Leadzyme

Secondary structure of a leadzyme sequence obtained using mfold. It consists of an asymmetric internal loop made up of six nucleotides.The arrow indicates the cleavage site.
The figure shows cartoon representations of the ground and pre-catalytic conformations of leadzyme. The green spheres represent Mg2+ ions and the red spheres represent Sr2+ ions.Figure rendered in pymol using coordinates from pdb file 1NUV.

Leadzyme is a small ribozyme (catalytic RNA), which catalyzes the cleavage of a specific phosphodiester bond. It was discovered using an in-vitro evolution study where the researchers were selecting for RNAs that specifically cleaved themselves in the presence of lead.[1][2] However, since then, it has been discovered in several natural systems.[3][4] Leadzyme was found to be efficient and dynamic [5] in the presence of micromolar concentrations of lead ions.[6] Unlike in other small self-cleaving ribozymes, other divalent metal ions cannot replace Pb2+ in the leadzyme.[7] Due to obligatory requirement for a lead, the ribozyme is called a metalloribozyme.

Leadzyme has been subjected to extensive biochemical and structural characterization.[8] The minimal secondary structure of leadzyme is surprisingly very simple . It comprises an asymmetric internal loop composed of six nucleotides and a helical region on each side of the internal loop. The cleavage site of leadzyme is located within a four-nucleotide long asymmetric internal loop that also consists of RNA helices on its both sides. This is shown in top figure on right, which is the secondary structure of leadzyme generated using mfold. The structures of leadzyme have also been solved using X-ray crystallography and NMR.[9][10] The crystal structures of the two conformations of leadzyme are shown in the lower figure on right.

  1. ^ Pan, T.; Uhlenbeck, O. C. (1992). "A small metalloribozyme with a two-step mechanism". Nature. 358 (6387): 560–563. Bibcode:1992Natur.358..560P. doi:10.1038/358560a0. PMID 1501711. S2CID 4361511.
  2. ^ Pan, T.; Uhlenbeck, O. C. (1992). "In vitro selection of RNAs that undergo autolytic cleavage with lead(2+)". Biochemistry. 31 (16): 3887–3895. doi:10.1021/bi00131a001. PMID 1373649.
  3. ^ Barciszewska, M. Z.; Wyszko, E.; Bald, R.; Erdmann, V. A.; Barciszewski, J. (2003). "5S rRNA Is a Leadzyme. A Molecular Basis for Lead Toxicity". Journal of Biochemistry. 133 (3): 309–315. doi:10.1093/jb/mvg042. PMID 12761166.
  4. ^ Kikovska, E.; Mikkelsen, N.-E.; Kirsebom, L. A. (2005). "The naturally trans-acting ribozyme RNase P RNA has leadzyme properties". Nucleic Acids Research. 33 (21): 6920–6930. doi:10.1093/nar/gki993. PMC 1310964. PMID 16332695.
  5. ^ Kadakkuzha, B. M.; Zhao, L.; Xia, T. (2009). "Conformational Distribution and Ultrafast Base Dynamics of Leadzyme". Biochemistry. 48 (18): 3807–3809. doi:10.1021/bi900256q. PMID 19301929.
  6. ^ Pan, T.; Uhlenbeck, O. C. (1992). "A small metalloribozyme with a two-step mechanism". Nature. 358 (6387): 560–563. Bibcode:1992Natur.358..560P. doi:10.1038/358560a0. PMID 1501711. S2CID 4361511.
  7. ^ Arciszewska, M. Z.; et al. (2005). "Lead toxicity through the leadzyme". Mutation Research/Reviews in Mutation Research. 589 (2): 103–110. doi:10.1016/j.mrrev.2004.11.002. PMID 15795164.
  8. ^ Sigel, Astrid; Operschall, Bert P.; Sigel, Helmut (2017). "Chapter 11. Complex Formation of Lead(II) with Nucleotides and Their Constituents". In Astrid, S.; Helmut, S.; Sigel, R. K. O. (eds.). Lead: Its Effects on Environment and Health. Metal Ions in Life Sciences. Vol. 17. de Gruyter. pp. 319–402. doi:10.1515/9783110434330-011. PMID 28731304.
  9. ^ Wedekind, J. E.; McKay, D. B. (1999). "Crystal structure of a lead-dependent ribozyme revealing metal binding sites relevant to catalysis". Nature Structural Biology. 6 (3): 261–268. doi:10.1038/6700. PMID 10074945. S2CID 23837.
  10. ^ Wedekind, J. E.; McKay, D. B. (2003). "Crystal Structure of the Leadzyme at 1.8 Å Resolution: Metal Ion Binding and the Implications for Catalytic Mechanism and Allo Site Ion Regulation†". Biochemistry. 42 (32): 9554–9563. doi:10.1021/bi0300783. PMID 12911297.