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J. Biol. Chem., Vol. 276, Issue 2, 1531-1537, January 12, 2001
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From the Institute for Cancer Research, Fox Chase Cancer Center,
Philadelphia, Pennsylvania 19111
Human porphobilinogen synthase (PBGS) is a main
target in lead poisoning. Human PBGS purifies with eight Zn(II) per
homo-octamer; four ZnA have predominantly nonsulfur ligands, and four
ZnB have predominantly sulfur ligands. Only four Zn(II) are required
for activity. To better elucidate the roles of Zn(II) and Pb(II), we
produced human PBGS mutants that are designed to lack either the ZnA or
ZnB sites. These proteins, MinusZnA (H131A, C223A) and MinusZnB (C122A,
C124A, C132A), each become purified with four Zn(II) per
octamer, thus confirming an asymmetry in the human PBGS structure.
MinusZnA is fully active, whereas MinusZnB is far less active,
verifying an important catalytic role for ZnB and the removed cysteine
residues. Kinetic properties of the mutants and wild type proteins are
described. Comparison of Pb(II) inhibition of the mutants shows that
ligands to both ZnA and ZnB interact with Pb(II). The ZnB
ligands preferentially interact with Pb(II). At least one ZnA ligand is
responsible for the slow tight binding behavior of Pb(II). The data
support a novel model where a high affinity lead site is a hybrid of
the ZnA and ZnB sites. We propose that the lone electron pair of Pb(II)
precludes Pb(II) to function in PBGS catalysis.
The Molecular Mechanism of Lead Inhibition of Human
Porphobilinogen Synthase*
,
*
This work was supported by Grant ES03654 (to E. K. J.)
from the NIEHS, National Institutes of Health (NIH), by NIH Grant
CA06927 (Institute for Cancer Research), and by an appropriation from the Commonwealth of Pennsylvania.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Institute for Cancer
Research, Fox Chase Cancer Ctr., 7701 Burholme Ave., Philadelphia, PA
19111. Tel.: 215-728-3695; Fax: 215-728-2412; E-mail:
EK_Jaffe@fccc.edu.
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