Spectrum of toxicities of amino acid methyl esters for myeloid cells is determined by distinct metabolic pathways

Dwain L Thiele, Peter E. Lipsky

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

L-leucine methyl ester (Leu-OMe), Leu-Leu-OMe, Phe-OMe, and Glu-(OMe)2 are toxic to mononuclear phagocytes (Mφ) and neutrophils. In the present studies, the mechanism of this toxicity was examined. A concentration of NH4Cl known to neutralize lysosomal pH and to block conversion of Leu-OMe to the dipeptide condensation product Leu-Leu-OMe inhibited Leu-OMe- or Glu- (OMe)2-but not Leu-Leu-OMe-mediated Mφ toxicity. Leu-OMe-, Glu-(OMe)2-, or Leu-Leu-OMe-mediated killing of Mφ was prevented by Gly-Phe-CHN2, a specific inhibitor of the thiol protease, dipeptidyl peptidase I (DPPI). Neither NH4Cl nor Gly-Phe-CHN2 prevented Phe-OMe-mediated Mφ toxicity. In contrast, inhibition of Mφ serine esterase activity prevented Phe-OMe- but not Leu-OMe- or Glu-(OMe)2-mediated killing of Mφ. The myeloid tumor lines U937, HL60, and THP-1 were found to be uniformly enriched in DPPI and susceptible to Leu-Leu-OMe but not Leu-OMe toxicity. Whereas HL60 were resistant to Phe-OMe, THP-1 cells were killed by this agent. Incubation of peripheral blood mononuclear cells with Leu-OMe resulted in loss of natural killer (NK) function and cytotoxic T lymphocytes (CTL) precursors, a process that requires the DPPI-dependent generation of membranolytic polymerization products. Phe-OMe had no toxic effects on NK cells or CTL precursors. These results indicate that Leu-OMe and Glu-(OMe)2 toxicity for Mφ is related to the production of higher molecular weight hydrophobic polymerization products via the sequential action of two nonserine esterase lysosomal enzymes. In contrast, Phe-OMe toxicity for myeloid cells was found to correlate with serine esterase-mediated intracellular trapping of high concentrations of the free amino acid Phe. These distinct enzymatic mechanisms may provide a unique means of targeting agents capable of selectively deleting cells of myeloid lineage.

Original languageEnglish (US)
Pages (from-to)964-971
Number of pages8
JournalBlood
Volume79
Issue number4
DOIs
StatePublished - 1992

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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