Arsenic Binding to Proteins

Arsenic is a trace element found in the earth’s crust at an average concentration of ∼5 μg/g (ppm). Although its relative abundance in the earth’s crust is about 54th, arsenic can become concentrated in some parts of the world because of natural mineralization. Arsenic is a component of 245 minerals, associated most frequently with other metals such as copper, gold, lead, and zinc in sulfidic ores.1−3 When disturbed by natural processes, such as weathering, biological activity, and volcanic eruption, arsenic may be released into the environment. Anthropogenic activities, such as combustion of fossil fuels, mining, ore smelting, and well drilling, also mobilize and introduce arsenic into the environment. Chronic exposure to arsenic from groundwater has been recognized to cause the largest environmental health disaster in the world, putting more than 100 million people at risk of cancer and other arsenic-related diseases.4,5 Because of its prevalence in the environment, potential for human exposure, and the magnitude and severity of health problems it causes, the United States Agency for Toxic Substances and Disease Registry (ATSDR) has ranked arsenic as No. 1 on its Priority List of Hazardous Substances for many years. The recent priority list, posted in 2011 (http://www.atsdr.cdc.gov/SPL/index.html), shows arsenic as No. 1, ahead of lead, mercury, and polychlorinated biphenyls (PCBs). Epidemiological studies of populations exposed to high levels of arsenic due to ingestion from water, including those from Taiwan,6−8 Argentina,9,10 Chile,11,12 West Bengal, India,13,14 Bangladesh,15−17 and Inner Mongolia, China,18,19 have repeatedly shown strong associations between the exposure to high concentrations of arsenic and the prevalence of several cancers,20−23 most severely bladder, lung, and skin cancers. Arsenic is classified as a human carcinogen by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency (EPA). Chronic exposure to elevated concentrations of arsenic has also been associated with the increased risk of a number of noncancerous effects.24−27 Although the adverse health effects arising from exposure to arsenic have been well-recognized, the mechanism(s) of action responsible for the diverse range of health effects are complicated and poorly understood.26−30 It is believed that inorganic arsenate (HAsO42-), which is a molecular analogue of phosphate (HPO42-), can compete for phosphate anion transporters and replace phosphate in some biochemical reactions.28 For example, generation of adenosine-5′-triphosphate (ATP) during oxidative phosphorylation can be inhibited by the replacement of phosphate with arsenate. Depletion of ATP by arsenate has been observed in cellular systems.28 However, the replacement of phosphate in DNA by arsenic is not firmly established.31−35 The toxicity of trivalent arsenicals likely occurs through the interaction of trivalent arsenic species with sulfhydryl groups in proteins. Arsenic binding to a specific protein could alter the conformation and function of the protein as well as its recruitment of and interaction with other functional proteins. Therefore, there has been much emphasis on studies of arsenic binding to proteins, for the purpose of understanding arsenic toxicity and developing arsenic-based therapeutics. This review summarizes various aspects of arsenic binding to proteins. It discusses the chemical basis and biological implications and consequences of arsenic binding to proteins. It also describes analytical techniques and the characterization of arsenic binding, including the binding affinity, kinetics, and speciation.