Heme Synthesis and Breakdown

Question 1

Structure of Heme

Answer 1

Heterocyclic porphyrin ring with iron present in center

Have 4 5-membered rings containing Nitrogen connected by single carbon bridges
Iron present in ferrous state (Fe2+)
Oxidation to ferric state (Fe3+) inactivates hemoglobin (methemoglobin)

Present in Hb, myoglobin, cytochromes

Question 2

Structure of Hemoglobin

Answer 2

Contains 4 globular protein subunits

Each bound to an iron containing heme

Question 3

ALA Synthase

Answer 3

Heme synthesis
Glycine + Succinyl CoA –> Delta aminolevulinic acid

Needs Vit B6 (Pyridoxal phosphate)
2 Isoforms:
1) ALAS I (ubiquitous) inhibited by heme and hemin
2) ALAS II (only in erythroid cells of BM) has iron response element in mRNA
-Presence of iron increases its transcription and translation

Question 4

Porphyrias

Answer 4

Inherited metabolic disorders
Greek for “Purple pigment”
Caused by defects in heme synthesis

Types depend on enzyme defect

1) Acute hepatic - neurological symptoms
2) Erythropoeitic - skin, photosensitivity

Question 5

Acute intermittent porphyria

Answer 5

Defective enzyme: PBG deaminase (in liver)
Hepatic porphyria

Rxn: PBG –> Hydroxymethylbilane

Question 6

Congenital erythropoietic porphyria

Answer 6

Defective enzyme: Uropophyrinogen III cosynthase (in erythrocytes)
Erythropoietic porphyria

Rxn: Hydroxymethylbilane –> Urophorphyrinogen III

Uroporphyrinogen III --> Uroporphyrinogen I accumulates
Red color in urine
Red flourescence in teeth
Destruction of RBCs 
Skin photosensitivity

Question 7

Porphyria cutanea tarda

Answer 7

Defective enzyme: Uroporphyrinogen decarboxylase
Hepatoerythropoietic prophyria
**Most common porphyria in US

Rxn: Uroporphyrinogen III –> Coproporphyrinogen III

Question 8

Variegate porphyria

Answer 8

Defective enzyme: Protoporphyrinogen IX oxidase
Hepatic porphyria

Rxn: Protoporphyrinogen IX –> Protoporphyrin IX

King George III
Intermittent abdominal pain
Delirium
Hallucinations
Convulsions
Medicines contained arsenic

Question 9

Crigler-Najjar Syndrome type I

Answer 9

Deficiency of UDP-GT enzyme
-Complete absence of gene

BR accumulates in brain of babies –> encephalopathy (kernicturus) & brain damage

Therapy:
Blood transfusions
Phototherapy
Heme Oxygenase inhibitors
Oral calcium phosphate and carbonate (form complexes with bilirubin in gut)
Liver transplant before brain damage occurs and before phototherapy becomes ineffective

Question 10

Crigler-Najjar Syndrome Type II

Answer 10

Mutation in UDP-GT
Benign form
Enzyme has less activity (10%)

Question 11

Gilbert Syndrome

Answer 11

Common benign disorder
Reduced activity of UDP-GT (25% activity)
Serum BR <6 mg/dL but may increase with fasting, stress, or alcohol consumption

Question 12

Hepatitis

Answer 12

Inflammation of liver –> liver dysfunction
Causes- Viral infections (Hep A, B, C), alcoholic cirrhosis, liver cancer

Increased lvls of unconjugated and conjugated BR in blood
BR accumulates in skin and sclera of the eyes –> yellow discoloration
Dark tea colored urine

Question 13

Color changes in bruises

Answer 13

Hemoglobin- reddish purple
Heme- red
Biliverdin - green
Bilirubin - reddish orange
Hemosiderin (iron) - reddish brown