Prediction of the mechanism of action of omuralide (clasto-lactacystin beta-lactone) on human cathepsin A based on a structural model of the yeast proteasome beta5/PRE2-subunit/omuralide complex.
Cathepsin A (CathA) is a lysosomal serine carboxypeptidase that exhibits homology and structural similarity to the yeast and wheat serine carboxypeptidases (CPY and CPW) belonging to the alpha/beta-hydrolase fold family. Human CathA (hCathA) and CPW have been demonstrated to be inhibited by a proteasome (threonine protease) inhibitor, lactacystin, and its active derivative, omuralide (clasto-lactacystin beta-lactone), as well as chymostatin. A hCathA/omuralide complex model constructed on the basis of the X-ray crystal structures of the CPW/chymostatin complex and the yeast proteasome beta-subunit (beta5/PRE2)/omuralide one predicted that the conformation of omuralide in the active-site cleft of proteasome beta5/PRE2 should be very similar to that of chymostatin at the S1 catalytic subsites in the hCathA- and CPW-complexes. The relative positions of the glycine residues, i.e., Gly57 in hCathA, Gly53 in CPW, and Gly47 in beta5/PRE2, present in the oxyanion hole of each enzyme were also highly conserved. These results suggest that omuralide might inhibit hCathA and CPW at the S1 subsite in their active-site clefts through direct binding to the active serine residue.
Aikawa
Sei-ichi
S
Celestar Lexico-Sciences, Inc., Mihama-ku, Chiba 261-8501, Japan.
Matsuzawa
Fumiko
F
Satoh
Yurie
Y
Kadota
Yoshito
Y
Doi
Hirofumi
H
Itoh
Kohji
K
D020134:Catalytic Domain; D043402:Cathepsin A / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D046911:Macromolecular Substances; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*
D007783:Lactones; D046911:Macromolecular Substances; D029701:Saccharomyces cerevisiae Proteins; C117645:omuralide; D043402:Cathepsin A; D003546:Cysteine Endopeptidases; C080044:PRE2 protein, S cerevisiae; D046988:Proteasome Endopeptidase Complex