8-Aminolevulinic acid synthase , lead

Several other classes of proteins have also been implicated as possible targets for lead, including other proteins in the heme biosynthetic pathway, leadbinding proteins in the kidney and brain, and heat shock proteins (342, 500-502). Lead is known to affect several steps in the heme biosynthetic pathway other than that catalyzed by ALAD Other profound effects include stimulation of 5-aminolevulinic acid synthase (ALAS) and decreased levels of iron incorporation into protoporphyrin by ferrochelatase (see Section VI.E.2 and Fig. 34) (10, 503-505). However, not all of these effects are due to direct interactions between lead and enzymes in the heme biosynthetic pathway. For instance, the widespread assertion that lead inhibits ferrochelatase is not supported by studies on the isolated enzyme (506, 507). Furthermore, increased levels of both erythrocyte protoporphyrin IX (EP) and zinc protoporphyrin (ZPP) are observed at high BLLs, suggesting that ferrochelatase is stiU competent to insert zinc into EP and that the increased levels of EP and ZPP associated with lead poisoning are most likely caused by lead interfering with iron uptake or transport (see Sections VI.C.4 and VI.E) (10, 506, 507). 

Goering PL, BA. 1987. Metal constitution of metallothionein influences inhibition of delta-aminolevulinic acid dehydratase (porphobiligen synthase) by lead. Biochem J 245 339-345. 

Figure 9-7. Pathway for heme biosynthesis. Regulation by hemin at the key aminolevulinic acid (ALA) synthase-catalyzed step and by lead at two steps is indicated.

Weaver, V.M., B.K. Lee, A.C. Todd, K.D. Ahn, W. Shi, B.G. Jaar, K.T. Kelsey, M.E. Lustberg, E.K. Silbergeld, P.J. Parsons, J. Wen, and B.S. Schwartz. 2006. Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers. Environ. Res. 102(l) 61-69. 

Theppyang, K., Schwartz, B.S., Lee, B.-K., 2004. Associations of patella lead with polymorphisms in the Vitamin D receptor, 6-aminolevulinic acid dehydratase and endothelial nitric oxide synthase genes. J. Occup. Med. 46, 528—537. 

Weaver, V.M., Schwartz, B.S., Ahn, K.-D., Stewart, W.F., Kelsey, KT., Todd, A.C., et al., 2003. Associations of renal function with polymorphisms in the 6-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers. Environ. Health Perspect. Ill, 1613—1619. 

Doss, M., Becker, U., Sixel, E., Geisse, S., Solcher, H., Schneider, J., 1982. Persistent proto-porphyrinemia in hereditary porphobilinogen synthase (8-aminolevulinic acid dehydrase) deficiency under low lead exposure a new molecular basis for the pathogenesis of lead intoxication. Klin. Wochenscr. 60, 599-606. 

---