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2.A.68 The p-Aminobenzoyl-glutamate Transporter (AbgT) Family

The AbgT family consists of the AbgT (YdaH) protein of E. coli (Hussein et al., 1998) and the MtrF drug exporter of Neisseria gonorrhoeae (Folster and Shafer, 2005). 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 (Km = 123 nM) and subsequent utilization of p-aminobenzoyl-glutamate as a source of p-aminobenzoate for p-aminobenzoate auxotrophs (Carter et al., 2007). p-Aminobenzoate is a constituent of and a precursor for the biosynthesis of folic acid. MtrF was annotated as a putative drug efflux pump (Folster and Shafer, 2005).

AbgT is 510 amino acyl residues long and has 12-13 putative transmembrane α-helical spanners (TMSs). MtrF is 522 aas long and has 11 or 12 putative TMSs. They are distant members of the Ion Transporter (IT) superfamily (Prakash et al., 2003; Rabus et al., 1999).The 3-d structures of MtrF and a YdaH homologue have been solved, and functional studies show that it is a drug exporter.  The 3-d structure shows that it has 9 TMSs with hairpin entry loops (Su et al. 2015). 

The abgT gene is preceded by two genes, abgA and abgB, which code for homologous amino acyl amino hydrolases and hydrolyze p-aminobenzoyl glutamate to p-aminobenzoate and glutamate (Carter et al,. 2007). Because of the structural similarity of p-aminobenzoyl-glutatmate to peptides, and the enzymatic activities of the abgA and abgB gene products, it has been suggested that AbgT is also a peptide transporter (Carter et al., 2007). Demonstration of an energy requirement suggested an H+-dependent mechanism (Carter et al., 2007). Expression of these genes is regulated by AbgR and an unknown effector.

As noted above, the AbgT family of transporters has been thought to contribute to bacterial folate biosynthesis by importing the catabolite p-aminobenzoyl-glutamate for producing folate. Approximately 13,000 putative family members were identified in 2015 (Delmar and Yu 2015). The X-ray structures of the full-length Alcanivorax borkumensis YdaH (AbgT) and Neisseria gonorrhoeae MtrF proteins. The structures revealed that these two transporters assemble as dimers with architectures distinct from all other families of transporters for which 3-d structures were available. Both YdaH and MtrF are bowl-shaped dimers with a solvent-filled basin extending from the cytoplasm halfway across the membrane bilayer. The protomers of YdaH and MtrF contain nine transmembrane helices and two hairpins (Delmar and Yu 2015) which suggested a plausible pathway for substrate transport. A combination of the crystal structure, genetic analyses and substrate accumulation assays indicated that both YdaH and MtrF behave as exporters, capable of removing the folate metabolite p-aminobenzoic acid from bacterial cells. In fact, it was shown that both YdaH and MtrF participate as antibiotic efflux pumps, mediating bacterial resistance to sulfonamide antimetabolite drugs. Possibly, many AbgT-family transporters act as exporters, conferring resistance to sulfonamides (Delmar and Yu 2015).

The generalized transport reaction initially proposed for AbgT is:

p-aminobenzoyl-glutamate (out) + nH+ (out) → p-aminobenzoyl-glutamate (in) + nH+ (in)

but the more recently proposed transport reaction is:

Sulfonamide drugs (in) + H+ (out) → Sulfonamide drugs (out) + H+ (in)

This family belongs to the: IT Superfamily.

References associated with 2.A.68 family:

Bolla, J.R., C.C. Su, J.A. Delmar, A. Radhakrishnan, N. Kumar, T.H. Chou, F. Long, K.R. Rajashankar, and E.W. Yu. (2015). Crystal structure of the Alcanivorax borkumensis YdaH transporter reveals an unusual topology. Nat Commun 6: 6874. 25892120
Carter, E.L., L. Jager, L. Gardner, C.C. Hall, S. Willis, and J.M. Green. (2007). Escherichia coli abg genes enable uptake and cleavage of the folate catabolite p-aminobenzoyl-glutamate. J. Bacteriol. 189: 3329-3334. 17307853
Delmar, J.A. and E.W. Yu. (2015). The AbgT family: A novel class of antimetabolite transporters. Protein. Sci. [Epub: Ahead of Print] 26443496
Folster, J.P. and W.M. Shafer. (2005). Regulation of mtrF expression in Neisseria gonorrhoeae and its role in high-level antimicrobial resistance. J. Bacteriol. 187: 3713-3720. 15901695
Hussein, M.J., J.M. Green, and B.P. Nichols (1998). Characterization of mutations that allow p-aminobenzoyl-glutatmate utilization by Escherichia coli. J. Bacteriol. 180: 6260-6268. 9829935
Prakash, S., G. Cooper, S. Singhi, and M.H. Saier, Jr. (2003). The ion transporter superfamily. Biochim. Biophys. Acta. 1618: 79-92. 14643936
Rabus, R., D.L. Jack, D.J. Kelly, and M.H. Saier, Jr. (1999). TRAP transporters: an ancient family of extracytoplasmic solute-receptor-dependent secondary active transporters. Microbiology 145: 3431-3445. 10627041
Su, C.C., J.R. Bolla, N. Kumar, A. Radhakrishnan, F. Long, J.A. Delmar, T.H. Chou, K.R. Rajashankar, W.M. Shafer, and E.W. Yu. (2015). Structure and Function of Neisseria gonorrhoeae MtrF Illuminates a Class of Antimetabolite Efflux Pumps. Cell Rep 11: 61-70. 25818299
Vergara-Jaque, A., C. Fenollar-Ferrer, C. Mulligan, J.A. Mindell, and L.R. Forrest. (2015). Family resemblances: A common fold for some dimeric ion-coupled secondary transporters. J Gen Physiol 146: 423-434. 26503722