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A method using active‐site sequence conservation to find functional shifts in protein families: Application to the enzymes of central metabolism, leading to the identification of an anomalous isocitrate dehydrogenase in pathogens
Author(s) -
Das Rajdeep,
Gerstein Mark
Publication year - 2004
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.10639
Subject(s) - active site , isocitrate dehydrogenase , biology , sequence alignment , enzyme , biochemistry , peptide sequence , sequence analysis , conserved sequence , protein sequencing , sequence (biology) , dehydrogenase , protein family , computational biology , gene
We have introduced a method to identify functional shifts in protein families. Our method is based on the calculation of an active‐site conservation ratio, which we call the “ASC ratio.” For a structurally based alignment of a protein family, this ratio is the average sequence similarity of the active‐site region compared to the full‐length protein. The active‐site region is defined as all the residues within a certain radius of the known functionally important groups. Using our method, we have analyzed enzymes of central metabolism from a large number of genomes (35). We found that for most of the enzymes, the active‐site region is more highly conserved than the full‐length sequence. However, for three tricarboxylic acid (TCA)‐cycle enzymes, active‐site sequences are considerably more diverged (than full‐length ones). In particular, we were able to identify in six pathogens a novel isocitrate dehydrogenase that has very low sequence similarity around the active site. Detailed sequence–structure analysis indicates that while the active‐site structure of isocitrate dehydrogenase is most likely similar between pathogens and nonpathogens, the unusual sequence divergence could result from an extra domain added at the N‐terminus. This domain has a leucine‐rich motif similar one in the Yersinia pestis cytotoxin and may therefore confer additional pathogenic functions. Proteins 2004. © 2004 Wiley‐Liss, Inc.