Arsenic Binding to Proteins

Overview

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Key numbers

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Department of Laboratory Medicine and Pathology, 10-102 Clinical Sciences Building, University of Alberta, Edmonton, Alberta,
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, Canada, V6T 1Z1
Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada, T6G
4.4. Biotinylated Arsenical Pull-Down 7779
4.5. Metalloproteomic Approaches 7780
1. Characterization of Protein Binding to Arsenic
5.1.1. X-ray Crystallography and Nuclear Mag-
5.1.3. Electrospray Ionization Mass Spectrom-
5.3. Binding Aﬃnity 7782
1. Introduction 7769 Associated Content 7785
1. Chemical Basis and Biological Implications of Supporting Information 7785
Arsenic Binding to Proteins 7770 Author Information 7785
2.1. Arsenic Biomethylation 7771 Corresponding Author 7785
2.2.1. Pyruvate Dehydrogenase (PDH) 7771 Biographies 7785
2.3. Resistance to Arsenic 7772
2.3.1. Metallothionein 7772
2.4. Arsenic Binding to Hemoglobin and Accu- Arsenic is a trace element found in the earth’s crust at an
mulation of Arsenic in Rat Blood 7774 average concentration of ∼5 μg/g (ppm). Although its relative
2.5. Arsenic-Induced Apoptosis 7775 abundance in the earth’s crust is about 54th, arsenic can
2.6. Arsenic Binding to Other Proteins 7776 become concentrated in some parts of the world because of
1. Determination of Arsenic Species Bound to natural mineralization. Arsenic is a component of 245 minerals,
Proteins 7776 associated most frequently with other metals such as copper,
3.1. Fractionation of Protein-Bound Arsenic 7776 gold, lead, and zinc in sulﬁdic ores.1−3 When disturbed by
3.2. Release of Arsenic Species from Proteins 7777 natural processes, such as weathering, biological activity, and
3.3. Determination of Arsenic Species Released volcanic eruption, arsenic may be released into the environ-
from Proteins 7777 ment. Anthropogenic activities, such as combustion of fossil
3.4. Direct Analysis of Arsenic Species by X-ray fuels, mining, ore smelting, and well drilling, also mobilize and
Spectroscopy 7777 introduce arsenic into the environment.
1. Identiﬁcation of Arsenic-Binding Proteins 7777 Chronic exposure to arsenic from groundwater has been
4.1. Autoradiography 7777 recognized to cause the largest environmental health disaster in
4.2. Fluorescent Arsenical Probes 7778 the world, putting more than 100 million people at risk of
4.3. Aﬃnity Chromatography 7778 cancer and other arsenic-related diseases.4,5 Because of its
4.3.1. Protein-Speciﬁc Immunological Aﬃnity
4.3.2. Arsenical Aﬃnity Chromatography 7778 Received: January 18, 2012
© 2013 American Chemical Society 7769 dx.doi.org/10.1021/cr300015c | Chem. Rev. 2013, 113, 7769−7792
Registry (ATSDR) has ranked arsenic as No. 1 on its Priority
priority list, posted in 2011 (http://www.atsdr.cdc.gov/SPL/
index.html), shows arsenic as No. 1, ahead of lead, mercury,
Taiwan,6−8 Argentina,9,10 Chile,11,12 West Bengal, India,13,14
to high concentrations of arsenic and the prevalence of several Figure 1. Binding of inorganic arsenite (iAsIII), monomethylarsonous
eﬀects.24−27 Although the adverse health eﬀects arising from
and DNA. Figure 2 shows a model of iAsIII binding to the

Methods (brief)

cancers,20−23 most severely bladder, lung, and skin cancers. acid (MMAIII), and dimethylarsinous acid (DMAIII) to cysteines in a
dimethylarsinous acid (DMAIII) to cysteine residues in repressor from the DNA, inducing gene expression. This
(iAsIII, MMAIII, and DMAIII) at biologically relevant concen-
DMAV) were found to inhibit the enzymes. All enzymes post-
Cysteine residues are shown as balls and sticks and colored green study (iAsIII, MMAIII, DMAIII, and PAO) bound to human Trx
C224, are believed to be involved in arsenic binding. (Reprinted with DMAIII, and PAO formed complexes with E. coli Trx, consistent
were shown to be inhibited by arsenic include glutathione MMAV, and DMAV) could be reduced by excess Trx at 37 °C
disulﬁde reductase responsible for maintaining proteins in their DMAIII) were shown to release zinc from the zinc ﬁnger
(iAsIII, MMAIII, and DMAIII) can inhibit DNA repair.115−117 nism by which arsenic induces metallothioneins remained
cysteines and one histidine residue (C3H1). Zinc ﬁngers are plasma atomic emission spectrometry (ICP-AES), UV
HPLC−ICP-MS and ESI-quadrupole-TOF-MS.151 The binding
bind up to six iAsIII, 10 MMAIII, and 20 DMAIII, consistent with
MMAIII, DMAIII, iAsV, MMAV, DMAV, and TMAOV) and arsRDABC operon.
MMAIII, and DMAIII). Higher percentages of the trivalent arsenicals cause cell death.174,175 With few exceptions, mitochondria
studies170 showed that DMAV was detected in rat hemoglobin, at the contact sites of the inner and outer membranes, is
further investigations revealed that DMAIII is the actual binding responsible for mitochondrial permeabilization. It is comprised
protein triad that is indispensable for induction of the phase II sac. Moreover, dialysis usually results in sample dilution, and
response, a major cellular reaction to oxidative/electrophile thus, subsequent sample concentration or redissolution after

Implications

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Update history

The five most recent substantive edits to this page, classified major (evidence or structure moved), correction (a published value or statement was wrong and has been fixed), or minor (narrative rewritten without changing the underlying evidence). Each description is derived from what the edit did to this page; the linked commit is the authoritative record, routine regeneration passes are excluded, and the full version history lives in git. When DOI minting comes online (see schema docs), each entry below will also link to a version-pinned DataCite DOI.

Commit	Date	Change	Description
3171d06	2026-08-02	major	1 section added
bc84bfc	2026-08-02	major	6 sections added; narrative text revised