Haem catabolism

Hemoxl Haem oxygenase Catabolism of cellular haem to bilirubin, carbon monoxide and free iron hemoxl- - mice (Poss and Tonegawa, 1997) Impaired haem catabolism impaired absorption of iron from meat anaemia inflammation... 

Zinc protoporphyrin IX is a normal metabolite that is formed in trace amounts during haem biosynthesis. However, in iron deficiency or in impaired iron utilization, zinc becomes an alternative substrate for ferrochelatase and elevated levels of zinc protoporphyrin IX, which has a known low affinity for oxygen, are formed. This zinc-for-iron substitution is one of the first biochemical responses to iron depletion, and erythrocyte zinc protoporphyrin is therefore a very sensitive index of bone-marrow iron status (Labbe et ah, 1999). In addition, zinc protoporphyrin may regulate haem catabolism by acting as a competitive inhibitor of haem oxygenase, the key enzyme of the haem degradation pathway. However, it has been reported... 

Bilirubin is the waste product derived from haem catabolism. In order to be eliminated from the body, mainly via the gut, bilirubin must be processed through the liver (see Section 6.4). Bilirubin is, however, insoluble in water, so to reach the liver from the spleen where a substantial amount of red cell destruction occurs, bilirubin must first be bound to albumin. As blood perfuses the liver, bilirubin is transported into the hepatocyte where it is conjugated with glucuronic acid prior to excretion. 

Free haem groups are ferroporphyrins (cyclic tetrapyrroles). The first reaction of haem catabolism is the release of iron this is followed by the opening of the ring to produce a linear tetrapyrrole called biliverdin. A molecule of carbon monoxide is released as the ring opens. Biliverdin is converted to bilirubin by reduction. These initial reactions may occur in the liver or in other tissues of the reticuloendothelial system, notably the spleen. 

Figure 6.36 (a) Haem catabolism overview, (b) Haem catabolism conversion of haem into bilirubin... 

Bilirubin and other pigments resulting from haem catabolism,... 

For pathogenic bacteria which can utilise haem as a source of iron, cytosolic iron release is carried out by a bacterial haem oxygenase, the enzyme involved in haem catabolism in many different organisms. 

Haem catabolism occurs in both the liver and gut. Microsomal haem oxygenase of the reticulo-endothelial cells and hepatic parenchymal cells convert haem to biliverdin, and thence rapidly to bilirubin via a reductase. In the gut reduction of methene and vinyl groups of bilirubin results in the formation of colourless urobilinogens which on oxidation produce orange stercobilins that appear in the faeces. All these pigments contain the 4 nitrogen atoms which were initially derived from glycine via haem. 

We should note at this point that the TCA cycle is more than just a means of producing NADH for oxidative phosphorylation. The pathway also provides a number of useful intermediates for other, often synthetic, pathways. For example, citrate is the starting substance for fat synthesis (Chapter 9) succinyl-CoA is required for haem production and 2-oxoglutarate and oxaloacetate in particular are involved with amino acid and pyrimidine metabolism. Pathways which have dual catabolic/anabolic functions are referred to as amphibolic . 

Red blood cells are amongst the most numerous of the human cell lines an average healthy 70 kg male having a total of approximately 25 x cells in his 51 of blood. A typical red cell contains in excess of 600 million haemoglobin molecules which equates to a total of about 300 g of haemoglobin, an amount that is far greater than for any other protein in the body. The lack of a nucleus clearly indicates that red cells cannot divide and at the end of their life, worn out RBCs are removed by the cells of the reticuloendothelial system. Approximately 2% (5 x 1011) of the red cell number are removed and replaced by new ones each day. Haem synthesis is outlined later in this chapter and its catabolism is discussed in Chapter 6. 

Two examples will be used to illustrate phase I and phase II reactions paracetamol and the catabolism of haem groups. 

Approximately 80-85% of the haem which undergoes catabolism each day derives from red blood cells. The remainder is from haem-containing enzymes such as cytochromes, peroxidases and catalase. 

The catabolism of haemoglobin yields haem, which is subsequently converted to bilirubin in a two-step process that takes place in the hepatocyte. First, the microsomal enzyme haem oxygenase cleaves the porphyrin ring of haem, generating biliverdin in an energy-utilising reaction. Following this, biliverdin is converted to bilirubin by the cytosolic enzyme biliverdin reductase. As the liver is the active site for biosynthesis of porphyrin and haem, deficiencies in some enzymes of the porphyrin pathway may lead to insufficient haem production and an increase in porphyrin levels, which causes acute porphyria attacks. 

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