Effects on Specific Steps of the Heme Biosynthetic Pathway

Metal Effects on Specific Steps of the Heme Biosynthetic Pathway 

Metals may impair the metabolism of porphyrins and other heme precursors by direct or indirect compromise of heme pathway enzymes or by reducing the availability of substrates and/or cofactors required for enzyme function. 

All eight steps of the heme biosynthetic pathway are catalyzed by enzymes which require functional sulfhydryl (-SH) groups for optimal catalytic activity, either as part of the active site configuration or to maintain their structural integrity. Since most metals have a strong affinity for nucleophilic ligands, each step of the heme biosynthetic pathway is theoretically susceptible to direct inhibition as a result of metal-mercaptide bond formation with functional SH groups. Several heme biosynthetic pathway enzymes have been shown to be particularly susceptible to impairment by specific metals in vitro. Evidence for direct metal-enzyme interactions in vivo, however, is less well substantiated. 

ALA dehydratase, the second enzyme of the heme biosynthetic pathway, is inhibited in vitro by metals and other SH-directed agents. Inhibition of ALA dehydratase in liver and erythrocytes in vitro has been observed with silver, iron, manganese, copper, and zinc ions (Gibson et al. 1955) and in vivo with lead (Sassa 1978) and cobalt (Nakemura et al. 1975). The inhibition of ALA dehydratase in erythrocytes by lead in vivo is well established, and this effect is considered a highly sensitive measure of lead exposure in human subjects (considered further in Sect. D.I, below). 

Porphobilinogen deaminase, which catalyzes the third step in heme biosynthesis, is also readily inhibited by numerous trace metals in vitro. Lead is a particularly effective inhibitor (Piper and Van Lier 1977 Anderson and Desnick 1980). Mercury, cadmium, copper, iron, magnesium, and calcium also impair the purified enzyme, although to a lesser degree than lead (Anderson and Desnick 1980). Studies in vivo have shown that platinum significantly inhibits renal PEG deaminase in kidney (Maines and Kappas 1977). Uroporphyrinogen III cosynthetase has also been shown to be directly inhibited by various metals in vitro, including Na, Mg, Ca , Zn, Cd, and Cu (Piper et al. 1983 Clement et al. 1982). 

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