Heme Synthesis and Breakdown

Question 1

Where does biosynthesis of Heme occur?

Answer 1

Liver and erythroid cells of bone marrow.

Question 2

What kind of Iron state inactivates Hemoglobin?

Answer 2

Ferric (Fe3+)

Question 3

Where does Phase I of Heme Biosynthesis take place?

What are the important steps?

Answer 3

Takes place in Mitochondria

Synthesis of delta-aminolevulinic acid (ALA) from Gly and succinyl CoA.

Question 4

Where does Phase II of Heme Biosynthesis take place?

What are the important steps?

Answer 4

In cytosol.
Condensation of 2 delta ALAs to form Porphobilinogen.
Condensation of 4 Porphobilinogen to form the Tetrapyrrole ring system of Coproporphyrinogen III.

Question 5

Where does Phase III of Heme Biosynthesis take place?

What are the important steps?

Answer 5

In Mitochondria.
Two oxidation reactions of Coproporphyrinogen III to instal the side chain Vinyl groups in Protoporphyrinogen IX and generate the fully conjugated ring system of protoporphyrin IX.
Insertion of Fe2+ by ferochelatase gives heme

Question 6

What coenzyme does ALA Synthase need?(deficiency in this enzyme causes anemia and evaluated iron stores)

Answer 6

Vitamin B6.

Question 7

Which enzymes does Lead inactivate in the Heme synthesis pathway?

Answer 7

ALA Dehydratase and Ferrochelatase.

Question 8

What kind of symptoms are present in Acute Hepatic Porphyria?

Answer 8

Neurological Symptoms (Liver)

Question 9

What kind of symptoms are present in Erythropoietic Porphyria?

Answer 9

Skin, photosensitivity (bone marrow).

Question 10

Which enzyme is affected in Acute Intermittent Porphyria?

What type of porphyria is this?

Answer 10

PBG Deaminase (liver)
Hepatic.

Question 11

Which enzyme is affected in Congenital erythropoietic Porphyria?
What type of porphyria is this?

Answer 11

Uroporphyrinogen III Synthase.
Erythropoietic.
the only Autosomal Recessive!!!

Question 12

Which enzyme is affected in Porphyria Cutanea Tarda?

What type of porphyria is this?

Answer 12

Uroporphyrinogen III Decarboxylase.

Hepatoerythropoietic.

Question 13

Which enzyme s affected in Variegate Porphyria?

What type of porphyria is this?

Answer 13

Protophorphirinogen IX Oxidase.

Hepatic

Question 14

Which system handles the Heme Degradation?

Answer 14

Reticulo-endothelial system

Question 15

Which enzyme removes the bridge between pyrrole rings of heme?
What molecule is released during this process?
Iron changed from what state to what state?
What is the product of this reaction?

Answer 15

Heme Oxygenase: CO2 is released.
Iron switches from Ferrous to Ferric state.
Biliverdin is formed.

Question 16

Which enzyme converts Biliverdin to Billirubin?

Answer 16

Biliverdin Reductase.

Question 17

Which protein transports unconjugated (indirect/free) Bilirubin to the liver?

Answer 17

Albumin

Question 18

How is Bilirubin conjugated(made soluble)?

Enumerate all steps and “material” used.

Answer 18

UDP Glucuronyl Tranferase enzyme in liver conjugates free BR with UDP-glucuronic acid. It makes BR monoglucuronide and then diglucuronide.

Question 19

Which enzyme is the Rate Limiting Step in removal of Bilirubin from blood?

Answer 19

UDP Glucuronyl Tranferase.

Question 20

In the intestine, Bilirubin-dicugluronide is ultimately reduced to?

Answer 20

Bilirubin and then Urobilinogen.

Question 21

What is Jaundice?

Answer 21

Hyperbilirubinemia. Imbalance between production and excretion of bilirubin.

Question 22

What is pre-hepatic Jaundice?
What are the findings of this condition?
Is Direct Bilirubin present or absent in urine?

Answer 22

Increase production of unconjugated Bilirubin.
Elevated blood levels of unconjugated Bilirubin
Normal blood levels of conjugated Bilirubin.
Normal ALT and AST.
Urobilinogen present in urine
Direct BR absent in urine.

Question 23

What is Intra-hepatic Jaundice?
What are its findings?
Is Direct Bilirubin present or absent in urine?

Answer 23

Impaired hepatic uptake, conjugation, or secretion of conjugated Bilirubin.

Variable increases in unconjugated and conjugated BR depending on the cause.
Increase in serum AST and ALT.
Urobilinogen leven in urine normal.
Conjugated BR present in urine.

Question 24

What is Post-hepatic Jaundice?
What are its findings?
Is Direct Bilirubin present or absent in urine?

Answer 24

Problems with BR excretions
AKA Cholestatic Jaundice or Cholestasis.

Elevated blood levels of conjugated BR. Small increases in unconjugated form.
Normal serum AST and ALT.
Elevated ALP.
Conjugated BR present in urine.
NO Urobilinogen in urine; NO Stercobilin in stool.

Question 25

What causes Crigler-Najjar Syndrome Type I ?

Answer 25

It is caused by complete absence of the gene UDP-GT.

Question 26

What causes Crigler-Najjar Syndrome Type II?

Answer 26

It is caused by a mutation in the UDP-GT gene. Enzyme has less activity (10%)

Question 27

What causes Gilbert Syndrome?

Answer 27

Results from reduced activity of UDP-GT (25% activity)