The extracellular regions of PSMA and the transferrin receptor contain an aminopeptidase domain: implications for drug design.
The Aeromonas proteolytica aminopeptidase (AMP), Pseudomonas sp. (RS-16) carboxypeptidase G2 (CPG2), and Streptomyces griseus aminopeptidase (SGAP) are zinc dependent proteolytic enzymes with cocatalytic zinc ion centers and a conserved aminopeptidase fold. A BLAST search with the sequence of the solved AMP structure indicated that a similar domain could be found in prostate-specific membrane antigen (PSMA) and the transferrin receptor (TfR). When the PSMA or TfR sequence was input into the THREADER program, the top structural matches were SGAP and AMP confirming that these are structurally conserved domains. Optimal sequence alignment of PSMA and TfR using the known three-dimensional structures of AMP, CPG2, and SGAP shows that the critical amino acids involved in forming the catalytic pocket are conserved in PSMA but absent in the TfR. The specificity pocket in AMP is formed from four aromatic side chains and the equivalent region in CPG2/PSMA has a changed sequence pattern. Since CPG2 and PSMA are folate hydrolases, the changed specificity pocket leaves space to accommodate the large pteroate moiety of folic acid. In contrast, no enzyme function has been ascribed to the TfR.
Mahadevan
D
D
Birkbeck College, University of London, United Kingdom.
Saldanha
J W
JW
D000333:Aeromonas / Q000201:enzymology; D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000737:chemistry*; D001426:Bacterial Proteins; D017124:Conserved Sequence; D015195:Drug Design; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011549:Pseudomonas / Q000201:enzymology; D011990:Receptors, Transferrin / Q000737:chemistry*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012984:Software; D013305:Streptomyces griseus / Q000201:enzymology; D016335:Zinc Fingers; D011623:gamma-Glutamyl Hydrolase / Q000737:chemistry
D001426:Bacterial Proteins; D011990:Receptors, Transferrin; D000626:Aminopeptidases; C038222:bacterial leucyl aminopeptidase; D011623:gamma-Glutamyl Hydrolase