Haem oxygenase

A stressed cell undergoes precise biochemical and morphological changes. General protein synthesis is switched off and a set of specific mRNAs are translated to produce the stress proteins. The intermediate filaments of the cytoskeleton become perinuclear and heat-shock proteins of the 70kDa family are translocated into the nucleus. The 70kDa family appears to play a role in differentiation and development and is crucial to the survival of stressed 

Furthermore, it has been shown both in vitro and in vivo that stress proteins are released during hypoxia/normoxia cycles [80] (ischaemia/reperfusion) and it has been suggested that SOD itself is a stress protein [81]. 

---

In the enterocyte as it enters the absorptive zone near to the villus tips, dietary iron is absorbed either directly as Fe(II) after reduction in the gastrointestinal tract by reductants like ascorbate, or after reduction of Fe(III) by the apical membrane ferrireductase Dcytb, via the divalent transporter Nramp2 (DCT1). Alternatively, haem is taken up at the apical surface, perhaps via a receptor, and is degraded by haem oxygenase to release Fe(II) into the same intracellular pool. The setting of IRPs (which are assumed to act as iron biosensors) determines the amount of iron that is retained within the enterocyte as ferritin, and that which is transferred to the circulation. This latter process is presumed to involve IREG 1 (ferroportin) and the GPI-linked hephaestin at the basolateral membrane with incorporation of iron into apotransferrin. (b) A representation of iron absorption in HFE-related haemochromatosis. 

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... 

Hockin, L.J. and Paine, A.J. (1983). The role of 5-aminolevulinate synthetase, haem oxygenase and ligand formation in the mechanism of maintenance of cytochrome P-450 concentration in hepatocyte culture. Biochem. Pharmacol. 210 855-857. 

Foresti R, Hoque M, Bains S, Green CJ, Motterlini R. 2003. Haem and nitric oxide Synergism in the modulation of the endothelial haem oxygenase-1 pathway. Biochem J 372 381-390. 

Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J, Motterlini R. 2003. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 371 887-895. 

Rajdev S., Fix A. S., and Sharp F. R. (1998). Acute phencyclidine neurotoxicity in rat forebrain induction of haem oxygenase-1 and attenuation by the antioxidant dimethylthiourea. Eur. J. Neurosci. 10 3840-3852. 

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. 

The oxidation of haem, a complex consisting of iron and protoporphyrin which is derived from haemoglobin, is effected by haem oxygenase to produce biliverdin IXa. This is converted to bilirubin IXa by biliverdin reductase. The reaction speed of this process is governed by the haem oxygenase. This enzyme complex contains the inducible cytochrome P 450, which accelerates bilirubin production when the haemoglobin level is elevated. A small proportion of bilirubin (20-30%) is produced from the degradation of other metalloporphyrins. (s. fig. 3.1)... 

The resonance Raman spectrum of hydroperoxo-myoglobin at 77 K gave the first observation of vFeO, at 617 cm-1 (592 cm-1 for 180).301 Dioxygen-bound haem oxygenase from Corynebacterium diphtheriae, has vFe-02 at 565 cm-1 and 8Fe-0-0 aat 415 cm-1.302... 

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. 

---