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2.A.2 The Glycoside-Pentoside-Hexuronide (GPH):Cation Symporter Family

GPH:cation symporters catalyze uptake of sugars (mostly, but not exclusively, glycosides) in symport with a monovalent cation (H+ or Na+). Mutants of two groups of these symporters (the melibiose permeases of enteric bacteria and the lactose permease of Streptococcus thermophilus) have been isolated and in which altered cation specificity is observed or in which sugar transport is uncoupled from cation symport (i.e., uniport is catalyzed). The various members of the family can use Na+, H+ or Li, Na+ or Li+, H+ or Li+, or only H+ as the symported cation. Most functionally characterized and sequenced members of the family are from bacteria except the distantly related sucrose:H+ symporters of plants and a yeast maltose/sucrose:H+ symporter of S. pombe. This yeast protein is about 24% identical to the plant sucrose:H+ symporters and is more distantly related to the bacterial members of the GPH family (Reinders and Ward, 2001). Homologues are found in archaea and all eukaryotic kingdoms.

Proteins of the GHP family are generally about 500 amino acids in length, although the Gram-positive bacterial lactose permeases are larger, due to a C-terminal hydrophilic domain that is involved in regulation by the phosphotransferase system (TC #4.A.1). All of these proteins possess twelve The GPH family is a member of the MFS. One member of the GPH family, LacS of Streptococcus thermophilus, appears to be a cooperative dimer with one sugar translocation pathway per monomer (Veenhoff et al., 2001).

X-ray crystal structures of MelBSt have revealed the molecular recognition mechanism for sugar binding. Markham et al. 2021 generated a complete single-Cys library containing 476 unique mutants by placing a Cys at each position on a functional Cys-less background. 105 mutants (21%) exhibited poor transport activities, although the expression levels of most mutants were comparable to that of the control. The affected positions are distributed throughout the protein. TMSs I and X and transmembrane residues, Asp and Tyr, are most affected by cysteine replacement, while helix IX, the cytoplasmic middle-loop, and C-terminal tail are least affected. Single-Cys replacements at the major sugar-binding positions (K18, D19, D124, W128, R149, and W342) or at positions important for cation binding (D55, N58, D59, and T121) abolished the Na+-coupled active transport (Markham et al. 2021).

The generalized transport reaction catalyzed by the GPH:cation symporter family is:

Sugar (out) + [H+ or Na+] (out) → Sugar (in) + [H+ or Na+] (in).



This family belongs to the: Major Facilitator (MFS) Superfamily.

References associated with 2.A.2 family:

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