Aminolevulinate active site

Heme, the most abundant iron cofactor, can play diversified roles in the cell. These roles include not only the already-mentioned regulatory and signal transduction processes, but also electron transfer, oxygen binding and transport, and direct involvement in the oxygen metabolism. The first step of the heme biosynthetic pathway in mammalian cells is catalyzed by 5-aminolevulinic acid synthase (ALAS), which is considered a rate-limiting step in the production of heme. The rate of synthesis of erythroid ALAS is directly dependent on the cellular iron concentration. Ferreira reviews recent structural and site-directed mutagenesis studies on ALAS (Chapter 2), which, for example, have revealed that the homodimeric enzyme s active site is located at the subunit interface and contains catalytically essential residues from both subunits. 

Enzyme Inhibition/Activation. A major site of toxic action for metals is interaction with enzymes, resulting in either enzyme inhibition or activation. Two mechanisms are of particular importance inhibition may occur as a result of interaction between the metal and sulfhydryl (SH) groups on the enzyme, or the metal may displace an essential metal cofactor of the enzyme. For example, lead may displace zinc in the zinc-dependent enzyme 5-aminolevulinic acid dehydratase (ALAD), thereby inhibiting the synthesis of heme, an important component of hemoglobin and heme-containing enzymes, such as cytochromes. 

The effect of tin on heme biosynthesis appears to be dependent on the concentration of zinc (Chmielnicka et al. 1992). Oral administration of tin can affect the heme synthesis by inhibiting e-aminolevulinic acid dehydratase (ALAD) activity in blood. Zinc is required for ALAD activity and provides a protective role in heme synthesis by increasing the activity of ALAD. It is postulated that when the tin and zinc are coadministered, these metals are probably attaching to similar binding sites in the ALAD enzyme (Chmielnicka et al. 1992). 

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