Integral membrane pyrophosphatases: a novel drug target for human pathogens?

Nita R. Shah; Keni Vidilaseris; Henri Xhaard; Adrian Goldman; Nita R. Shah; Keni Vidilaseris; Henri Xhaard; Adrian Goldman

doi:10.3934/biophy.2016.1.171

AIMS Biophysics

2016, Volume 3, Issue 1: 171-194. doi: 10.3934/biophy.2016.1.171

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Integral membrane pyrophosphatases: a novel drug target for human pathogens?

1.
School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
2.
Department of Biosciences, Division of Biochemistry, University of Helsinki, Helsinki, Finland.
3.
Faculty of Pharmacy, Centre for Drug Research, University of Helsinki, Helsinki, Finland

Received: 30 December 2015 Accepted: 01 March 2016 Published: 07 March 2016

Membrane-integral pyrophosphatases (mPPases) are found in several human pathogens, including Plasmodium species, the protozoan parasites that cause malaria. These enzymes hydrolyze pyrophosphate and couple this to the pumping of ions (H⁺ and/or Na⁺) across a membrane to generate an electrochemical gradient. mPPases play an important role in stress tolerance in plants, protozoan parasites, and bacteria. The solved structures of mPPases from Vigna radiata and Thermotoga maritima open the possibility of using structure-based drug design to generate novel molecules or repurpose known molecules against this enzyme. Here, we review the current state of knowledge regarding mPPases, focusing on their structure, the proposed mechanism of action, and their role in human pathogens. We also summarize different methodologies in structure-based drug design and propose an example region on the mPPase structure that can be exploited by these structure-based methods for drug targeting. Since mPPases are not found in animals and humans, this enzyme is a promising potential drug target against livestock and human pathogens.
- pyrophosphatase,
- structure-based drug design,
- membrane,
- human pathogens,
- malaria
Citation: Nita R. Shah, Keni Vidilaseris, Henri Xhaard, Adrian Goldman. Integral membrane pyrophosphatases: a novel drug target for human pathogens?[J]. AIMS Biophysics, 2016, 3(1): 171-194. doi: 10.3934/biophy.2016.1.171

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Abstract

Membrane-integral pyrophosphatases (mPPases) are found in several human pathogens, including Plasmodium species, the protozoan parasites that cause malaria. These enzymes hydrolyze pyrophosphate and couple this to the pumping of ions (H⁺ and/or Na⁺) across a membrane to generate an electrochemical gradient. mPPases play an important role in stress tolerance in plants, protozoan parasites, and bacteria. The solved structures of mPPases from Vigna radiata and Thermotoga maritima open the possibility of using structure-based drug design to generate novel molecules or repurpose known molecules against this enzyme. Here, we review the current state of knowledge regarding mPPases, focusing on their structure, the proposed mechanism of action, and their role in human pathogens. We also summarize different methodologies in structure-based drug design and propose an example region on the mPPase structure that can be exploited by these structure-based methods for drug targeting. Since mPPases are not found in animals and humans, this enzyme is a promising potential drug target against livestock and human pathogens.

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