Heme Metabolism

Question 1

What is the difference between heme and hemin

Answer 1

Heme = Fe2+
Hemin= Fe3+

Question 2

Two main places where heme synthesis occurs?

However, heme synthesis happens in all cells EXCEPT

Site within the cell of heme synthesis?

Answer 2

Liver and bone marrow

RBCs

Mitochondria and cytoplasm

Question 3

What assists in heme synthesis in the liver

Answer 3

Cytochrome p450

Question 4

For our purposes, which 2 steps happen in the mitochondria?

Answer 4

1st step and last 3 steps; rest occur in cytoplasm

Question 5

Two things required for heme biosynthesis

Answer 5

Glycine and succinyl CoA (these are the beginning substrates for first step)

Question 6

First step of heme synthesis?

By which enzyme?

Answer 6

Glycine and succinyl CoA decarboxylate to form ALA by ALA synthase

Question 7

First step of heme synthesis requires?

Answer 7

Vitamin B6 (pyridoxal phosphate)

Question 8

What is the rate limiting enzyme in heme synthesis

What inhibits this enzyme?

Answer 8

ALA synthase

Heme/hemin

Question 9

What happens in step 2 of heme synthesis

What does this enzyme require?

What is significant about the enzyme in this step

Answer 9

2 molecules of ALA condense to form porphobilinogen by ALA dehydratase

Requires zinc

It is inhibited by heavy metals (lead)

Question 10

Lead poisoning will lead to what two things?

Answer 10

Anemia and elevation of ALA and zinc protoporphyrin

Question 11

Besides ALA dehydratase, what other enzyme is inhibited by lead?

Answer 11

Ferrochelatase

~so these 2 enzymes are the cause of anemia in lead poisoning

Question 12

Deficiency in any of the other enzymes of heme synthesis that have not been mentioned cause what?

Answer 12

A condition known as porphyria

Question 13

Name the following enzyme used for the last 3 steps of heme synthesis:

1. Coproporphyrinogen III -> protoporphyrinogen IX
2. Protoporphyrinogen IX -> protoporphryrin IX
3. Protoporphyrin IX -> heme

Answer 13

1. Coproporphyrinogen III oxidase
2. Protoporphyrinogen oxidase
3. Ferrochelastase

Question 14

1. Disorders in any of the beginning steps of heme synthesis will have what kind of symptoms?
2. Disorders in the ending steps?

Answer 14

1. Either GI or neuro/psych

2. Either photosensitive or skin

Question 15

Porphyrias:

1. Caused due to a defect in?
2. Reduced heme formation will lead to increase function of which enzyme?
3. Cells of which two organs will be most affected by these disorders

Answer 15

1. Heme sythesis
2. ALA synthase
3. Bone marrow (erythropoietic) and liver (hepatic)

Question 16

Erythropoietic porphyria:
1. Characterized by

2. Complications

Answer 16

1. Skin rashes and blisters that appear early in childhood

2. Liver cirrhosis/progressive hepatic failure

Question 17

Two subsections for hepatic porphyrias

Answer 17

Acute and chronic

Question 18

Acute (intermittent) porphyria:

1. 2 other types
2. Symptoms

Answer 18

1. Hereditary coproporphyria, variegate porphyria

2. Acute attacks of GI, neuro/psych, and cardiovascular symptoms

Question 19

Chronic porphyrias:

1. 2 types
2. Symptoms

Answer 19

1. Porphyria cutanea tarda and hepatoerythropoetic (rare)

2. Sensitivity to sunlight and blisters on the skin

Question 20

Acute intermittent porphyria:

1. Deficiency in what enzyme? (Give both names for the enzyme)
2. Leads to accumulation of
3. Symptoms
4. What can cause an acute attack

Answer 20

1. PBG deaminase / HMB synthase
2. ALA and PBG
3. Abdominal pain and neuro/pysch
4. Barbiturates and ethanol (induction of cytochrome p450)

Question 21

Porphyria cutanea tarda:

1. Deficiency in what enzyme
2. Chronic disease of __ and __
3. Onset?
4. Clinical expression is influenced by?
5. Leads to accumulation of
6. Clinical symptoms?

Answer 21

1. Uroporphyrinogen decarboxylase
2. Liver and erythroid tissue
3. Late; 40s-50s
4. Iron overload, exposure to sun, and infection
5. Porphyrins
6. Skin / urine will turn from red to brown; “werewolf” appearance

Question 22

What two things can repress ALA synthase?

Answer 22

High carbs and administration of hemin

Question 23

Patients with photosensitivity may benefit from?

Answer 23

Beta carotene (lessen production of free radicals)

Question 24

Catabolism of heme occurs in what type of cells? In what two organs, mainly?

~85% get degraded this way, how do the other 15% get degraded?

Answer 24

Reticuloendothelial cells; liver and spleen mainly

From turnover of immature RBCs and cytochromes from extraerythroid tissues

Question 25

Two parts of heme? What is globin composed of? Which of the above answers can be reused?

Answer 25

Porphyrin and iron Amino acids Iron and amino acids can be reused; porphyrin cannot

Question 26

Name 3 functions of carbon monoxide (CO)

Answer 26

Anti-inflammatory, signaling molecule, and vasodilator

Question 27

What is indirect/unconjugated bilirubin

Answer 27

Orange/yellowish bilirubin that is formed in extra-hepatic tissues

Question 28

Main difference between conjugated and unconjugated bilirubin

Answer 28

Conjugated is soluble in water so can be secreted in the urine/blood

Question 29

Tissues in the reticuloendothelial system that these extra-hepatic processes can happen in

Answer 29

Spleen, macrophage, lymph tissue

Question 30

Formation of indirect bilirubin requires what two things? What does formation of indirect bilirubin produce?

Answer 30

NADPH and oxygen Biliverdin, CO, iron, and NADP+

Question 31

Next step is converting biliverdin to bilirubin - what enzyme does this?

Answer 31

Biliverdin reductase

Question 32

Bruises change color based on biliverdin/bilirubin - what are the colors of each

Answer 32

Biliverdin- green | Bilirubin - yellow/orange

Question 33

If indirect bilirubin is formed outside of the liver, what does it require in order to get into the liver?

Answer 33

Facilitated transport via albumin

Question 34

What are the two sites that albumin has for bilirubin?

Answer 34

High affinity and low affinity sites

Question 35

What happens once indirect bilirubin enters the liver?

Answer 35

It gets converted to direct/conjugated bilirubin (bilirubin diglucuronide) by bilirubin glucuronyl-transferase which uses 2 UDP-glucuronic acid

Question 36

How does conjugated bilirubin leave the liver and go into bile? What is significant about this

Answer 36

Active transport - requires energy Rate limiting for the entire process of hepatic bilirubin metabolism

Question 37

Bilirubin glucuronyltransferase can be induced by ?

Answer 37

Phenobarbital

Question 38

3 inherited unconjugated hyperbilirubinemias? All 3 of these disorders have to do with a deficiency in which enzyme

Answer 38

Crigler-Najjar 1, Crigler-Najjar 2, and Gilberts syndrome UDP glucuronyl transferase deficiency

Question 39

Main difference between the 3 disorders

Answer 39

CN1 is complete deficiency of enzyme-poor survival CN2 is partial deficiency- medium severity Gilberts is minimal deficiency- not clinically significant

Question 40

2 inherited conjugated hyperbilirubinemia disorders? Both occur when there is a defect in?

Answer 40

Dubin Johnson syndrome (major effect) and Rotors syndrome (minor effect) Excretion of bilirubin into the bile

Question 41

Symptoms of dubin johnson? Symptoms of rotors?

Answer 41

Black pigmented liver Liver-no pigmentation

Question 42

In the intestine, what happens to bilirubin

Answer 42

It goes back to unconjugated bilirubin and then converted to urobilinogen which is reabsorbed/reexcreted to the liver and excreted in urine

Question 43

Small percentage of bilirubin does not convert to urobilinogen, instead it oxidizes to?

Answer 43

Stercobilin (excreted in feces - responsible for brown color)

Question 44

Identify if the following is describing conjugated or unconjugated bilirubin: 1. Soluble in methanol 2. Absent in urine 3. Excreted in bile

Answer 44

1. Unconjugated (conjugated is soluble in water/blood) 2. Unconjugated 3. Conjugated

Question 45

Total bilirubin= 1.0 mg/dl Conjugated bilirubin=? Unconjugated bilirubin=?

Answer 45

Conjugated= 0-0.2 mg/dl | Unconjugated=0.2-0.6 mg/dl

Question 46

What is hyperbilirubinemia? What sign/symptom can it result in

Answer 46

When bilirubin in blood exceeds 1 mg/dl Jaundice (when serum bilirubin >2 mg/dl

Question 47

Jaundice: 1. Yellowing of what areas of the body? 2. How do you measure this? 3. What causes the yellowing?

Answer 47

1. Skin, nail beds, and sclera 2. Van den Bergh reaction 3. Deposition of bilirubin