11. Heme Synthesis

Question 1

What is heme made of?

Answer 1

Each heme subunit is made of a porphyrin ring and an iron.

(Porphyrin rings are made up of four pyrrole rings)

Question 2

Where do the three stages of heme synthesis occur generally? (Organs)

Where does each of the three steps occur?

Answer 2

Primarily in the liver and erythroid cells of the bone marrow

1. Mintochondria
2. Cytosol
3. Mitochondria again

Question 3

What happens overall in phase 1 of heme synthesis?

Answer 3

Glycine + Succinyl CoA form delta-aminolevulinic acid (ALA)

Question 4

What vitamin does the first phase of heme synthesis need to continue?

What happens if it doesn’t get this?

Answer 4

B6 - Pyridoxal phosphate

Heme synthesis is diminished, red blood cells look pale and iron stores back up and become elevated.

Question 5

What are the players in heme synthesis’s feedback inhibition to phase 1?

Answer 5

Heme itself blocks ALA synthase in step one

Question 6

What heme synthesis enzymes do lead inactivate?

What does this cause?

Answer 6

Inactivates ALA dehydratase (phase 2) and ferrochelatase (phase 3 / final step)

Backup of Protoporphoryn IX and ALA as well as Anemia

(This also will impact energy production by disabling synthesis of cytochromes)

Question 7

What enzyme defect is associated with:

Acute Intermittent Porphyria?

Is this Hepatic or Erythropoietic?

Answer 7

Porphobillinogen Deaminase

Bill is known for being unreliable, so his porphyria is intermittent

Hepatic

Question 8

What enzyme defect is associated with:

Congenital Erythropoietic Porphyria?

Is this Hepatic or Erythropoietic?

Answer 8

Uroporphyrinogen III Cosynthase

Congenital defects happen as a child is being made, so the porphyria is a cosynthase

Erythropoietic

Question 9

What enzyme defect is associated with:

Porphyria Cutanea Tarda

Is this Hepatic or Erythropoietic?

Answer 9

Uroporphyrinogen Decarboxylase

Most common in America - Americans could eat less carbs - de_carb_oxylase

Hepatoerythropoietic

Question 10

What enzyme defect is associated with:

Variegate Porphyria

Is this Hepatic or Erythropoietic?

Answer 10

Protoporphyrinogen Oxidase

Variegate means “different colors”, oxides are often different colors than their precursors: protoporphyrinogen oxidase

Hepatic

Question 11

Which of the porphyrias is most common in the US, and what enzyme deficiency causes it?

Answer 11

Porphyria Cutania Tarda (PCT)

Uroporphyrinogen decarboxylase

Question 12

What does a deficiency in uroporphyrinogen III synthase cause a buildup of?

Answer 12

Uroporphyrinogen I and it’s product, Uroporphyrin I

Question 13

What system handles the breakdown of hemoglobin?

Answer 13

The Reticulo-Endothelial system

Question 14

What enzyme breaks down heme’s bridges?

Answer 14

Heme oxygenase

Question 15

What toxic compound does heme oxygenase release?

Answer 15

Carbon monoxide

Question 16

What enzyme converts Biliverdin into Bilirubin?

Answer 16

Biliverdin Reductase

Question 17

What carries insoluable billirubin through the bloodstream?

Answer 17

Albumen

Question 18

Where is billirubin taken up?

What keeps it soluable in those cells?

What do we call the complex?

Answer 18

The liver (mediated by a protien carrier)

Glucuronic acid

Conjugated / Direct Billirubin

Question 19

What enzyme takes UDP-Glucose and makes UDP-glucuronate?

Why does it do this?

Answer 19

UDP-Glucose dehydrogenase

It is the first step of billirubin conjugation.

Question 20

What enzyme takes ready-to-go UDP-glucuronate and attatches it to bilirubin?

What does the glucuronate become when attached to bilirubin?

What does the enzyme do next?

Answer 20

Bilirubin UDP glucuronyltransferase

UDP-glucuronic acid

It attaches another one. (Monoglucuronide bilirubin → Diuronide bilirubin)

Question 21

When bilirubin is conjugated in the liver, where is it sent?

What will it do there?

Answer 21

Gall bladder (as bile)

Be secreted into the small intestine in response to food.

Question 22

After bilirubin is secreted into the small intestine, what does it become?

What two paths can it take from there?

Answer 22

Urobilinogen (microbes reduce it for us)

It can become Urobilin in the urine

or it can become stercobilin in the feces

Question 23

What might be a cause of pre-hepatic jaundice?

Answer 23

Hemolytic anemia

Internal hemorrhage

Reduced capacity of liver to conjugate bilirubin

Erythroblastosis fetalis

Question 24

What might you find clinically in pre-hepatic jaundice?

Answer 24

Elevated production of unconjugated BR

Normal levels of ALT and AST

Normal levels of conjugated bilirubin

Direct bilirubin absent in urine (normal)

Question 25

How might Glucose 6 Phosphate dehydrogenase deficiency cause jaundice?

What kind of jaundice would it cause?

Answer 25

Decreased replenishment of glutathione means more ROS - which can cause hemolytic anemia

Pre-hepatic jaundice

Question 26

What can cause Intra-Hepatic Jaundice?

Answer 26

Deficiency in liver uptake of bilirubin, conjugation of bilirubin, or release of conjugated bilirubin. (Basically all of the things the liver does)

Examples: Liver trauma, hepatitis, cirrosis,

Criggler-Najjar syndrome

Gilbert Syndrome

Question 27

Clinically, what will you see in intra-hepatic jaundice?

Answer 27

Either unconjugated or conjugated bilirubin will be elevated, depending on the issue.

Increase in serum AST and ALT!

Urobilinogen levels are still normal, because nothing is affecting that area.

Question 28

What is the common factor for post hepatic jaundice?

Answer 28

Problems with conjugated bilirubin secretion

Question 29

What are the clinical findings for post-hepatic jaundice?

Answer 29

Elevated blood levels of conjugated bilirubin

Conjugated bilirubin is present in urine (dark)

Sercobilin is absent from feces (pale)

Question 30

What gene is absent in Type 1 Crigler-Najjar Syndrome?

What are affected individuals unable to do?

Answer 30

UDP-Glucuronyltransferase

Conjugate bilirubin

Question 31

What are the symptoms of Type 1 Crigler-Najjar syndrome?

Answer 31

Jaundice

Kernicturus (jaundice related brain damage and encephalopathy)

Question 32

What is physiological jaundice in newborns?

What is the treatment?

Answer 32

Jaundice related to the conversion of fetal hemoglobin to adult hemoglobin

Phototherapy and possibly injection of tin-mesoporphyrin

Question 33

What is Gilbert syndrome?

When might someone see symptoms?

Answer 33

Benign disorder reflecting a reduced UDP-Glucuronosyltransferase

Question 34

Describe Lead Poisoning

Answer 34

inactivates ALA dehydratase and Ferrochelatase

ALA and Protoporphyrin IX accumulate and are neurotoxic (ALA) acting like GABA

causes anemia (microcytic, hypochromic)

impacts ATP synthesis and energy metabolism

Question 35

What are the two key enzymes that turn Heme into Billirubin

Answer 35

Heme oxygenase (to biliverdin)

Biliverdin Reductase (to bilurubin)

Question 36

Bilirubin is super insoluble in it’s unconjugated/free form. What enzyme adds sugar to it so that it can be more soluble?

Answer 36

UDP glucuronyl transferase adds glucuronates to the bilirubin and is the RATE limiting enzyme in this process

Question 37

Hepatitis

Answer 37

inflammation of the liver leading to liver dysfunction

caused by viral infections, ETOH or cancer

causes increase in level of unconjugated and conjugated bilirubin in blood

BR accumulates in skin, sclera causing yellow (jaundice)

dark brown urine

Question 38

What is the stage of hemoglobin breakdown seen in bruising?

Answer 38

initially: hemoglobin to heme (redish blue/purple)

biliverdin (green)

bilirubin (yellow)

iron (hemosiderin/reddish brown color)