Heme synthesis 2 catabolism

Haem Catabolism

Edwin F. Laing

Dept of Molecular Medicine

School of Medicine and Dentistry

KNUST

Haem catabolism What is the source of haem ?

Haem is derived from:

Haemoglobin in senescent red blood cells removed from circulation by the reticuloendothelial system especially in the spleen

Cytochrome P450 group of enzymes

Other haem proteins

Haem from ineffective erythropoiesis (pernicious anaemia and thalassaemia)

What kind of enzyme is Haem Oxygenase which breaks down haem?

It is substrate inducible

It cleaves the  methine bridge which joins the two pyrrole residues containing the vinyl substituents

It catalyses the only reaction that endogenously releases CO

It only cleaves haem. Free protoporhyrin IX is not a substrate

Catabolism of Haem to Bilirubin

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Conjugation of Bilirubin

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Uridine diphosphate glucuronate: Glucuronidation of substrates 

Gluguronidation reactions

Conjugation of bilirubin

Bilirubin + 2 UDP glucuronate 

Bilirubin diglucuronide + 2 UDP

Conjugation of bilirubin

Bilirubin is transported to the liver bound to albumin and -globulins

In the liver, each of the propionic acid side chains is esterified to the hydroxyl group at C-1 of glucuronic acid to form the water soluble bilirubin diglucuronide

Bilirubin Diglucuronide

Fate of bilirubin diglucuronide

It is poorly absorbed by the intestinal mucosa

The glucuronide residues are removed in the terminal ileum and large intestine by bacterial hydrolases

The released free bilirubin is reduced to colourless linear tetra-pyrroles known as urobilinogens (stercobilinogens)

Urobilinogens can be oxidised to coloured products known as urobilins (stercobilins)

Haem degradation

Causes of Jaundice…..1

Prehepatic (mainly haemolytic)

Neonatal jaundice: physiologic: immature conjugating system

Haemolysis: A,B,O and Rh incompatibilities, G6PD deficiency, Sickle Hb, Thalassaemias

Ineffective erythropoiesis /haemolysis

Autoimmune causes

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Causes of Jaundice…..2

Hepatic

Infection: Viral Hepatits A,B,C: Intra-hepatic cholestasis, Regurgitation of conjugated bilirubin into the serum

Chemical/ Drug: methyl testosterone, phenothiazines, acetaminophen, alcohol

Genetic errors in bilirubin metabolism: uptake and conjugation: Gilbert’s, Crigler Najja syndromes

Genetic errors: specific proteins: Wilson’s disease

Causes of Jaundice…..2

α-1 antitrypsin

Difficulty with excretion of conjugated bilirubin: Dubin-Johnson, Rotor’s syndromes

Autoimmune: Chronic active hepatitis

Causes of Jaundice…..3

Post-Hepatic

Intrahepatic bile ducts: Drugs (oral contraceptives) primary biliary cirrhosis, cholangitis

Extra hepatic bile ducts: Blockage of bile ducts by gall stones

Tumorous processes, cancer of the head of pancreas, cholangiocarcinoma

Causes of Hyperbilirubinemia

Phototherapy: a solution for neonatal jaundice

Uses blue wavelengths of light to alter unconjugated bilirubin in the skin.

Bilirubin is converted to less toxic water-soluble photoisomers

Photoisomers are excreted in the bile and urine without conjugation

Haem degradation