Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Current Topics - Rotational Catalysis and Diverse Functions of Proton-Pumping ATPases
Foreword
Mayumi Nakanishi-Matsui
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2022 Volume 45 Issue 10 Pages 1403

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F-type ATPase (ATP synthase, F-ATPase) and V-type ATPase (vacuolar-type ATPase, V-ATPase) are proton-pumping ATPases that couple the synthesis or hydrolysis of ATP with proton transport across the membrane, and have been the subject of considerable fascination for more than a half century. In these enzymes, a complex of rotor subunits rotates against another part of the enzyme just like a merry-go-round, to couple catalysis and proton transport. No other enzyme is known to rotate in this manner. Subunit rotation of F-ATPase was predicted mainly based on biochemical analyses, but single molecule visualization was crucial for demonstrating conclusively the rotation of F-ATPase and later V-ATPase. Single molecule observations, together with structural analysis, have provided powerful methods to analyze rotational catalysis, and have highlighted unexpected features of enzymatic catalysis and the detailed mechanism at the amino acid level. Rotational catalysis allows highly efficient energy transduction, and must be a well-established mechanism for ATP generation since most organisms from bacteria to mammals share the same enzyme.

In this series of mini reviews, the first one entitled “Proton-Pumping ATPases: Rotational Catalysis, Physiological Roles in Oral Pathogenic Bacteria, and Inhibitors,” written by Dr. Sekiya, provides an overview of the mechanism underlying rotational catalysis of bacterial proton-pumping ATPases, as revealed by single molecule observations. The review also summarizes the roles of F- and V-ATPases in oral pathogenic bacteria, such as Streptococcus mutans and Porphyromonas gingivalis, and discusses the possibility that bacterial ATPases could be targeted to develop novel antimicrobial agents.

Subunit rotation coupled with catalysis must be regulated to facilitate adaptation to changing conditions. The second review entitled “Regulatory Mechanisms and Environmental Adaptation of the F-ATPase Family” written by Dr. Iwamoto-Kihara covers the regulatory mechanisms of F-ATPases in mammals, bacteria, and plants. Interestingly, each organism has developed its own strategy to control F-ATPase activity. The review also describes how oral bacteria utilize their F-ATPase to survive in an acidic microenvironment generated by them.

Another interesting aspect of these proton pumps is that the structure of V-ATPase resembles that of F-ATPase, but unlike that of F-ATPase, V-ATPase possesses a diversity of subunit isoforms: six subunits among those of V-ATPase have cell/organelle-specific isoforms, and thereby, this proton pump shows considerable structural diversity. Importantly, the structural diversity enables V-ATPase to perform a wide variety of functions. To date, V-ATPase is reported to be involved in organelle trafficking, cell signaling, establishment of cell polarity, metastasis, and acid addiction of cancer cells.

The third review entitled “Exploring the Link between Vacuolar-Type Proton ATPase and Epithelial Cell Polarity” by Drs. Sun-Wada and Wada provides a brief overview of the function of V-ATPase and V-ATPase-driven luminal acidification of the endomembrane in the establishment and maintenance of apical-basal polarity of epithelial cells. Morphogenesis of epithelial cells is important for their fundamental physiological functions, including secretion, selective absorption, transcellular transport, and sensing. Luminal acidification by V-ATPase plays regulatory roles in vesicular trafficking, which is required for the establishment and maintenance of cell polarity.

The last review, entitled “V-ATPase a3 Subunit in Secretory Lysosome Trafficking in Osteoclasts,” by myself describes the function of V-ATPase in organelle trafficking. Lysosomal digestive enzymes are secreted into the extracellular space from osteoclasts, which is essential for bone resorption. We found that lysosomal V-ATPase plays a key role in anterograde trafficking of secretory lysosomes in osteoclasts. In this context, the V-ATPase recruits regulators for lysosomal trafficking.

This series of mini reviews provide a deeper understanding of the unique mechanisms underlaying rotational catalysis of proton-pumping ATPases and their diverse functions in oral bacteria and mammalian cells. I hope that this issue of Current Topics will inspire your research and encourage you to envisage the possibility that proton-pumping ATPases may be implicated in the biological systems under study in your field of scientific research.

 
© 2022 The Pharmaceutical Society of Japan
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