ReviewThe biological chemistry of lead
Introduction
Lead poisoning is the one of the most common pediatric health problems in the United States, affecting approximately 890 000 children nationwide at any given time [1]. The sources of this exposure are primarily leaded paint, which was not banned in the United States until 1978, and contaminated soil. Recent studies suggest that much of the existing soil contamination is probably a result of deposition from exhaust from cars that used leaded gasoline, in addition to leaded paint used on the exterior of buildings [2]. Lead from these sources exists as or evolves into a variety of Pb2+ compounds, which are remarkably persistent in the environment. Unfortunately, these sources of exposure are often expensive to remediate, and the politics surrounding this issue are complex, suggesting that the legacy of lead poisoning will continue to plague mankind for many years to come 3., 4..
Lead poisoning can afflict both children and adults, but the greatest concern is for children, who experience symptoms at significantly lower blood lead levels (BLLs) than do adults [1]. In addition, children tend to develop permanent developmental and neurological problems when exposed chronically to lead, whereas many of the symptoms experienced by adults are reversed when exposure is ceased. Although a broad range of epidemiological studies has been conducted on lead poisoning, its molecular underpinnings have remained relatively obscure. However, recent advances in biophysics and molecular biology have provided the tools necessary to study the biological chemistry of lead. These studies have helped to provide insights into the following questions:
- 1.
Out of all of the molecular targets that have been proposed for lead, which ones are physiologically relevant?
- 2.
How does lead binding affect the structure and dynamics of target proteins?
- 3.
Is lead binding to proteins under thermodynamic or kinetic control?
These studies and questions are the subject of this review, which focuses particularly on work from the past two years.
Section snippets
Molecular targets for lead
Several classes of molecular targets have been proposed to account for the symptoms associated with lead poisoning. With few exceptions, these targets fall into two primary categories: proteins that naturally bind calcium and proteins that naturally bind zinc 5., 6., 7., 8., 9. If these interactions are to be physiologically relevant, lead must bind tightly enough to the proposed target to occupy the site(s) under physiologically relevant conditions. To ascertain whether lead binds ‘tightly
How much bioavailable lead is present in cells?
The amount of bioavailable (or ‘free’) lead has not been determined experimentally for most cell types, because of the lack of sensitive and selective fluorescent probes for lead 10, 11. A child is considered to have lead poisoning if he or she has a total BLL (as measured by atomic absorption spectroscopy) greater than or equal to 10 μg/dl (0.5 μM or 100 parts per billion) [1]. By contrast, a typical person in the United States today who does not have lead poisoning will have a BLL of ∼2 μg/dl
Interactions between lead and zinc proteins
The target for lead that has been studied most thoroughly in vitro and in vivo is the zinc enzyme δ-aminolevulinic acid dehydratase (ALAD, also called porphobilinogen synthase) [8] (Fig. 1). ALAD catalyzes the second reaction in the heme biosynthetic pathway, and inhibition of this enzyme by lead explains (at least in part) the anemia often seen in adults and children with high BLLs (≥40 μg/dl) [8]. The log of the activity of ALAD in erythrocytes decreases linearly with the individual's BLL [18]
Interactions between lead and calcium proteins
In addition to causing developmental problems, lead poisoning results in pervasive neurological problems in both children and adults [30]. Lead interferes with the ability of calcium to trigger exocytosis of neurotransmitters in neuronal cells [31], suggesting that lead might generally target proteins involved in calcium-mediated signal transduction [6]. This hypothesis was bolstered by the observation by Markovac and Goldstein [13] that picomolar concentrations of lead can activate
Conclusions and remaining questions
Over the past five years, a quantum leap has been made in our understanding of the molecular mechanism of lead poisoning. Detailed biophysical studies have revealed that lead binds tightly to both zinc and calcium sites in proteins and alters their activity. However, lead binds to the ‘best’ (cysteine-rich) zinc sites many orders of magnitude more tightly than to the ‘best’ (C2 domain) calcium sites. This tempts the chemist to say that effects of lead on zinc proteins are ‘more important’ than
Update
Recent work has demonstrated not only that Pb2+-TFIIIA does not bind to DNA, but also that addition of Pb2+ to the Zn2+-TFIIIA-DNA adduct causes dissociation of the protein from DNA [47].
Acknowledgements
The original experimental work described herein that was conducted by HAG and co-workers was supported by the Burroughs Wellcome Fund (New Investigator Award in Toxicology to HAG) and the National Institutes of Health (R01 GM58183). HAG is a recipient of a Camille and Henry Dreyfus New Faculty Award, a National Science Foundation CAREER Award, a Camille Dreyfus Teacher-Scholar Award, and a Sloan Research Fellowship.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
of special interest
of outstanding interest
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