Structure of the formate transporter FocA reveals a pentameric aquaporin-like channel

Wang, Yi; Huang, Yongjian; Wang, Jiawei; Cheng, Chao; Huang, Weijiao; Lu, Pinyan; Xu, Yanan; Wang, Peng‐Ye; Yan, Nieng; Shi, Yigong

doi:10.1038/nature08610

Cited by 150 publications

(234 citation statements)

References 35 publications

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“…PFC0725c encodes a single putative formate-nitrite transporter (PfFNT, 34.4 kDa) whose expression profile 11,12 parallels that of the plasmodial HT (Fig. 1b), the lactate dehydrogenase and all glycolytic enzymes ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We used the available crystal data of various bacterial FNTs 12,[14][15][16] ( Supplementary Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

“…4 and Supplementary Table 2). Generally, FNTs are restricted to microorganisms and operate as pentameric, aquaporin-like transporters for formate [12][13][14] , nitrite 15 and hydrosulfide 16 . Yet, none of these anions have been reported to be relevant in plasmodial metabolism.…”

Section: Resultsmentioning

confidence: 99%

“…Deletion of the PfFNT gene, for which a conditional knockout system is likely to be required, will ultimately reveal its contribution to P. falciparum viability and virulence. It is particularly appealing that PfFNT is structurally unrelated to human transporters and that crystal data are available from homologous bacterial FNTs [12][13][14][15][16] , enabling development of lactate transport as a novel antimalarial drug target. Conversely, the identification of PfFNT inhibitors may aid development of antibiotics.…”

Section: Discussionmentioning

confidence: 99%

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Identity of a Plasmodium lactate/H+ symporter structurally unrelated to human transporters

et al. 2015

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Maintenance of a high glycolytic flow rate is critical for the rapid growth and virulence of malarial parasites. The parasites release two moles of lactic acid per mole of glucose as the anaerobic end product. However, the molecular identity of the Plasmodium lactate transporter is unknown. Here we show that a member of the microbial formate-nitrite transporter family, PfFNT, acts as a lactate/proton symporter in Plasmodium falciparum. Besides L-lactate, PfFNT transports physiologically relevant D-lactate, as well as pyruvate, acetate and formate, and is inhibited by the antiplasmodial compounds phloretin, furosemide and cinnamate derivatives, but not by p-chloromercuribenzene sulfonate (pCMBS). Our data on PfFNT monocarboxylate transport are consistent with those obtained with living parasites. Moreover, PfFNT is the only transporter of the plasmodial glycolytic pathway for which structure information is available from crystals of homologous proteins, rendering it amenable to further evaluation as a novel antimalarial drug target.

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Section: Resultsmentioning

confidence: 99%

“…We used the available crystal data of various bacterial FNTs 12,[14][15][16] ( Supplementary Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identity of a Plasmodium lactate/H+ symporter structurally unrelated to human transporters

et al. 2015

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“…Indeed, recent fi ndings have demonstrated that a formate transporter shows an AQP-like channel structure [34,35] , thus lending support to the radical notion that an aquaporin structure may have the potential to function as a unidirectional water transporter in cooperation with other molecules, at least under certain circumstances.…”

Section: Efficient Sperm Volume Regulation Is a Prerequisite For Normmentioning

confidence: 84%

Aquaporins in sperm osmoadaptation: an emerging role for volume regulation

Chen

Duan

2011

Acta Pharmacol Sin

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Upon ejaculation, mammalian sperm experience a natural osmotic decrease during male to female reproductive tract transition. This hypo-osmotic exposure not only activates sperm motility, but also poses potential harm to sperm structure and function by inducing unwanted cell swelling. In this physiological context, regulatory volume decrease (RVD) is the major mechanism that protects cells from detrimental swelling, and is essential to sperm survival and normal function. Aquaporins are selective water channels that enable rapid water transport across cell membranes. Aquaporins have been implicated in sperm osmoregulation. Recent discoveries show that Aquaporin-3 (AQP3), a water channel protein, is localized in sperm tail membranes and that AQP3 mutant sperm show defects in volume regulation and excessive cell swelling upon physiological hypotonic stress in the female reproductive tract, thereby highlighting the importance of AQP3 in the postcopulatory sperm RVD process. In this paper, we discuss current knowledge, remaining questions and hypotheses about the function and mechanismic basis of aquaporins for volume regulation in sperm and other cell types. Efficient sperm volume regulation is a prerequisite for normal sperm functionIn most mammalian species studied, the journey of sperm from the male to the female reproductive tract experience a natural osmotic decrease [1] , an evolutionary vestige from freshwater fi sh species [2] . Before ejaculation, the mammalian sperm are quiescent in the relatively hypertonic male reproductive tract with no or very low motility. Upon copulation, the sperm enter into the relatively hypotonic female reproductive tract and quickly show motility activation [3,4] , indicating that osmotic changes are beneficial for initial sperm motility activation. However, postcopulatory hypotonic stress also has a negative effects as it induces osmotic cell swelling, which if uncontrolled, can be detrimental to sperm function and survival [5] . Mammalian sperm have evolved to effectively reduce the negative impact of hypotonic cell swelling by means of regulatory volume decrease (RVD), which was proposed to involve efficient volume regulation driven by active solute transport and rapid transmembrane water movement [6] .Functional importance of aquaporins in sperm volume regulation: emerging evidence from AQP3 knockout miceIn the early 1970s, it was demonstrated that the water permeability coefficient of bull spermatozoa was quite high, about four times greater than that of bovine erythrocytes and between ten and thirty times greater than that of artificial bimolecular lipid membranes [7] . According to these observations, the author made an insightful conclusion that the chief route for the passage of water through the sperm membrane must be via "pores" [7] . Similar high water permeability coefficients have been discovered in other mammalian species, including humans [8,9] .In the past two decades, the understanding of the movement of water through cell membranes has been greatly advanced by ...

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Structural Biology of Membrane Proteins

Salom

Palczewski

2011

Production of Membrane Proteins

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Structure of the formate transporter FocA reveals a pentameric aquaporin-like channel

Cited by 150 publications

References 35 publications

Identity of a Plasmodium lactate/H+ symporter structurally unrelated to human transporters

Identity of a Plasmodium lactate/H+ symporter structurally unrelated to human transporters

Aquaporins in sperm osmoadaptation: an emerging role for volume regulation

Structural Biology of Membrane Proteins

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