Linking enzyme sequence to function using conserved property difference locator to identify and annotate positions likely to control specific functionality

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Abstract

BACKGROUND: Families of homologous enzymes evolved from common progenitors. The availability of multiple sequences representing each activity presents an opportunity for extracting information specifying the functionality of individual homologs. We present a straightforward method for the identification of residues likely to determine class specific functionality in which multiple sequence alignments are converted to an annotated graphical form by the Conserved Property Difference Locator (CPDL) program. RESULTS: Three test cases, each comprised of two groups of functionally-distinct homologs, are presented. Of the test cases, one is a membrane and two are soluble enzyme families. The desaturase/hydroxylase data was used to design and test the CPDL algorithm because a comparative sequence approach had been successfully applied to manipulate the specificity of these enzymes. The other two cases, ATP/GTP cyclases, and MurD/MurE synthases were chosen because they are well characterized structurally and biochemically. For the desaturase/hydroxylase enzymes, the ATP/GTP cyclases and the MurD/MurE synthases, groups of 8 (of approximately 400), 4 (of approximately 150) and 10 (of >400) residues, respectively, of interest were identified that contain empirically defined specificity determining positions. CONCLUSION: CPDL consistently identifies positions near enzyme active sites that include those predicted from structural and/or biochemical studies to be important for specificity and/or function. This suggests that CPDL will have broad utility for the identification of potential class determining residues based on multiple sequence analysis of groups of homologous proteins. Because the method is sequence, rather than structure, based it is equally well suited for designing structure-function experiments to investigate membrane and soluble proteins.

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Mayer, K. M., McCorkle, S. R., & Shanklin, J. (2005). Linking enzyme sequence to function using conserved property difference locator to identify and annotate positions likely to control specific functionality. BMC Bioinformatics, 6. https://doi.org/10.1186/1471-2105-6-284

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