Rational Identification of Enoxacin as a Novel V-ATPase-Directed Osteoclast Inhibitor

Author(s): Edgardo J. Toro, David A. Ostrov, Thomas J. Wronski, L. Shannon Holliday.

Journal Name: Current Protein & Peptide Science

Volume 13 , Issue 2 , 2012

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Abstract:

Binding between vacuolar H+-ATPases (V-ATPases) and microfilaments is mediated by an actin binding domain in the B-subunit. Both isoforms of mammalian B-subunit bind microfilaments with high affinity. A similar actinbinding activity has been demonstrated in the B-subunit of yeast. A conserved “profilin-like” domain in the B-subunit mediates this actin-binding activity, named due to its sequence and structural similarity to an actin-binding surface of the canonical actin binding protein profilin. Subtle mutations in the “profilin-like” domain eliminate actin binding activity without disrupting the ability of the altered protein to associate with the other subunits of V-ATPase to form a functional proton pump. Analysis of these mutated B-subunits suggests that the actin-binding activity is not required for the “housekeeping” functions of V-ATPases, but is important for certain specialized roles. In osteoclasts, the actin-binding activity is required for transport of V-ATPases to the plasma membrane, a prerequisite for bone resorption. A virtual screen led to the identification of enoxacin as a small molecule that bound to the actin-binding surface of the B2-subunit and competitively inhibited B2-subunit and actin interaction. Enoxacin disrupted osteoclastic bone resorption in vitro, but did not affect osteoblast formation or mineralization. Recently, enoxacin was identified as an inhibitor of the virulence of Candida albicans and more importantly of cancer growth and metastasis. Efforts are underway to determine the mechanisms by which enoxacin and other small molecule inhibitors of B2 and microfilament binding interaction selectively block bone resorption, the virulence of Candida, cancer growth, and metastasis.

Keywords: Osteoclast, vacuolar ATPase, actin, microfilaments, enoxacin, cancer, Candida, Other Cytoskeletal Elements, V-ATPases Bind Microfilaments, immunoprecipitates

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Article Details

VOLUME: 13
ISSUE: 2
Year: 2012
Page: [180 - 191]
Pages: 12
DOI: 10.2174/138920312800493151

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