Ferrochelatase deficiency

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... 

The last enzyme in the pathway, heme synthase (ferrochelatase), introduces the Pe into the heme ring. Deficiency of iron produces a microcytic hypochromic anemia. 

The insertion of ferrous iron into the porphyrin ring in the biosynthesis of heme is catalyzed by the enzyme ferrochelatase. A deficiency in ferrochelatase activity results in an accumulation or the excretion of unchelated protoporphyrin in patients with erythrohepatic protoporphyria. Ferrochelatase catalyzes the synthesis of a range of metalloporphyrins,628 and, for example, produces zinc protoporphyrin in erythrocytes of patients with iron-deficiency anaemia. 

Frataxin involvement in heme synthesis was suggested due to the striking phenotype of frataxin deficient yeast mutants almost completely lacking heme biosynthetic activity while retaining zinc chelatase activity 4). A direct interaction between frataxin and ferrochelatase was originally shown with the... 

Methionine deficiency leads to coproporphyrin accumulation. Lascelles and Hatch [145] suggested that heme formation may be inhibited under these conditions, perhaps at the iron insertion step because methionine is required for the synthesis of phosphatidyl choline and the latter appears to be needed for ferrochelatase activity. Tait [147a] reported that under anaerobic conditions the conversion of coproporphyrinogen to protoporphyrinogen required methionine, ATP, and ferrous ions. 

An alternate mechanism to explain the etiology of elevated erythrocyte ZPP during lead exposure has its basis in the relative affinities of iron and zinc as substrates for ferrochelatase. Ferrous iron is the preferential substrate of ferrochelatase and is also an effective inhibitor of zinc utilization by this enzyme. However, when the concentration of iron as Fe decreases to suboptimal levels, as in iron deficiency, zinc is utilized by ferrochelatase as a substrate. Studies have suggested that lead decreases the availability of Fe as a substrate for ferrochelatase by inhibiting the enzymatic reduction of Fe " to Fe within mitochondria (Taketani et al. 1985), as required for use... 

Mitochondria play a key role in iron metabolism since heme and various iron-sulfur (Fe-S)-cluster containing proteins are synthesized in them. The last step in heme biosynthesis, the insertion of Fe into protoporphyrin IX by ferrochelatase, takes place in the mitochondrial matrix. Fe-S clusters are synthesized mainly, if not entirely, in mitochondria and are combined with mitochondrial apo-proteins to form mature proteins or are exported from mitochondria for utilization by cytosolic and nuclear proteins. Table 8.2 summarizes some known proteins involved in mitochondrial iron homeostasis and utilization and their deficiency-related human disorders. 

Lead also has a toxic effect on the last step in the haem synthesis pathway, which is the insertion of iron into protoporphyrin to create haem. If the enzyme ferrochelatase, responsible for this change, is inhibited by lead, this fails to take place. The amount of protoporphyrin in the erythrocytes, called zinc-protoporphyrin or erythrocyte protoporphyrin (ZZP or EPP), can be used as a measure of this effect. However, it is a less useful measure in studies of the effects of low levels of lead exposure, as an increase in EPP may not be detected at blood levels below about 20jUg/dl (Piomelli et al, 1982), although this threshold for the effect may vary with age (Succop et al,this volume). Other factors, such as iron deficiency, can also cause an increase in EPP levels in the blood... 

---