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Title:   Author  item
                                            Richards, Gary
  Submitted to: Biochimica et Biophysica Acta
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 8/13/2004
                                    Publication  Date: 9/25/2004
                                    Citation: Richards, G.P. 2004. Structural and functional analyses of phosphoglucose isomerase from Vibrio vulnificus and its lysyl aminopeptidase activity. Biochimica et Biophysica Acta. 1702:89-102.Interpretive Summary: Vibrio vulnificus is a naturally-occurring marine bacterium associated with the marine environment.  Oysters and other shellfish may contain high levels of V. vulnificus and the death rate among susceptible shellfish consumers approaches 60%.  About 20 deaths occur in the United States each year.  Particularly susceptible are consumers who eat raw shellfish and have liver disease (like cirrhosis), diabetes, or have weakened immune systems.  Phosphoglucose isomerase (PGI) is an enzyme that was recently isolated from V. vulnificus.  PGI has a novel function to cleave an amino acid (lysine) from the ends of proteins.  Such a function may be important for Vibrio to evade host defenses and enhance bacterial spread in infected individuals.  The enzyme is found on or near the surface of Vibrio cells.  Computer models suggest two regions on the PGI molecule that may interact with the bacterial membrane.  Under natural conditions, two different sized molecules of PGI form a complex which exhibits the novel enzyme activity.  To better understand this novel activity, a computer search was conducted comparing PGI from V. vulnificus, rabbits and humans.  The search revealed 194 different regions representing different potential functions of the enzyme.  By comparison, 124 of the same regions were found in rabbit PGI and 127 in human PGI.  Each of the PGIs contained three regions that could lead to the cleavage of the lysine from proteins.  These regions also contain sequences that indicate the binding of calcium to PGI.  The addition of calcium to Vibrio PGI dramatically reduced the novel enzyme activity, suggesting that calcium may be a natural regulator for PGI.  Together, these results suggest a possible mechanism which may enhance the invasiveness of V. vulnificus in humans.
                                Technical Abstract: Phosphoglucose isomerase (PGI) with a novel lysyl aminopeptidase (LysAP) activity was recently isolated and partially characterized from the human pathogen, Vibrio vulnificus.  This PGI is a heterodimer consisting of 60.8-kDa and 23.4-kDa subunits, which together provide LysAP activity.  The present study further characterizes the complex structure and functions of Vibrio PGI and draws parallels with rabbit and human PGI.  A Proscan search of Vibrio PGI revealed 194 different structural motifs of which 124 and 127 were also found in rabbit and human PGI, respectively.  Vibrio PGI contains motifs for the serine, histidine and aspartic acid active sites of the subtilase family of serine proteases which form a putative catalytic triad consisting of His534 and Ser159 on the 60.8-kDa subunit and Asp53 on the 23.4-kDa subunit.  Together, they form one LysAP site for each heterodimer.  Each active site motif is overlapped by motifs for EF-hand calcium binding domains.  The LysAP activity was inhibited by the addition of >10 microM calcium, suggesting that the EF-hand calcium-binding domain may be a natural regulatory region for LysAP activity.  In contrast, PGI's isomerase activity was enhanced at calcium concentrations >100 microM.  PGI-LysAP cleaved the amino-terminal lysyl residue from des-Arg10-kallidin producing des-Arg9-bradykinin; therefore, Vibrio PGI-LysAP may serve as a virulence factor to enhance Vibrio invasiveness.  Together, these data provide a framework to account for PGI's LysAP activity and further demonstrate the structural complexity and functional importance of this molecule.


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