Affiliations: [a] Department of Atomic and Molecular Physics, Manipal University, Manipal 576104, Karnataka, India | [b] Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami 33199, FL, USA
Correspondence:
[*]
Corresponding author: A. Abdul Ajees, Department of Atomic and Molecular Physics, Manipal University, Manipal 576104, Karnataka, India. Tel.: +91 8147966458; E-mail:[email protected]
Abstract: Over the past three decades the occurrence of
high environmental concentrations of arsenic has been recognized as a major
public health concern. Arsenic is a carcinogen and causative agent for
number of diseases. The toxic and carcinogenic effects of arsenic are the
result of inactivation of specific enzymes of metabolism, induction of
oxidative stress, inhibition of DNA repair mechanisms and deregulation of
cell proliferation. Despite its toxicity, arsenic has a long history of
usage as chemotherapeutic agent. Today, drugs containing arsenic (and the
related metalloid antimony) are used for treating acute promyelocytic
leukemia and diseases caused by protozoan parasites. In response to its
toxicity, many microorganisms have developed arsenic resistance mechanism.
In bacteria, arsenic resistance genes are organized in ars operons. The best
characterized, the ars operon from Escherichia coli plasmid R773, has five genes, arsRDABC. ArsC is a
reductase that reduces inorganic As(V) to As(III). ArsR is a 117-residue
homodimeric As(III)-responsive transcriptional repressor with high affinity
for the ars promoter. ArsA is an ATPase, which is the catalytic subunit of the
ArsAB efflux pump, and ArsD is an As(III) chaperone to the ArsAB pump. ArsD
is a homodimer of two 120-residue subunits with three vicinal cysteine
pairs, Cys12-Cys13, Cys112-Cys113 and Cys119-Cys120. A fully-active
truncated version of ArsD protein with 109 residues (ArsD109) has been
crystallized, and the structure has been solved using X-ray crystallography.
Biochemical studies suggested that wild-type ArsD binds three As(III) per
monomer, while the derivative with a truncation at residue 109 binds only a
single As(III). To understand the secondary structure and folding of the
C-terminus of ArsD, which includes two cysteine pairs Cys112-Cys113 and
Cys119-Cys120, Molecular Dynamics (MD) simulations were employed using
AMBER software in presence or absence of arsenite [As(III)] ligand.
