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The transmembrane transport of weak acid and base metabolites depends on the local pH conditions that affect the protonation status of the substrates and the availability of co-substrates, typically protons. Different protein designs ensure the attraction of substrates and co-substrates to the transporter entry sites. These include electrostatic surface charges on the transport proteins and complexation with seemingly transport-unrelated proteins that provide substrate and/or proton antenna, or enzymatically generate substrates in place. Such protein assemblies affect transport rates and directionality. The lipid membrane surface also collects and transfers protons. The complexity in the various systems enables adjustability and regulation in a given physiological or pathophysiological situation. This review describes experimentally shown principles in the attraction and facilitation of weak acid and base transport substrates, including monocarboxylates, ammonium, bicarbonate, and arsenite, plus protons as a co-substrate.
Transport of weak acid and base metabolites across the cell membrane is critical for numerous vital processes, including energy metabolism and pH regulation. Acidic metabolites, e.g., lactic, acetic, or pyruvic acid, exhibit pK
Values around 4, rendering them >99% deprotonated to their anionic form, i.e., lactate, acetate, and pyruvate, at neutral pH. Basic metabolites, e.g., ammonia, in turn, with pK
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Values around 9, accept a proton under physiological pH conditions, giving rise to positively charged ammonium. As charged entities, the passage of such metabolites across cell membranes is strongly hampered.
Transport proteins facilitate the transfer of metabolite ions across the membrane by dealing properly with the accompanying protons. Contrary to primary active transporters that use the release of chemical energy from hydrolysis of ATP to transport even against existing transmembrane gradients, secondary active transporters, e.g., for lactate/H
, use the ionic force derived from the transmembrane gradient of one substrate to transport another. Their activity depends on the complex regulation of substrate and proton gradients around their transport sites.
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Calculations indicate that the high cytosolic concentration in the millimolar range of household metabolites, such as lactate, pyruvate, and also ATP, make it impossible for the relatively slow transporters to deplete the concentration around their transport site before being regenerated by the Brownian diffusion [1]. For these high-concentration metabolites, the cytosol is comparable to a well-mixed compartment of homogenous concentration. However, the same is not true for the co-transported protons. Their much lower concentration in the nanomolar range seems at odds with the observed turnover rate of some transporters (85 s
For human monocarboxylate transporter 1 (MCT1)) [2]. The transporter activity should have depleted the substrate concentration around the entry sites, even taking into account that protons move five–seven times faster by the Grotthuss mechanism than diffusing ions. This suggests that weak acid metabolite transporters replenish the local concentration of their substrate and protons faster than simple diffusion would allow for [3]. In fact, micro-domains have been shown to exist at the transporting proteins themselves or at accessory proteins that locally increase substrate ion and/or proton concentrations for steeper transmembrane gradients. This occurs by attracting substrate molecules to the transporter entry sites, or by generating them in place by linked enzyme moieties.
This review describes processes by which metabolite transporters involved in the facilitation of low-concentration substrates maintain their transport functionality by local substrate enrichment. Specific examples of transporter proteins are used to illustrate these principles.
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Aquaporins (AQP) are a large, ancient family of homotetrameric channel proteins for water and neutral-solute transmembrane facilitation [4, 5]. Two constrictions in the channels are highly conserved across the AQPs. One, termed the selectivity filter, is located close to the extracellular or periplasmic side of each AQP protomer and is typically composed of aromatic amino acids around a positively charged arginine (ar/R). The other lies in the center of the protomer and is named after its Asn-Pro-Ala signature motifs, i.e., NPA region [6]. Two NPA motifs cap two short helices at their positive ends. These positively charged constrictions act concertedly to strictly exclude protons and other cations [7, 8]. In addition to vital functions in the human water and salt homeostasis, or glycerol metabolism, additional roles, e.g., in the modulation of the immune system, have been identified, rendering them attractive drug targets even though inhibitor development is hampered by the tight space in the substrate transduction path [9].
Certain AQPs, e.g., from lactic acid bacteria [10] or human AQP9 [11], facilitate transmembrane diffusion at physiological pH conditions of lactic acid, as well as the typical AQP substrate spectrum [12]. The diffusion of lactic acid via such AQPs exceeds the buffer substrate concentration derived from the lactate/lactic acid protonation equilibrium (pK
3.86). Poisson–Boltzmann calculations of the electrostatic surface potential of respective AQPs revealed a strongly positively charged protein surface. To this end, the AQP9 tetramer, for instance, carries a cluster of eight arginine residues (4 × Arg51/Arg53). It was hypothesized that the positive surface charge attracts the predominant lactate anion form that indirectly enhances the local concentration of the neutral lactic acid substrate due to the protonation equilibrium (Figure 1, left) [11]. This view was supported by mutational replacement of the positive arginines by negatively charged glutamic acid residues. Indeed, the inversion of the AQP9 surface charge significantly decreased the passage of lactic acid.
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, can lead to a massive accumulation of lactate in the compartment at the less acidic side of the membrane, i.e., an ion trap [13]. In this compartment, protons are buffered, leaving the lactate ion that is excluded by the AQP and, thus, remaining trapped when there are no alternative transmembrane transporters with lactate-transport capability present.
Homopentameric formate-nitrite transporters (FNT) are expressed exclusively in microorganisms, mainly bacteria [14], but also in single-celled eucaryotes, such as malaria parasites [15]. Structure-wise, they almost perfectly mimic the fold of the AQP channel protomer, despite the absence of sequence similarity [16]. In terms of functionality, however, FNTs act like secondary-active transporters, using the transmembrane proton gradient as a driving force for the bi-directional transport of small, weak monoacids. As such, they are key elements in bacterial mixed acid fermentation [14], nitrogen fixation [17], and hydrosulfide detoxification [18]. The lactate/H
Transporting FNT from malaria parasites represents a novel, valid drug target [19, 20] for which recently potent small-molecule inhibitors with high antimalarial potency have been discovered [21, 22, 23]. Similar to the AQPs, the substrate path through the FNT protein structure holds a central region that is flanked by two lipophilic constrictions and excludes the passage of charged compounds [17, 24]. Nevertheless, weak acid substrate-transport is highly efficient even in the neutral pH range, indicating that the FNTs accept the anionic species as a substrate and make use of protons as a co-substrate [25]. How is this achieved?
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The responsible feature in the FNT structure is the placement of a positively charged lysine each, deep inside two vestibule regions that lead to the lipophilic constrictions from either side of the membrane. Other than lactic acid-facilitating AQPs with a positive amino-acid cluster on the external protein surface, the FNTs steer the weak acid anion by charge attraction into an increasingly lipophilic protein environment. As a consequence, at a certain point along the pathway, the decreasing permittivity of the dielectric environment decreases the acidity of the substrate, leading to substrate protonation from the bulk and allowing the neutralized weak acid to cross the constrictions (Figure 1, center) [26]. We termed this mechanism the “dielectric slide” [27].
As non-flexible membrane proteins with an internal rigid and narrow substrate pathway, the FNTs are clearly channel-like. Furthermore, the entry sites on both sides of the membrane are permanently accessible to substrates. Such properties contradict the classical definition of transport proteins, according to which a substrate is bound only at one open side, the cis side, followed by a large conformational change of the protein that opens up the trans side for substrate release (secondary-active transporters are discussed in Section 3 and depicted in Figure 2). However, the FNT transport activity is equally efficient as that of classical secondary-active monocarboxylate transporters, showing that the FNT class of proteins represents a linking intermediate between channels and transporters.
) which represents the predominant species. Transmembrane facilitators
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