title: In silico and in vitro investigations of the mutability of disease-causing missense mutation sites in spermine synthase.
abstract: BACKGROUND
  Spermine synthase (SMS) is a key enzyme controlling the concentration of spermidine and spermine in the cell. The importance of SMS is manifested by the fact that single missense mutations were found to cause Snyder-Robinson Syndrome (SRS). At the same time, currently there are no non-synonymous single nucleoside polymorphisms, nsSNPs (harmless mutations), found in SMS, which may imply that the SMS does not tolerate amino acid substitutions, i.e. is not mutable.
  
  
  RESULTS
  To investigate the mutability of the SMS, we carried out in silico analysis and in vitro experiments of the effects of amino acid substitutions at the missense mutation sites (G56, V132 and I150) that have been shown to cause SRS. Our investigation showed that the mutation sites have different degree of mutability depending on their structural micro-environment and involvement in the function and structural integrity of the SMS. It was found that the I150 site does not tolerate any mutation, while V132, despite its key position at the interface of SMS dimer, is quite mutable. The G56 site is in the middle of the spectra, but still quite sensitive to charge residue replacement.
  
  
  CONCLUSIONS
  The performed analysis showed that mutability depends on the detail of the structural and functional factors and cannot be predicted based on conservation of wild type properties alone. Also, harmless nsSNPs can be expected to occur even at sites at which missense mutations were found to cause diseases.
authors.affiliation: Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, South Carolina, United States of America.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.forename: Joy
authors.initials: J
authors.lastname: Norris
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.forename: Emil
authors.initials: E
authors.lastname: Alexov
mesh_terms: D019295:Computational Biology; D004252:DNA Mutational Analysis; D004795:Enzyme Stability; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D038901:X-Linked Intellectual Disability / Q000201:enzymology* / Q000235:genetics*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013097:Spermine Synthase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
chemical_list: D013097:Spermine Synthase