Heme Synthesis and Breakdown

Question 1

Features of porphyrin rings:

Answer 1

They have 4 five-membered rings containing nitrogen.
Iron is present in the ferrous state (2+)
If the ferrous state is oxidized to ferric, Hb is inactivated.

Question 2

Phases of Biosynthesis of Heme and where it occurs

Answer 2

Phase I - in mitochondria.
Phase II - in cytosol.
Phase III - in mitochondria
Occurs in the liver and eryhtroid cells of bone marrow.

Question 3

Phase I

Answer 3

Gly + succinyl CoA —> ALA (ALA synthase, vit B6 as a cofactor).
ALA enters the cytosol via its channel.

Question 4

Phase II

Answer 4

ALA + ALA —> PBG (ALA dehydrogenase)
4 PBG —> Hydroxymethylbilane (porphobilinogen deaminase) —> Uroporphyrinogen III (uroporphyrinogen III synthase) —> coproporphyrinogen III (uroporphyrinogen decarboxylase)

Question 5

ALA Synthase

Answer 5

Needs Vit B6.
2 isoforms (ALAS I - ubiquitous. ALAS II - only in erythroid cells in BM).
ALAS II has an iron response element in mRNA (the presence of iron increases its transcription/translation).

Question 6

Pb Poisoning

Answer 6

Pb inactivates ALA dehydratase (has Zn) and ferrochelatase (has Fe).
ALA and protoporphyrin IX accumulate.
Lowered heme production —> anemia.
Lowered energy level as cytochromes not produced.

Question 7

Polyphorias

Answer 7

Inherited metabolic disorders.

Caused by defects in heme synthesis.

Question 8

Acute intermittent porphyria (defective enzyme, type of porphyria and sx)

Answer 8

PBG deaminase.
Hepatic.
Abdominal pain, *psychiatric problems.

Question 9

Congenital erythropoetic porphyria (defective enzyme, type of porphyria and sx)

Answer 9

Uroporphyria synthase III.
Erythropoetic.
Red urine, red teeth, skin photosensitivity, destruction of RBCs.

Question 10

Uroporphyrinogen decarboxylase (defective enzyme, type of porphyria)

Answer 10

PCT.
Hepatoerythropoietic.
Most common polyphyria in US.

Question 11

Protoporphyrinogen IX oxidase (defective enzyme, type of porphyria)

Answer 11

Variegate porphyria.

Hepatic.

Question 12

Phase III (dismiss first 2 enzymes)

Answer 12

Coproporphyrinogen III —> protoporphyrinogen IX
protoporphyrinogen IX –> protoporphyrin IX
protoporphyrin IX –> Heme (ferrochelatase)

Question 13

How is heme degraded?

Answer 13

Reticulo-endothelial system, which degrades Hb.

Globin to AAs and heme removed for degredation.

Question 14

Conjugation of Bilirubin overview

Answer 14

BR released into blood and transported via albumin as it is insoluble.
Taken up in liver where it is conjugated with glucuronic acid.

Question 15

Mechanism of conjugation of bilirubin

Answer 15

UDP-glucose is converted to UDP-glucuronate (UDP-glucose dehydrogenase).
Bilirubin UDP-glucoronyltransferase conjugase free BR with UDP-glucoronate —> conjugated bilirubin.

Question 16

Breakdown of BR

Answer 16

LIVER: 
BR ---> BR-monoglucuronide (UDP-glucoronyl transferase). ---> BR-diglucuronide (UDP-glucoronyl transferase) 
SI:
---> BR ---> Urobilinogen
KIDNEY:
 ---> Urobilin (yellow and excreted)

Question 17

Stercobilin

Answer 17

Some urobilinogen is reduced further to stercobilin (brown) and excreted in feces.

Question 18

Jaundice

Answer 18

Elevated BR.
Normal unconjugated: 0.2-0.9
Normal conjuagted: 0.1-0.3
There is an imbalance between production and excretion of BR.

Question 19

Pre-hepatic Jaundice

Answer 19

Increased production of unconjugated BR.
Norml levels of BR.
Normal ALT and AST.
Urobilinogen present in urine (capacity to conjugate BR and excrete is not impaired).
No BR in urine.

Question 20

Intra-hepatic Jaundice

Answer 20

Impaired hepatic uptake, conjugation, or secretion of conjugated BR,
Increase in serum ALT and AST.
Conjugated BR in urine.
(ex: Cirrhosis, viral hep, Criggler-Najjar syndrome and Gilbert syndrome).

Question 21

Post-hepatic Jaundice

Answer 21

Problem with BR excretion.
Caused by obstruction in lve/bile duct, lesions, drugs.
Elevated conjugated BR.
Normal serum AST and ALT.
Elevated ALP.
Conjugated BR present in urine.
Pale stool (no stercobilin).

Question 22

Neonatal Jaundice

Answer 22

“Physiological jaundice”
Immature hepatic metabolic pathways are unable to conjugate and excrete bilirubin.
Deficiency of UDP-GT enzyme.
Breakdown of fetal Hb and is replaced with HbA.

Question 23

Phototherapy

Answer 23

When exposed to fluorescence, BR is converted to more soluble isomers.

Question 24

Crigler-Najjar Syndrome Type I

Answer 24

Deficiency of UDP-GT.
Type I: complete absence of gene.
Severe hyperbilirubinemia —> BR accumulates in brain of baby. Can cause kernicturus.

Question 25

Therapies for C-N Syndrome Type 1

Answer 25

Blood transfusions
Phototherapy
Heme oxygenase inhibitors.
Oral CaPO4 and carbonate.
Liver transplant.

Question 26

C-N Syndrome Type II

Answer 26

Benign form. Mutation in UDP-GT gene.

Question 27

Gilbert Syndrome

Answer 27

Common. Reduced activity of UDP-GT. Mild jaundice from fasting, alcohol, stress.

Question 28

Hepatitis

Answer 28

Caused from viral infection or alcoholism.
Increased levels of unconjugated and conjugated BR.
BR accumulates in skin and sclera.
Dark urine.