Substrate specificity of prostate-specific membrane antigen

Bioorg Med Chem. 2007 Nov 1;15(21):6678-86. doi: 10.1016/j.bmc.2007.08.006. Epub 2007 Aug 11.

Abstract

A series of putative dipeptide substrates of prostate-specific membrane antigen (PSMA) was prepared that explored alpha- and beta/gamma-linked acidic residues at the P1 position and various chromophores at the P2 position, while keeping the P1' residue constant as L-Glu. Four chromophores were examined, including 4-phenylazobenzoyl, 1-pyrenebutyryl, 9-anthracenylcarboxyl-gamma-aminobutyryl, and 4-nitrophenylbutyryl. When evaluating these chromophores, it was found that a substrate containing 4-phenylazobenzoyl at the P2 position was consumed most efficiently. Substitution at the P1 position with acidic residues showed that only gamma-linked L-Glu and D-Glu were recognized by the enzyme, with the former being more readily proteolyzed. Lastly, binding modes of endogenous substrates and our best synthetic substrate (4-phenylazobenzoyl-Glu-gamma-Glu) were proposed by computational docking studies into an X-ray crystal structure of the PSMA extracellular domain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, Surface / chemistry*
  • Chromatophores / chemistry
  • Crystallography, X-Ray
  • Dipeptides / chemistry*
  • Glutamate Carboxypeptidase II / chemistry*
  • Humans
  • Male
  • Models, Molecular
  • Protein Structure, Tertiary
  • Substrate Specificity

Substances

  • 4-phenylazobenzoyl-Glu-gamma-Glu
  • Antigens, Surface
  • Dipeptides
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II