Evolutionary trace analysis of the a-D-phosphohexomutase superfamily [abstract]
Abstract
Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of hospital-acquired
infections. It is a common cause of infections in cystic fibrosis, immunocompromised, and burn
patients. Adding to its pathogenicity, P. aeruginosa produces multiple virulence factors, including
lipopolysaccharide, rhamnolipid, and alginate. These exoproducts render the bacterium resistant to
antibiotic treatment and the host immune response, and proteins involved in their biosynthesis are thus
attractive candidates for inhibitor design. One enzyme in particular,
phosphomannomutase/phosphoglucomutase (PMM/PGM), is required for the production of all three
exoproducts, and has been characterized both structurally and mechanistically. PMM/PGM is a member
of the phosphohexomutase superfamily, which encompasses four groups of enzymes: PMM/PGM,
phosphoglucomutase, phosphoglucosaminemutase, and phosphoacetylglucosaminemutase. These
proteins catalyze a reversible, intramolecular phosphoryl transfer for a variety of phosphosugar
substrates in bacteria, eukaryotes, and archae. Recently, we have used the evolutionary trace analysis
to examine sixty-nine members of the phosphohexomutase superfamily. This method uses sequencesequence
and sequence-structure comparisons to identify residues that are evolutionarily conserved
and therefore presumably of structural and/or functional importance. According to this analysis, many
active site residues important for the generic phosphoryl transfer mechanism are conserved throughout
the enzyme family. Also, some important regions show class-specific differences in sequence that
appear to be correlated with differences in substrate specificity exhibited by subgroups of the family.
The results from this research provide new insight into enzyme mechanism and substrate recognition by
the phosphohexomutase family.