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9.A.18 The Peptide Uptake Permease (PUP) Family

Two proteins, the SbmA protein (406 aas) of E. coli and the BacA protein (420 aas) of Rhizobium meliloti comprise the PUP family. SbmA has been reported to be the permease for uptake of thiazole ring-containing peptide antibiotics such as Microcin B17 and Microcin J25 as well as the non-peptide antibiotic, bleomycin, across the cytoplasmic membrane (Salomón and Farías, 1995), and BacA is a nodulation protein essential for bacterial development when Rhizobium is in symbiosis with a leguminous plant such as alfalfa (Glazebrook et al., 1993). These two proteins exhibit 64% identity and are functionally interchangeable in both E. coli and R. meliloti (Ichige et al., 1997).

R. meliloti bacA null mutants show increased resistance to bleomycin and certain aminoglycosides as well as increased sensitivity to ethanol and detergents. The latter properties are not characteristic of E. coli sbmA mutants. It has been hypothesized that BacA may take up peptide substances required for developmental progression towards bacteroid formation. BacA (but not SbmA) may also play a role in the maintenance of membrane integrity (see below).

PUP family proteins are homologous to, but show a low degree of sequence similarity to, a few putative ABC-type transporters in Gram-negative and Gram-positive bacteria which, unlike SbmA and BacA, possess ATP-binding cassette (ABC)-containing domains. SbmA and BacA also differ from these putative ABC proteins in possessing 7 rather than 6 putative transmembrane α-helical spanners. It is possible that ABC-protein constituents of the PUP family will be found, but the mechanism of energy coupling to PUP family permeases is not currently known. A BacA homologue in Mycobacterium tuberculosis with an ATP hydrolyzing domain takes up antimicrobial peptides and bleomycin, (Q50614; TC#3.A.1.203.4; Domenech et al. 2009). It is possible that all BacA homologues will prove to belong to the ABC superfamily, but the cytoplasmic ATPase domains of the Rhizobial and Escherichia homologues have not been identifited.

Ferguson et al., 2004 reported (1) that BacA of Sinhorizobium and Brucella shows sequence similarity to the long-chain fatty acid transporter ABCD1 (ALD, the adrenoleukodystrophy protein; TC #3.A.1.203.3), (2) that bacA mutants show increased sensitivity to detergents and other cell disrupting agents, and (3) that BacA affects the very long-chain fatty acid (27-hydroxy-C28:0 and 29-hydroxy-C30:0 fatty acids) content of the lipid A constituent of lipopolysaccharides. This led to the postulate that BacA is an export permease for activated long-chain fatty acids, required for the synthesis of lipid A (Ferguson et al., 2004). Direct transport and mode of energy coupling have yet to be demonstrated. However, Ardissone et al. (2011) showed that BacA of a Rhizobium species is a peptide uniporter essential for bacteroid differentiation.

The generalized reactions currently proposed for proteins of the PUP family are:

(1) Peptide antibiotic (periplasm) →  Peptide antibiotic (cytoplasm)

(2) Activated long-chain fatty acid (cytoplasm)  →  Activated long-chain fatty acid (periplasm)

References associated with 9.A.18 family:

Ardissone, S., H. Kobayashi, K. Kambara, C. Rummel, K.D. Noel, G.C. Walker, W.J. Broughton, and W.J. Deakin. (2011). Role of BacA in lipopolysaccharide synthesis, peptide transport, and nodulation by Rhizobium sp. strain NGR234. J. Bacteriol. 193: 2218-2228. 21357487
Domenech, P., H. Kobayashi, K. LeVier, G.C. Walker, and C.E. Barry, 3rd. (2009). BacA, an ABC transporter involved in maintenance of chronic murine infections with Mycobacterium tuberculosis. J. Bacteriol. 191: 477-485. 18996991
Ferguson, G.P., A. Datta, J. Baumgartner, R.M. Roop, 2nd, R.W. Carlson, and G.C. Walker. (2004). Similarity to peroxisomal-membrane protein family reveals that Sinorhizobium and Brucella BacA affect lipid-A fatty acids. Proc. Natl. Acad. Sci. USA 101: 5012-5017. 15044696
Glazebrook, J., A. Ichige, and G.C. Walker. (1993). A Rhizobium meliloti homolog of the Escherichia coli peptide-antibiotic transport protein SbmA is essential for bacteroid development. Genes Dev. 7: 1485-1497. 8393417
Haag, A.F., M.F. Arnold, K.K. Myka, B. Kerscher, S. Dall''Angelo, M. Zanda, P. Mergaert, and G.P. Ferguson. (2013). Molecular insights into bacteroid development during Rhizobium-legume symbiosis. FEMS Microbiol. Rev. 37: 364-383. 22998605
Ichige, A. and G.C. Walker. (1997). Genetic analysis of the Rhizobium meliloti bacA gene: functional interchangeability with the Escherichia coli sbmA gene and phenotypes of mutants. J. Bacteriol. 179: 209-216. 8982000
Marlow, V.L., A.F. Haag, H. Kobayashi, V. Fletcher, M. Scocchi, G.C. Walker, and G.P. Ferguson. (2009). Essential role for the BacA protein in the uptake of a truncated eukaryotic peptide in Sinorhizobium meliloti. J. Bacteriol. 191: 1519-1527. 19074376
Maruya, J. and K. Saeki. (2010). The bacA gene homolog, mlr7400, in Mesorhizobium loti MAFF303099 is dispensable for symbiosis with Lotus japonicus but partially capable of supporting the symbiotic function of bacA in Sinorhizobium meliloti. Plant Cell Physiol. 51: 1443-1452. 20668224
Salomón, R.A. and R.N. Farías. (1995). The peptide antibiotic Microcin 25 is imported through the TonB pathway and the SbmA protein. J. Bacteriol. 177: 3323-3325. 7768835
Travin, D.Y., R. Jouan, A. Vigouroux, S. Inaba-Inoue, J. Lachat, F. Haq, T. Timchenko, D. Sutormin, S. Dubiley, K. Beis, S. Moréra, K. Severinov, and P. Mergaert. (2023). Dual-Uptake Mode of the Antibiotic Phazolicin Prevents Resistance Acquisition by Gram-Negative Bacteria. mBio e0021723. [Epub: Ahead of Print] 36802165
Usui, M., Y. Yoshii, S. Thiriet-Rupert, J.M. Ghigo, and C. Beloin. (2023). Intermittent antibiotic treatment of bacterial biofilms favors the rapid evolution of resistance. Commun Biol 6: 275. 36928386