Ferrochelatase

Lead-induced anemia results from impairment of heme biosynthesis and acceleration of red blood cell destmction (10,13). Lead-induced inhibition of heme biosynthesis is caused by inhibition of S-aminolevulinic acid dehydratase and ferrochelatase which starts to occur at blood lead levels of 10 to 20 pu gjdL and 25 to 30 //g/dL, respectively (10,13). Anemia, however, is not manifested until higher levels are reached. 

Ferretane reactions, 1, 667 Ferrochelatase, 4, 396 Ferrosilacyclopentane properties, 1, 594 Fervenulin applications, 3, 456 Filter dyes... 

The final step in heme synthesis involves the incorporation of ferrous iron into protoporphyrin in a reaction catalyzed by ferrochelatase (heme synthase), another mitochondrial enzyme (Figure 32-4). 

In summary, lead inhibits the activity of certain enzymes involved in heme biosynthesis, namely, 5-aminolevulinic acid dehydratase (ALAD), and ferrochelatase. As a consequence of these changes, heme biosynthesis is decreased and the activity of the rate limiting enzyme of the pathway,... 

ALAD, and ferrochelatase. Lead indirectly stimulates the mitochondrial enzyme ALAS, which catalyzes the condensation of glycine and succinyl-coenzyme A to form ALA. The activity of ALAS is the rate-limiting step in heme biosynthesis increase of ALAS activity occurs through feedback derepression. Lead... 

Inhibition of ferrochelatase in the heme pathway causes accumulation of protoporphyrin in erythrocytes (CDC 1985). Most protoporphyrin in erythrocytes (about 90%) exists as zinc protoporphyrin (ZnPP). This fraction is preferentially measured by hematofluorometers. Extraction methods measure all the protoporphyrin present, but strip the zinc from the ZnPP during the extraction process. For this reason,... 

Cerklewski and Forbes 1976). Also, excess zinc protects zinc-containing enzymes like ALAS, ferrochelatase, and ALAD. In vivo, aqueous solution containing zinc administered to rats significantly reduced the genotoxic effects induced by lead (Kowalska-Wochna et al. 1988). It was postulated that zinc s protective action may be related to its functioning in DNA and RNA polymerases and consequent enhancement of cell repair processes. 

Figure 7.2 (a) Schematic representation of the structure of B. subtilis ferrochelatase. Domain I is coloured green and domain II blue. The parts of the chain in red build up the walls of the cleft, and the region in yellow makes the connection between the domains. The N- and C-termini are marked, (b) The proposed active site of ferrochelatase with protoporphyrin IX molecule (red) modelled into the site. The backbone atoms of the protein are in purple, the side-chains in blue. Reprinted from Al-Karadaghi et ah, 1997. Copyright (1997), with permission from Elsevier Science. 

Figure 7.1 The overall pathway of haem biosynthesis. 5-AminolaevuIinate (ALA) is synthesized in the mitochondrion, and is transferred to the cytosol where it is converted to porphobilinogen, four molecules of which condense to form a porphyrin ring. The next three steps involve oxidation of the pyrrole ring substituents to give protoporphyrinogen fX, whose formation is accompanied by its transport back into the mitochondrion. After oxidation to protoporphyrin IX, ferrochelatase inserts Fe2+ to yield haem. A, P, M and V represent, respectively acetyl, propionyl, methyl and vinyl (—CH2=CH2) groups. From Voet and Voet, 1995. Reproduced by permission of John Wiley Sons, Inc.

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 haem molecule would be incomplete without iron so this must be delivered to the progenitor red cells. Iron is toxic so it is carried in the plasma bound to a specific protein named transferrin (Tf). Uptake of iron is via a Tf receptor, of which there are approximately 300 000 per cell. The whole iron/Tf complex is taken into the cell by endocytosis where the iron is released and made available for incorporation into the porphyrin ring by ferrochelatase. 

Antibodies also well catalyze the reactions where a molecule should he forced to adopt a particular and reactive conformation, thanks to privileged interactions with the amino acids of the binding site. For example, ahzymes with a ferrochelatase activity, 7G12, force the mesoporphyrin IX ring to adopt a distorted conformation favorable to the insertion of a Cu ion in the center of the macrocycle,thanks to an interaction with the HlOOc methionine which constrains one of the pyrrole rings to be left outside the plane of porphyrin (Figure 24). 

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

Lead inactivates many enzjnnes including ALA dehydrase and ferrochelatase (hetne synthase), and can produce a microcytic sideroblastic anemia with ringed sideroblasts in the bone marrow. Other symptoms include ... 

Answer C. Lead inhibits both ferrochelatase (increasing the zinc protoporphyrin) and ALA dehydrase (increasing 5-ALA). 

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