Lactonase Explained

acyl-L-homoserine-lactone lactonohydrolase
Ec Number:3.1.1.81
Cas Number:389867-43-0

Lactonase (EC 3.1.1.81, acyl-homoserine lactonase; systematic name N-acyl-L-homoserine-lactone lactonohydrolase) is a metalloenzyme, produced by certain species of bacteria, which targets and inactivates acylated homoserine lactones (AHLs). It catalyzes the reaction

an N-acyl-L-homoserine lactone + H2O

\rightleftharpoons

an N-acyl-L-homoserine

Many species of α-, β-, and γ-proteobacteria produce acylated homoserine lactones, 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.

Other names for these types of enzymes are Quorum-quenching N-acyl-homoserine lactonase, acyl homoserine degrading enzyme, acyl-homoserine lactone acylase, AHL lactonase, AHL-degrading enzyme, AHL-inactivating enzyme, AHLase, AhlD, AhlK, AiiA, AiiA lactonase, AiiA-like protein, AiiB, AiiC, AttM, delactonase, lactonase-like enzyme, N-acyl homoserine lactonase, N-acyl homoserine lactone hydrolase, N-acyl-homoserine lactone lactonase, N-acyl-L-homoserine lactone hydrolase, quorum-quenching lactonase, quorum-quenching N-acyl homoserine lactone hydrolase.[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

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.[13]

Enzyme Structure

A dinuclear zinc binding site is conserved in all known lactonases and essential for enzyme activity and protein folding.[14]

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.[15]

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 Hyphomicrobiales species.[16]

Lactonases have been reported for Bacillus, Agrobacterium, Rhodococcus, Streptomyces, Arthrobacter, Pseudomonas, and Klebsiella.[17] 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.[18] 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.[19]

The primary activity of the anti-atherosclerotic paraoxonase (PON) enzymes is as lactonase.[20] Oxidized polyunsaturated fatty acids (notably in oxidized low-density lipoprotein) form lactone-like structures that are PON substrates.

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.[21]

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.[22]

Pseudomonas aeruginosa, is an AHL-producing bacteria an opportunistic pathogen that infects immuno-compromised patients,[23] and is found in lung infections of cystic fibrosis patients. P. aeruginosa relies on quorum 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.[24]

Erwinia carotovora is a plant pathogen that causes soft rot in a number of crops such as potatoes and carrots [25] by using N-hexanoyl-l-HSL (C6-HSL) quorum sensing to evade the plant's defense systems and coordinate its production of pectate lyase during the infection process.[26]

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 quorum-sensing systems driving virulence gene expression.[18]

See also

References

  1. Fuqua, C. . Winans, S. C. . Greenberg, E. P. . Census and consensus in bacterial ecosystems: the LuxR-LuxI family of quorum-sensing transcriptional regulators. . Annu. Rev. Microbiol. . 50 . 727–751 . 1996 . 8905097 . 10.1146/annurev.micro.50.1.727.
  2. Thomas PW, Stone EM, Costello AL, Tierney DL, Fast W . The quorum-quenching lactonase from Bacillus thuringiensis is a metalloprotein . Biochemistry . 44 . 20 . 7559–69 . May 2005 . 15895999 . 10.1021/bi050050m .
  3. Dong YH, Gusti AR, Zhang Q, Xu JL, Zhang LH . Identification of quorum-quenching N-acyl homoserine lactonases from Bacillus species . Applied and Environmental Microbiology . 68 . 4 . 1754–9 . April 2002 . 11916693 . 123891 . 10.1128/AEM.68.4.1754-1759.2002 .
  4. Wang LH, Weng LX, Dong YH, Zhang LH . Specificity and enzyme kinetics of the quorum-quenching N-Acyl homoserine lactone lactonase (AHL-lactonase) . The Journal of Biological Chemistry . 279 . 14 . 13645–51 . April 2004 . 14734559 . 10.1074/jbc.M311194200 . free .
  5. Dong YH, Xu JL, Li XZ, Zhang LH . AiiA, an enzyme that inactivates the acylhomoserine lactone quorum-sensing signal and attenuates the virulence of Erwinia carotovora . Proceedings of the National Academy of Sciences of the United States of America . 97 . 7 . 3526–31 . March 2000 . 10716724 . 16273 . 10.1073/pnas.060023897 . free .
  6. Dong YH, Wang LH, Xu JL, Zhang HB, Zhang XF, Zhang LH . Quenching quorum-sensing-dependent bacterial infection by an N-acyl homoserine lactonase . Nature . 411 . 6839 . 813–7 . June 2001 . 11459062 . 10.1038/35081101 . 4324448 .
  7. Lee SJ, Park SY, Lee JJ, Yum DY, Koo BT, Lee JK . Genes encoding the N-acyl homoserine lactone-degrading enzyme are widespread in many subspecies of Bacillus thuringiensis . Applied and Environmental Microbiology . 68 . 8 . 3919–24 . August 2002 . 12147491 . 124016 . 10.1128/aem.68.8.3919-3924.2002 .
  8. Park SY, Lee SJ, Oh TK, Oh JW, Koo BT, Yum DY, Lee JK . AhlD, an N-acylhomoserine lactonase in Arthrobacter sp., and predicted homologues in other bacteria . Microbiology . 149 . Pt 6 . 1541–50 . June 2003 . 12777494 . 10.1099/mic.0.26269-0 . free .
  9. Ulrich RL . Quorum quenching: enzymatic disruption of N-acylhomoserine lactone-mediated bacterial communication in Burkholderia thailandensis . Applied and Environmental Microbiology . 70 . 10 . 6173–80 . October 2004 . 15466564 . 522112 . 10.1128/AEM.70.10.6173-6180.2004 .
  10. Kim MH, Choi WC, Kang HO, Lee JS, Kang BS, Kim KJ, Derewenda ZS, Oh TK, Lee CH, Lee JK . The molecular structure and catalytic mechanism of a quorum-quenching N-acyl-L-homoserine lactone hydrolase . Proceedings of the National Academy of Sciences of the United States of America . 102 . 49 . 17606–11 . December 2005 . 16314577 . 1295591 . 10.1073/pnas.0504996102 . free .
  11. Liu D, Lepore BW, Petsko GA, Thomas PW, Stone EM, Fast W, Ringe D . Three-dimensional structure of the quorum-quenching N-acyl homoserine lactone hydrolase from Bacillus thuringiensis . Proceedings of the National Academy of Sciences of the United States of America . 102 . 33 . 11882–7 . August 2005 . 16087890 . 1187999 . 10.1073/pnas.0505255102 . free .
  12. Yang F, Wang LH, Wang J, Dong YH, Hu JY, Zhang LH . Quorum quenching enzyme activity is widely conserved in the sera of mammalian species . FEBS Letters . 579 . 17 . 3713–7 . July 2005 . 15963993 . 10.1016/j.febslet.2005.05.060 . free .
  13. Dong, Y. . Wang, L. . Xu, J. . Zhang, H. . Zhang, X. . Zhang, L. . Quencing quorum-sensing-dependent bacterial infection by an N-acyl homoserine lactonase. . Nature . 411 . 6839 . 813–817 . 2001 . 11459062 . 10.1038/35081101. 2001Natur.411..813D . 4324448 .
  14. Thomas P. W. . Stone E. M. . Costello A. L. . Tierney D. L. . Fast W. . The quorum-quenching lactonase from Bacillus thuringiensis is a metalloprotein. . Biochemistry . 44 . 7559–7569 . 2005 . 10.1021/bi050050m . 15895999 . 20 .
  15. Momb J. . Wang C. . Liu D. . Thomas P. W. . Petsko G. A. . Guo H. . Ringe D . Fast W. . Mechanism of the quorum-quenching lactonae (AiiA) from Bacillus thuringiensis. 2. Substrate modeling and active site mutations . Biochemistry . 47 . 7715–7725 . 2008 . 18627130 . 10.1021/bi8003704 . 29 . 2646874.
  16. Riaz K. . Elmerich, C. . Moreira, D. . Raffoux A. . Dessaux Y. . Faure D. . A metagenomic analysis of soil bacteria extends the diversity of quorum-quenching lactonases . Environmental Microbiology . 10 . 560–570 . 2008 . 10.1111/j.1462-2920.2007.01475.x . 18201196 . 3 .
  17. Schipper C. . Hornung C. . Bijtenhoorn P. . Quitschau M. . Grond S. . Streit W. R. . Metagenome-derived clones encoding two novel lactonase family proteins involved in biofilm inhibition in Pseudomonas aeruginosa . Applied and Environmental Microbiology . 75 . 1 . 224–233 . 2009 . 10.1128/aem.01389-08 . 18997026 . 2612230.
  18. Dong Y. H. . Gusti A. R. . Zhang Q. . Xu J. L. . Zhang, L. H. . Identification of quorum-quenching N-acyl homoserine lactonases from Bacillus species . Applied and Environmental Microbiology . 68 . 1754–1759 . 2002 . 10.1128/AEM.68.4.1754-1759.2002 . 11916693 . 4 . 123891 .
  19. Haudecoeur E. . Tannieres M. . Cirou A. . Raffoux A . Dessaux Y. . Faure D. . Different regulation and roles of lactonases AiiB and AttM in Agrobacterium tumefaciens C58 . Molecular Plant-Microbe Interactions . 22 . 529–537 . 2009 . 19348571 . 10.1094/MPMI-22-5-0529 . 5.
  20. Chistiakov DA, Melnichenko AA, Orekhov AN, Bobryshev YV . Paraoxonase and atherosclerosis-related cardiovascular diseases . . 132 . 19–27 . 2017 . 10.1016/j.biochi.2016.10.010 . 27771368.
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  23. Whitehead, N. A. . Barnard A. M. L. . Slater H. . Simpson, N. J. L. . Salmond, G. P. C. . Quorum sensing in Gram-negative bacteria . FEMS Microbiol. Rev.. 25 . 4 . 365–404 . 2001 . 11524130 . 10.1111/j.1574-6976.2001.tb00583.x. free . .
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  25. Pirhonen, M. . Flegom, D. . Heikinheimo, R. . Palva, E. T.. 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 . 1993 . 8508772 . 10.1002/j.1460-2075.1993.tb05901.x. 413482 .
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