Therapeutic and analytical applications of arsenic binding to proteins

Abstract

Arsenic binding to proteins plays a pivotal role in the health effects of arsenic. Further knowledge of arsenic binding to proteins will advance the development of bioanalytical techniques and therapeutic drugs. This review summarizes recent work on arsenic-based drugs, imaging of cellular events, capture and purification of arsenic-binding proteins, and biosensing of arsenic. Binding of arsenic to the promyelocytic leukemia fusion oncoprotein (PML-RARα) is a plausible mode of action leading to the successful treatment of acute promyelocytic leukemia (APL). Identification of other oncoproteins critical to other cancers and the development of various arsenicals and targeted delivery systems are promising approaches to the treatment of other types of cancers. Techniques for capture, purification, and identification of arsenic-binding proteins make use of specific binding between trivalent arsenicals and the thiols in proteins. Biarsenical probes, such as FlAsH-EDT2 and ReAsH-EDT2, coupled with tetracysteine tags that are genetically incorporated into the target proteins, are used for site-specific fluorescence labelling and imaging of the target proteins in living cells. These allow protein dynamics and protein-protein interactions to be studied. Arsenic affinity chromatography is useful for purification of thiol-containing proteins, and its combination with mass spectrometry provides a targeted proteomic approach for studying the interactions between arsenicals and proteins in cells. Arsenic biosensors evolved from the knowledge of arsenic resistance and arsenic binding to proteins in bacteria, and have now been developed into analytical techniques that are suitable for the detection of arsenic in the field. Examples in the four areas, arsenic-based drugs, imaging of cellular events, purification of specific proteins, and arsenic biosensors, demonstrate important therapeutic and analytical applications of arsenic protein binding.

Effect of Metals, Metalloids and Metallic Nanoparticles on Microalgae Growth and Industrial Product Biosynthesis: A Review

“…Content and compositions of arsenoorganics formed in microalgae Chlorella and Monoraphidium [ 65 ], Dunaliella and Phaeodactylum [ 163 ], Chlamydomonas [ 160 ] or cyanobacteria Synechocystis [ 157 , 161 ] and Nostoc [ 161 ] cells depends on microalgae strain used, as well as on arsenic(V) concentration applied, exposure time and phosphate availability. Arsenolipids and arsenosugars are currently evaluated as possible therapeutic agents [ 164 ]. However, application of As-containing compounds is limited due to high toxicity and so far, only derivatives of arsenolipids have been reported to possess any medical applications [ 159 ].…”

Organic Arsenicals as Functional Motifs in Polymer and Biomaterials Science

“…The specificity can be enhanced further by protein engineering and/or molecule design strategies. Tetra‐cysteine sequences Cys‐Cys‐Xxx‐Xxx‐Cys‐Cys engineered into native protein sequences bind organic bis‐arsenicals with much greater affinity than mono and native dithiol equivalents and have been utilized to develop highly specific fluorescent labels (vide infra) . More notably, controlling the spacing between the arsenical functional groups in bis‐ and tris‐arsenicals elicits stronger binding ( K d ≈ 50 × 10 −9 m ) to native proteins that contain redox‐active thiol and disulfide rich domains, such as those associated with protein folding (e.g., protein disulfide isomerase) and redox homeostasis (e.g., thioredoxin), than mono‐arsenical analogues ( K d ≈ 1 × 10 −6 m ) …”

Mechanisms of Arsenic-Induced Toxicity with Special Emphasis on Arsenic-Binding Proteins

“…From the mechanistic standpoint, arsenic binding to cellular proteins can be a plausible mechanism of toxicity based on two hypotheses premised on functional disruption arising out of (a) sulfhydryl groups in proteins forming covalent bond with arsenite [8] and (b) the phosphate groups in proteins replaced by an arsenate. Arsenic binding to a specific protein could change the conformation and interaction with other functional proteins [9].…”