This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lead poisoning is one of the leading causes of mental retardation in children. Anemia resulting from lead exposure is thought to be a result of Pb(II) binding to delta-aminolevulinc acid dehydratase, an enzyme in the heme biosynthetic pathway, whose active site contains Zn(II) coordinated by three cysteine ligands. In addition, Pb(II) may bind to other Zn(II) thiolate sites such as the estrogen receptor protein. Despite the widespread clinical relevance of lead toxicity, little fundamental chemistry describing the rates of reaction of Pb(II) with protein associated thiolates is known. Particularly striking is the absence of detailed studies comparing the affinity and rates of reaction for thiolates with the native metal, Zn(II), and with the most important toxic metal, Pb(II). This proposal seeks to define the metal sites in well-defined metal-thiolate peptide complexes. We have shown previously that Pb binds to the zinc-finger consensus peptide (CP) with PbS3 stoichiometry, even when four sulfur ligands are available. However, we found surprisingly that the Pb site appeared to bind to histidine in preference to cysteine in a subset of these proteins. If correct, this would indicate a previously unanticipated variability in Pb ligation. Alternatively, this could reflect loss of Pb from the peptide on freezing. To test for this, it was necessary to measure XAS data at room temperature. To do so, we constructed a flow cell capable of measuring protein XAS data at room temperature without radiation damage. Initial measurements confirm our expectation that all of the CP derivatives have the same Pb site at room temperature.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZRG1-BBCA (40))
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Illinois Institute of Technology
Other Basic Sciences
Schools of Arts and Sciences
United States
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