Molecular and Structural Basis of Drift in the Functions of
Closely-Related Homologous Enzyme Domains: Implications for Function Annotation
Based on Homology Searches and Structural Genomics
Abstract: Using a large database of protein domain families of known 3-D
structure we present an analysis on the relationships among sequences,
structures and functions of closely-related enzymes performed at the level of
catalytic domains. Only in 38% of the pairs of homologous catalytic domains
characterized by over about 60% of sequence identity the functions are almost
completely identical. Nearly 43% of the pairs differ in their substrate
specificity. Hence the most common variation of enzyme function among the
closely-related homologues is the differences in the substrate specificity. For
homologous pairs characterized by a sequence identity of 30–60%, if the
structural difference metric is less than about 30, the functions are highly
conserved. For clearly homologous protein domain pairs, usually sharing less
than 40% sequence identity, we observe that often the chemical groups involved
in the functions, and the cofactors differ. We also report of extremely unusual
cases of closely-related homologues belonging to entirely different classes of
enzymes. Such drastic shifts in the gross functions of homologues seem to be
achieved by retooling of catalytic residues or by altering the stability of the
intermediates in the biochemical reactions. Our work provides guidelines on the
functional annotation based on homology searches and in structural genomics
initiatives.
Keywords: Enzyme classification, homologous proteins, protein evolution, protein function, protein structure
