Lead Binding Reexamined

BIOCHEMISTRY

Lead poisoning may be due to an unanticipated coordination geometry for lead in sulfur-rich sites, a new study suggests.

In the past decade, biologists have found evidence that low levels of lead can cause developmental disorders in children by disrupting the function of regulatory proteins called transcription factors. The prevailing hypothesis is that lead displaces zinc from sulfur-rich structural binding pockets in the proteins, causing them to fold improperly. Yet a detailed chemical understanding of how lead acts differently from zinc to reshape and disable the proteins has been lacking.

A new study shows that lead preferentially binds to only three sulfurs in a trigonal pyramidal configuration, even when additional sulfurs are available (J. Am. Chem. Soc. 2005, 127, 9495). Zinc, on the other hand, binds sulfur in a four-coordinate, tetrahedral fashion. A team of scientists led by chemistry professor Hilary A. Godwin and graduate student John S. Magyar at Northwestern University, along with chemistry professor James E. Penner-Hahn and his group at the University of Michigan, carried out the work.

Godwin says the observed difference in binding explains how lead could cause improper protein folding. That lead would coordinate with sulfur-rich binding sites in a trigonal fashion even when four thiol groups are available never occurred to us, Godwin says. The chemical literature has widely suggested that lead binds sulfur in a four-coordinate fashion.