ArsB and ArsAB transporters

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Arsenite and Antimonite Efflux Pump
Identifiers
SymbolArsA
Pfam PF02374
InterPro IPR027541
SMART SM00382
TCDB 3.A.4
OPM superfamily 124
OPM protein 3sja
Arsenical pump membrane protein
Identifiers
SymbolArsB
Pfam PF02040
InterPro IPR000802
TCDB 2.A.45

Arsenite resistance (Ars) efflux pumps of bacteria may consist of two proteins, ArsB (TC# 2.A.45.1.1; the integral membrane constituent with twelve transmembrane spanners) and ArsA (TC# 3.A.4.1.1; the ATP-hydrolyzing, transport energizing subunit, as for the chromosomally-encoded E. coli system), or of one protein (just the ArsB integral membrane protein of the plasmid-encoded Staphylococcus system). [1] [2] [3] ArsA proteins have two ATP binding domains and probably arose by a tandem gene duplication event. ArsB proteins all possess twelve transmembrane spanners and may also have arisen by a tandem gene duplication event. Structurally, the Ars pumps resemble ABC-type efflux pumps, but there is no significant sequence similarity between the Ars and ABC pumps. When only ArsB is present, the system operates by a pmf-dependent mechanism, and consequently belongs in TC subclass 2.A (i.e.,TC# 2.A.45). When ArsA is also present, ATP hydrolysis drives efflux, and consequently the system belongs in TC subclass 3.A (i.e., TC# 3.A.4). ArsB therefore appears twice in the TC system (ArsB and ArsAB) but ArsA appears only once. These pumps actively expel both arsenite and antimonite. [1] [2] [3] [4]

Contents

Homology

Homologues of ArsB are found in Gram-negative and Gram-positive bacteria as well as cyanobacteria. Homologues are also found in archaea and eukarya. Several paralogues may sometimes be found in a single organism. Among the distant homologues found in eukaryotes are members of the DASS family (TC# 2.A.47) including the rat renal Na+:sulfate cotransporter (Q07782) and the human renal Na+:dicarboxylate cotransporter (gbU26209 [ permanent dead link ]). ArsB proteins are therefore members of a superfamily (called the IT (ion transporter) superfamily). [5] [6] However, ArsB has uniquely gained the ability to function in conjunction with ArsA in order to couple ATP hydrolysis to anion efflux. ArsAB belongs to the ArsA ATPase Superfamily.

A unique member of the ArsB family is the rice silicon (silicate) efflux pump, Lsi2 (TC# 2.A.45.2.4). The silicon uptake systems, Lsi1 (TC# 1.A.8.12.2), and Lsi2 are expressed in roots, on the plasma membranes of cells in both the exodermis and the endodermis. In contrast to Lsi1, which is localized on the distal side, Lsi2 is localized on the proximal side of the same cells. Thus these cells have an influx transporter on one side and an efflux transporter on the other side of the cell to permit the effective transcellular transport of the nutrient. [7] [8]

ArsA proteins are homologous to nitrogenase iron (NifH) proteins 2 of bacteria and to protochlorophyllide reductase iron sulfur ATP-binding proteins of cyanobacteria, algae and plants.

Mechanism

ArsA homologues are found in bacteria, archaea and eukarya (both animals and plants), but there are far fewer of them in the databases than ArsB proteins, suggesting that many ArsB homologues function by a pmf-dependent mechanism, probably an arsenite:H+ antiport mechanism. [9]

In the E. coli ArsAB transporter, both ArsA and ArsB recognize and bind their anionic substrates. A model has been proposed in which ArsA alternates between two virtually exclusive conformations. [10] In one, (ArsA1) the A1 site is closed but the A2 site is open, but in the other (ArsA2) the opposite is true. Antimonite [Sb(III)] sequesters ArsA in the ArsA1 conformation which catalyzes ATP hydrolysis at A2 to drive ArsA between conformations that have high (nucleotide-bound ArsA) and low (nucleotide-free ArsA) affinity for antimonite. It is proposed that ArsA uses this process to sequester Sb(III) and eject it into the ArsB channel. [10] [9] [11]

In the case of ArsAB, at the interface of these two halves are two nucleotide-binding domains and a metalloid-binding domain. [12] Cys-113 and Cys-422 have been shown to form a high-affinity metalloid binding site. The crystal structure of ArsA shows two other bound metalloid atoms, one liganded to Cys-172 and His-453, and the other liganded to His-148 and Ser-420. There is only a single high-affinity metalloid binding site in ArsA. Cys-172 controls the affinity of this site for metalloid and hence the efficiency of metalloactivation of the ArsAB efflux pump. [12]

Transport Reaction

The overall reaction catalyzed by ArsB (presumably by uniport) is:

Arsenite or Antimonite (in) → Arsenite or Antimonite (out).

The overall reaction catalyzed by ArsB-ArsA is:

Arsenite or Antimonite (in) + ATP ⇌ Arsenite or Antimonite (out) + ADP + Pi.

See also

Related Research Articles

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion or active transport. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.

ATP-binding cassette transporter Gene family

The ATP-binding cassette transporters are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transporters belong to translocases.

The Transporter Classification Database is an International Union of Biochemistry and Molecular Biology (IUBMB)-approved classification system for membrane transport proteins, including ion channels.

Ion transporter

In biology, a transporter is a transmembrane protein that moves ions across a biological membrane to accomplish many different biological functions including, cellular communication, maintaining homeostasis, energy production, etc. There are different types of transporters including, pumps, uniporters, antiporters, and symporters. Active transporters or ion pumps are transporters that convert energy from various sources—including adenosine triphosphate (ATP), sunlight, and other redox reactions—to potential energy by pumping an ion up its concentration gradient. This potential energy could then be used by secondary transporters, including ion carriers and ion channels, to drive vital cellular processes, such as ATP synthesis.

Efflux (microbiology) Protein complexes that move compounds, generally toxic, out of bacterial cells

All microorganisms, with a few exceptions, have highly conserved DNA sequences in their genome that are transcribed and translated to efflux pumps. Efflux pumps are capable of moving a variety of different toxic compounds out of cells, such as antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals, bacterial metabolites and neurotransmitters via active efflux, which is vital part for xenobiotic metabolism. This active efflux mechanism is responsible for various types of resistance to bacterial pathogens within bacterial species - the most concerning being antibiotic resistance because microorganisms can have adapted efflux pumps to divert toxins out of the cytoplasm and into extracellular media.

In enzymology, an arsenite-transporting ATPase (EC 3.6.3.16) is an enzyme that catalyzes the chemical reaction

P-type ATPase

The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon their ability to catalyze auto- (or self-) phosphorylation (hence P) of a key conserved aspartate residue within the pump and their energy source, adenosine triphosphate (ATP). In addition, they all appear to interconvert between at least two different conformations, denoted by E1 and E2. P-type ATPases fall under the P-type ATPase (P-ATPase) Superfamily (TC# 3.A.3) which, as of early 2016, includes 20 different protein families.

ATPase ASNA1 Protein-coding gene in the species Homo sapiens

ATPase ASNA1 also known as arsenical pump-driving ATPase and arsenite-stimulated ATPase is an enzyme that in humans is encoded by the ASNA1 gene.

Multi-antimicrobial extrusion protein (MATE) also known as multidrug and toxin extrusion or multidrug and toxic compound extrusion is a family of proteins which function as drug/sodium or proton antiporters.

Ars operon

In molecular biology, the ars operon is an operon found in several bacterial taxon. It is required for the detoxification of arsenate, arsenite, and antimonite. This system transports arsenite and antimonite out of the cell. The pump is composed of two polypeptides, the products of the arsA and arsB genes. This two-subunit enzyme produces resistance to arsenite and antimonite. Arsenate, however, must first be reduced to arsenite before it is extruded. A third gene, arsC, expands the substrate specificity to allow for arsenate pumping and resistance. ArsC is an approximately 150-residue arsenate reductase that uses reduced glutathione (GSH) to convert arsenate to arsenite with a redox active cysteine residue in the active site. ArsC forms an active quaternary complex with GSH, arsenate, and glutaredoxin 1 (Grx1). The three ligands must be present simultaneously for reduction to occur.

The lysosomal cystine transporter (LCT) family is part of the TOG Superfamily and includes secondary transport proteins that are derived from animals, plants, fungi and other eukaryotes. They exhibit 7 putative transmembrane α-helical spanners (TMSs) and vary in size between about 200 and 500 amino acyl residues, although most have between 300 and 400 residues.

The multidrug/oligosaccharidyl-lipid/polysaccharide (MOP) flippase superfamily is a group of integral membrane protein families. The MOP flippase superfamily includes twelve distantly related families, six for which functional data are available:

  1. One ubiquitous family (MATE) specific for drugs - (TC# 2.A.66.1) The Multi Antimicrobial Extrusion (MATE) Family
  2. One (PST) specific for polysaccharides and/or their lipid-linked precursors in prokaryotes - (TC# 2.A.66.2) The Polysaccharide Transport (PST) Family
  3. One (OLF) specific for lipid-linked oligosaccharide precursors of glycoproteins in eukaryotes - (TC# 2.A.66.3) The Oligosaccharidyl-lipid Flippase (OLF) Family
  4. One (MVF) lipid-peptidoglycan precursor flippase involved in cell wall biosynthesis - (TC# 2.A.66.4) The Mouse Virulence Factor (MVF) Family
  5. One (AgnG) which includes a single functionally characterized member that extrudes the antibiotic, Agrocin 84 - (TC# 2.A.66.5) The Agrocin 84 Antibiotic Exporter (AgnG) Family
  6. And finally, one (Ank) that shuttles inorganic pyrophosphate (PPi) - (TC# 2.A.66.9) The Progressive Ankylosis (Ank) Family

The Nickel/Cobalt Transporter (NicO) Family is a member of the Lysine Exporter (LysE) Superfamily.

Arsenite-antimonite transporters are membrane transporters that pump arsenite or antimonite out of a cell. Antimonite is the salt of antimony and has been found to significantly impact the toxicity of arsenite. The similar structure of As(III) and Sb(III) makes it plausible that certain transporters function in the efflux of both substrates. Arsenic efflux transporters exist in almost every organism and serve to remove this toxic compound from the cell.

The p-aminobenzoyl-glutamate transporter(AbgT) family is a family of transporter proteins belonging to the ion transporter (IT) superfamily. The AbgT family consists of the AbgT protein of E. coli and the MtrF drug exporter of Neisseria gonorrhoeae. The former protein is apparently cryptic in wild-type cells, but when expressed on a high copy number plasmid, or when expressed at higher levels due to mutation, it appeared to allow uptake and subsequent utilization of p-aminobenzoyl-glutamate as a source of p-aminobenzoate for p-aminobenzoate auxotrophs. p-Aminobenzoate is a constituent of and a precursor for the biosynthesis of folic acid. MtrF was annotated as a putative drug efflux pump.

The ion transporter (IT) superfamily is a superfamily of secondary carriers that transport charged substrates.

The Bile/Arsenite/Riboflavin Transporter (BART) superfamily is a superfamily of ubiquitous transport proteins. As of early 2016, the superfamily contains seven established families. Functional data for members of all of these families are available. The seven families are in the Transporter Classification Database with the following TC numbers, names and abbreviations include:

The arsenical resistance-3 (ACR3) family is a member of the BART superfamily. Based on operon analyses, ARC3 homologues may function either as secondary carriers or as primary active transporters, similarly to the ArsB and ArsAB families. In the latter case ATP hydrolysis again energizes transport. ARC3 homologues transport the same anions as ArsA/AB homologues, though ArsB homologues are members of the IT Superfamily and homologues of the ARC3 family are within the BART Superfamily suggesting they may not be evolutionarily related.

The 6TMS Neutral Amino Acid Transporter (NAAT) Family is a family of transporters belonging to the Lysine Exporter (LysE) Superfamily. Homologues are found in numerous Gram-negative and Gram-positive bacteria including many human pathogens. Several archaea also encode MarC homologues. Some of these organisms have 2 or more paralogues. Most of these proteins are of about the same size although a few are larger. They exhibit 6 putative TMSs. A representative list of members belonging to the NAAT family can be found in the Transporter Classification Database.

Resistance-nodulation-cell division superfamily

Resistance-nodulation-division (RND) family transporters are a category of bacterial efflux pumps, especially identified in Gram-negative bacteria and located in the cytoplasmic membrane, that actively transport substrates. The RND superfamily includes seven families: the heavy metal efflux (HME), the hydrophobe/amphiphile efflux-1, the nodulation factor exporter family (NFE), the SecDF protein-secretion accessory protein family, the hydrophobe/amphiphile efflux-2 family, the eukaryotic sterol homeostasis family, and the hydrophobe/amphiphile efflux-3 family. These RND systems are involved in maintaining homeostasis of the cell, removal of toxic compounds, and export of virulence determinants. They have a broad substrate spectrum and can lead to the diminished activity of unrelated drug classes if over-expressed. The first reports of drug resistant bacterial infections were reported in the 1940s after the first mass production of antibiotics. Most of the RND superfamily transport systems are made of large polypeptide chains. RND proteins exist primarily in gram-negative bacteria but can also be found in gram-positive bacteria, archaea, and eukaryotes.

References

  1. 1 2 Rensing C, Ghosh M, Rosen BP (October 1999). "Families of soft-metal-ion-transporting ATPases". Journal of Bacteriology. 181 (19): 5891–7. doi:10.1128/JB.181.19.5891-5897.1999. PMC   103614 . PMID   10498699.
  2. 1 2 Rosen BP (1999-01-01). "The role of efflux in bacterial resistance to soft metals and metalloids". Essays in Biochemistry. 34: 1–15. doi:10.1042/bse0340001. PMID   10730185.
  3. 1 2 Xu C, Zhou T, Kuroda M, Rosen BP (January 1998). "Metalloid resistance mechanisms in prokaryotes". Journal of Biochemistry. 123 (1): 16–23. doi:10.1093/oxfordjournals.jbchem.a021904. PMID   9504403.
  4. ↑ "2.A.45 The Arsenite-Antimonite (ArsB) Efflux Family". Transporter Classification Database. Retrieved 2016-03-03.
  5. ↑ Prakash S, Cooper G, Singhi S, Saier MH (December 2003). "The ion transporter superfamily". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1618 (1): 79–92. doi: 10.1016/j.bbamem.2003.10.010 . PMID   14643936.
  6. ↑ Rabus R, Jack DL, Kelly DJ, Saier MH (December 1999). "TRAP transporters: an ancient family of extracytoplasmic solute-receptor-dependent secondary active transporters". Microbiology. 145 ( Pt 12) (12): 3431–45. doi: 10.1099/00221287-145-12-3431 . PMID   10627041.
  7. ↑ Ma JF, Yamaji N, Mitani N, Tamai K, Konishi S, Fujiwara T, Katsuhara M, Yano M (July 2007). "An efflux transporter of silicon in rice". Nature. 448 (7150): 209–12. Bibcode:2007Natur.448..209M. doi:10.1038/nature05964. PMID   17625566. S2CID   4406965.
  8. ↑ Ma JF, Yamaji N, Tamai K, Mitani N (November 2007). "Genotypic difference in silicon uptake and expression of silicon transporter genes in rice". Plant Physiology. 145 (3): 919–24. doi:10.1104/pp.107.107599. PMC   2048782 . PMID   17905867.
  9. 1 2 Meng YL, Liu Z, Rosen BP (April 2004). "As(III) and Sb(III) uptake by GlpF and efflux by ArsB in Escherichia coli". The Journal of Biological Chemistry. 279 (18): 18334–41. doi: 10.1074/jbc.M400037200 . PMID   14970228.
  10. 1 2 Walmsley AR, Zhou T, Borges-Walmsley MI, Rosen BP (March 2001). "A kinetic model for the action of a resistance efflux pump". The Journal of Biological Chemistry. 276 (9): 6378–91. doi: 10.1074/jbc.M008105200 . PMID   11096086.
  11. ↑ Yang J, Rawat S, Stemmler TL, Rosen BP (May 2010). "Arsenic binding and transfer by the ArsD As(III) metallochaperone". Biochemistry. 49 (17): 3658–66. doi:10.1021/bi100026a. PMC   2920133 . PMID   20361763.
  12. 1 2 Ruan X, Bhattacharjee H, Rosen BP (January 2008). "Characterization of the metalloactivation domain of an arsenite/antimonite resistance pump". Molecular Microbiology. 67 (2): 392–402. doi: 10.1111/j.1365-2958.2007.06049.x . PMID   18067540. S2CID   8472652.

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