# Monovalent cation:proton antiporter-3

The Monovalent Cation (K$^+$ or Na$^+$):Proton Antiporter-3 (CPA3) Family (TC# 2.A.63) is a member of the Na$^+$ transporting Mrp superfamily. The CPA3 family consists of bacterial multicomponent K$^+$:H$^+$ and Na$^+$:H$^+$ antiporters. The best characterized systems are the PhaABCDEFG system of Sinorhizobium meliloti (TC# 2.A.63.1.1) that functions in pH adaptation and as a K$^+$ efflux system, and the MnhABCDEFG system of Staphylococcus aureus (TC# 2.A.63.1.3) that functions as a Na$^+$ efflux Na$^+$:H$^+$ antiporter.

## Homology

A homologous, but only partially sequenced, system was earlier reported to catalyze Na$^+$:H$^+$ antiport in an alkalophilic Bacillus strain. PhaA and PhaD are respectively homologous to the ND5 and ND4 subunits of the H$^+$-pumping NADH:ubiquinone oxidoreductase (TC #3.D.1). Homologous protein subunits from E. coli NADH:quinone oxidoreductase can functionally replace MrpA and MrpD in Bacillus subtilis.
Homologues of PhaA, B, C and D and Nha1, 2, 3 and 4 of an alkalophilic Bacillus strain are the Yuf(Mrp)T, U, V and D genes of Bacillus subtilis. In this system, YufT is believed to be responsible for Na$^+$:H$^+$ antiporter activity, but it does not have activity in the absence of other constituents of the operon.

## Structure

The seven Pha proteins are of the following sizes (in #aas) and exhibit the following putative numbers of transmembrane α-helical spanners (TMSs):
* PhaA - 725 and 17
* PhaB - 257 and 5
* PhaC - 115 and 3
* PhaD - 547 and 13
* PhaE - 161 and 3
* PhaF - 92 and 3
* PhaG - 120 and 3
All are predicted to be integral membrane proteins.
Corresponding values for the S. aureus Mnh system are:
* MnhA - 801 and 18
* MnhB - 142 and 4
* MnhC - 113 and 3
* MnhD - 498 and 13
* MnhE - 159 and 4
* MnhF - 97 and 3
* MnhG - 118 and 3
In view of the complexity of the system, large variation in subunit structure, and the homology with NDH family protein constituents, a complicated energy coupling mechanism, possibly involving a redox reaction, cannot be ruled out.

## Function

Na$^+$ or Li$^+$ does, but K$^+$, Ca$^{2+}$, and Mg$^{2+}$ do not, support significant antiport by the Gram-positive bacterial systems (TC# 2.A.6.3.1.2 and TC# 2.A.6.3.1.3). Na$^+$(Li$^+$)/H$^+$ antiporters have alkaline pH optima and apparent K$_m$ values for Na$^+$ that are among the lowest reported for bacterial Na$^+$/H$^+$ antiporters. Na$^+$/H$^+$antiport consumes the pmf and therefore is probably electrogenic.
YufF (MrpF) appears to catalyze cholate efflux, possibly by a Na$^+$ symport mechanism. It plays a major role in Na$^+$ extrusion and is required for initiation of sporulation. Additionally, another component of the operon, MrpF (equivalent to PhaF of R. meliloti) has been implicated in choline and Na$^+$ efflux. The MrpA-G proteins of B. subtilis have been shown to be present in a single multicomponent complex. They provide Na$^+$/H$^+$ antiport activity and function in multiple compound resistance and pH homeostasis.

### Transport Reaction

The generalized reaction believed to be catalyzed by CPA3 family members is:
   [K$^+$ or Na$^+$] (in) + H$^+$ (out) ⇌ [K$^+$ or Na$^+$] (out) + H$^+$ (in).