYNTHASE

SYMPTOMS: both NEURAL DAMAGE AND DAMAGE OF THE SKIN

Question 11

True of False:

Porphyrias (the diseases) are caused by a DECREASE in heme synthesis.

Answer 11

INCREASE IN METABOLIC INTERMEDIATES

Question 12

What 3 enzymes from the HEME biosynthesis pathway are inhibited by lead poisoning?

What substances in the pathway are elevated as a result?

Which of these serves as a marker for lead ingestion (where is it measured)?

Answer 12

1. ALA dehydratase
2. Corproporphyrinogen Oxidase
3. Ferrochelatase
4. ALA
5. Coproporphyrinogen
6. Protoporphyrin III

PROTOPORPHYRIN III (and the other 3?) In RBCS!

Question 13

1. What is the half life of the erythrocyte?
2. What eventually takes up the RBC?
3. What is degraded and what is reutilized in HEME CATABOLISM?

Answer 13

1. 120 days
2. Phagocytic cells of the RETICULOENDOTHELIAL system
3. Heme (protein) is degraded & the heme group
   IRON IS REUTILIZED

Question 14

When heme is catabolized, what is formed 1st? Second?

Answer 14

1. Bilviruden

2. Bilirubin

Question 15

Describe how unconjugated bilirubin is carried in the plasma.

Where is it delivered?

What happens here?

Answer 15

1. Carried in plasma bound to ALBUMIN (since unconjugated bilirubin is insoluble in plasma)
2. LIVER
3. In the liver it is taken up by active transport and CONJUGATED

Question 16

What happens with Conjugated bilirubin?

Where is it deconjugated and by what? How is this related to stool color?

What gives uric its classic yellow color?

Answer 16

1. Actively secreted into the BILE CANALICULUS
2. Deconjugated in the COLON (Intestine) by the BACTERIAL FLORA and oxidized to colored STERCOBILINS
   - give stool its brown color
3. UROBILIN
   - oxidized form of urobilinogen

Question 17

HYPERBILIRUBINEMIA:

1. What is elevated? (number?)
2. Conjugated or Unconjugated?
3. What happens when this level is greater than 2-2.5 mg/dl?

Answer 17

1. BILIRUBIN
2. BOTH conjugated an dun conjugated
3. JAUNDICE –> bilirubin can diffuse into tissues making them appear yellow (apparent in the sclera)

Question 18

Which of the following is benign and which is a concern (when specifically in relation to bilirubin levels)?

1. Conjugated Bilirubin
2. Unconjugated Bilirubin

Which causes toxic encephalopathy?

Answer 18

1. Conjugated Bilirubin
   - BENIGN
2. Unconjugated Bilirubin
   - benign only when LESS than 25 mg/dL of bilirubin
   - at GREATER than 25, causes TOXIC encephalopathy (kernicutus) because unconjugated bilirubin can cross the BBB

Question 19

What determines the max amount of unconjugated bilirubin that can be present in the blood before TOXIC ENCEPHALOPATHY occurs?

Answer 19

the max amount (25mg/dL) is the capacity that ALBUMIN can handle (binds to unconjugated bilirubin and transports it in the systemic circulation)

Question 20

Which can cross the BBB:

Conjugated or unconjugated bilirubin?

Answer 20

UNCONJUGATED (lipid soluble)

Question 21

What is hemolysis?

Does it result in increased Conjugated or Unconjugated Bilirubin?

Answer 21

1. Destruction of Erythrocytes

2. UNCONJUGATED

Question 22

Biliary obstruction results in increased conjugated or unconjugated bilirubin?

What are the clinical signs?

Answer 22

CONJUGATED

1. Dark urine
2. Feces can be chalky white because of the absence of stercobilins

Question 23

What pathology results in mixed hyperbilirubinemia?

Answer 23

DECREASED CONJUGATION & excretion of bilirubin

HEPATIC CIRRHOSIS or HEPATITIS
- increase in both conjugated & unconjugated bilirubin

Question 24

What are some causes of Neonatal Physiological Jaundice?

Does it result in increased Conjugated or Unconjugated Bilirubin?

What else can this cause?

What is a useful treatment?

Answer 24

1. Fragile erythrocytes
2. Immature hepatic system of newborn
   - decreased uptake, conjugation, and excretion of bilirubin

INCREASED UNCONJUGATED BILIRUBIN
(if it reaches over 25mg/dL, will cause kernicterus)
- bilirubin-induced brain dysfunction

TX: blue light

Question 25

How does blue light treat neonatal jaundice?

Answer 25

to convert insoluble and BBB permeable unconjugated bilirubin to one of its ISOMERS that are more soluble in plasma & excreted