Lactonase

Lactonase (also acyl-homoserine lactonase) is a metalloenzyme, produced by certain species of bacteria, which targets and inactivates acylated homoserine lactones (AHLs).

General chemical structure of an N-acyl homoserine lactone

Many species of Proteobacteria from the alpha, beta and gamma classes have been shown to produce acylated homoserine lactones, which are small hormone-like molecules commonly used as communication signals between bacterial cells in a population to regulate certain gene expression and phenotypic behaviours.[1] This type of gene regulation is known as quorum sensing.

Enzyme mechanism

Lactonase hydrolyzes the ester bond of the homoserine lactone ring of acylated homoserine lactones. In hydrolysing the lactone bond, lactonase prevents these signaling molecules from binding to their target transcriptional regulators, thus inhibiting quorum sensing.[2]

Enzyme Structure

A dinuclear zinc binding site is conserved in all known lactonases and essential for enzyme activity and protein folding.[3]

Zn1 is tetracoordinated by His104, His106, His169, and the bridging hydroxide ion. Zn2 has five ligands, including Asp191, His235, His109, Asp108, and the bridging hydroxide ion. The metal ions assist in polarizing the lactone bond, increasing the electrophilicity of the lactone ring’s carbonyl carbon. Isotopic labeling studies indicated that the ring opening occurs via an addition elimination reaction with water addition shown below.[4]

Biological Function

Lactonases are able to interfere with AHL-mediated quorum sensing. Some examples of these lactonases are AiiA produced by Bacillus species, AttM and AiiB produced by Agrobacterium tumefaciens, and QIcA produced by Rhizobiales species.[5]

Lactonases have been reported for Bacillus, Agrobacterium, Rhodococcus, Streptomyces, Arthrobacter, Pseudomonas, and Klebsiella.[6] The Bacillus cereus group (consisting of B. cereus, B. thuringiensis, B. mycoides, and B. anthracis) was found to contain nine genes homologous to the AiiA gene that encode AHL-inactivating enzymes, with the catalytic zinc-binding motif conserved in all cases.[7]

In the phytopathogen A. tumefaciens, AiiB lactonase acts as a fine modulator that essentially delays the release of lactone OC8-HSL and the resultant number of tumors produced by the pathogen. AttM lactonase mediates the degradation of the lactone OC8-HSL in wounded plant tissues.[8]

The primary activity of the anti-atherosclerotic paraoxonase (PON) enzymes is as lactonase.[9] Oxidized polyunsaturated fatty acids (notably in oxidized low-density lipoprotein) form lactone-like structures that are PON substrates. [9]

Ecology

It is still unclear the ecological effects of lactonase but it has been proposed that since bacteria mostly coexist with other microorganisms in the environment, some bacteria strains could have evolved its feeding strategies and utilize AHLs as their main resource for energy and nitrogen.[10]

Applications

Understanding the mechanisms and purposes of lactonase activity could lead to potential applied roles for these lactonases to control bacterial infections by inhibiting quorum-sensing activity and bring about profound effects on human health and the environment. However, in both the chemical and enzymatic lactonolysis, the reaction is reversible, complicating direct therapeutic application of lactonases.[11]

Pseudomonas aeruginosa, is an AHL-producing bacteria an opportunistic pathogen that infects immuno-compromised patients,[12] and is found in lung infections of cystic fibrosis patients. P. aeruginosa relies on quorom sensing via production of lactones N-butanoyl-l-homoserine (C4-HSL) and N-(3-oxododecanoyl)-l-HSL (3-oxo-C12-HSL) to regulate swarming, toxin and protease production, and proper biofilm formation. The absence of one or more components of the quorum-sensing system results in a significant reduction in virulence of the pathogen.[13]

Erwinia carotovora is a plant pathogen that causes soft rot in a number of crops such as potatoes and carrots [14] by using N-hexanoyl-l-HSL (C6-HSL) quorom sensing to evade the plant's defense systems and coordinate its production of pectate lyase during the infection process.[15]

Plants expressing AHL-Lactonase were shown to demonstrate enhanced resistance to infection from the pathogen Erwinia carotovora. Expression of virulence genes in E. Carotovora is regulated by N-(3-oxohexanoyl)-l-homoserine lactone (OHHL). Presumably, OHHL-hydrolysis via lactonase reduced OHHL levels, inhibiting the quorom-sensing systems driving virulence gene expression.[16]

See also

References
  1. Fuqua, C.; Winans, S. C.; Greenberg, E. P. (1996). "Census and consensus in bacterial ecosystems: the LuxR-LuxI family of quorum-sensing transcriptional regulators". Annu. Rev. Microbiol. 50: 727–751. doi:10.1146/annurev.micro.50.1.727. PMID 8905097.
  2. Dong, Y.; Wang, L.; Xu, J.; Zhang, H.; Zhang, X.; Zhang, L. (2001). "Quencing quorum-sensing-dependent bacterial infection by an N-acyl homoserine lactonase". Nature. 411 (6839): 813–817. doi:10.1038/35081101. PMID 11459062.
  3. Thomas P. W.; Stone E. M.; Costello A. L.; Tierney D. L.; Fast W. (2005). "The quorum-quenching lactonase from Bacillus thuringiensis is a metalloprotein". Biochemistry. 44 (20): 7559–7569. doi:10.1021/bi050050m. PMID 15895999.
  4. Momb J.; Wang C.; Liu D.; Thomas P. W.; Petsko G. A.; Guo H.; Ringe D; Fast W. (2008). "Mechanism of the quorum-quenching lactonae (AiiA) from Bacillus thuringiensis. 2. Substrate modeling and active site mutations". Biochemistry. 47 (29): 7715–7725. doi:10.1021/bi8003704. PMC 2646874. PMID 18627130.
  5. Riaz K.; Elmerich, C.; Moreira, D.; Raffoux A.; Dessaux Y.; Faure D. (2008). "A metagenomic analysis of soil bacteria extends the diversity of quorum-quenching lactonases". Environmental Microbiology. 10 (3): 560–570. doi:10.1111/j.1462-2920.2007.01475.x. PMID 18201196.
  6. Schipper C.; Hornung C.; Bijtenhoorn P.; Quitschau M.; Grond S.; Streit W. R. (2009). "Metagenome-derived clones encoding two novel lactonase family proteins involved in biofilm inhibition in Pseudomonas aeruginosa". Molecular Plant-Microbe Interactions. 75 (1): 224–233. doi:10.1128/aem.01389-08. PMC 2612230. PMID 18997026.
  7. Dong Y. H.; Gusti A. R.; Zhang Q.; Xu J. L.; Zhang, L. H. (2002). "Identification of quorum-quenching N-acyl homoserine lactonases from Bacillus species". Applied and Environmental Microbiology. 68 (4): 1754–1759. doi:10.1128/AEM.68.4.1754-1759.2002. PMC 123891. PMID 11916693.
  8. Haudecoeur E.; Tannieres M.; Cirou A.; Raffoux A; Dessaux Y.; Faure D. (2009). "Different regulation and roles of lactonases AiiB and AttM in Agrobacterium tumefaciens C58". Annual Review of Phytopathology. 22 (5): 529–537. doi:10.1094/MPMI-22-5-0529. PMID 19348571.
  9. Chistiakov DA, Melnichenko AA, Orekhov AN, Bobryshev YV (2017). "Paraoxonase and atherosclerosis-related cardiovascular diseases". Biochimie. 132: 19–27. doi:10.1016/j.biochi.2016.10.010. PMID 27771368.
  10. Leadbetter, J. R. G.; Greenberg, E. P. (2000). "Metabolism of acyl-homoserine lactone quorum-sensing signals by Variovorax paradoxus". J. Bacteriol. 182 (24): 6921–6926. doi:10.1128/JB.182.24.6921-6926.2000. PMC 94816. PMID 11092851.
  11. Rasmussen T. B.; Givskov M. (2006). "Quorum-sensing inhibitors as anti-pathogenic drugs". International Journal of Medical Microbiology. 296 (2–3): 149–161. doi:10.1016/j.ijmm.2006.02.005. PMID 16503194.
  12. Whitehead, N. A.; Barnard A. M. L.; Slater H.; Simpson, N. J. L.; Salmond, G. P. C. (2001). "Quorum sensing in Gram-negative bacteria". FEMS Microbiol. Rev. 25 (4): 365–404. doi:10.1111/j.1574-6976.2001.tb00583.x. PMID 11524130..
  13. Smith R. S.; Iglewski B. H. (2003). "P. aeruginosa quorum-sensing systems and virulence". Current Opinion in Microbiology. 6 (1): 56–60. doi:10.1016/S1369-5274(03)00008-0. PMID 12615220.
  14. Pirhonen, M.; Flegom, D.; Heikinheimo, R.; Palva, E. T. (1993). "A small diffusible signal molecule is responsible for the global control of virulence and exoenzyme production in the plant pathogen Erwinia carotovora". EMBO J. 12 (6): 2467–2476. doi:10.1002/j.1460-2075.1993.tb05901.x. PMC 413482. PMID 8508772.
  15. Von Bodman S. B.; Bauer W. D.; Coplin D. L. (2003). "Quorum-sensing in plant-pathogenic bacteria". Annual Review of Phytopathology. 41: 455–482. doi:10.1146/annurev.phyto.41.052002.095652. PMID 12730390.
  16. Dong Y. H.; Gusti A. R.; Zhang Q.; Xu J. L.; Zhang, L. H. (2002). "Identification of quorum-quenching N-acyl homoserine lactonases from Bacillus species". Applied and Environmental Microbiology. 68 (4): 1754–1759. doi:10.1128/AEM.68.4.1754-1759.2002. PMC 123891. PMID 11916693.
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