Phospho-azatyrosine, a less effective protein-tyrosine phosphatase substrate than phosphotyrosine

Terrence R. Burke, Zhu Jun Yao, Bin Ye, Kengo Miyoshi, Akira Otaka, Li Wu, Zhong-Yin Zhang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Azatyrosine (AzaTyr, 4) is a natural product isolated from Streptomyces chibanesis, whose structure is characterized by a nitrogen atom in the aryl ring of a tyrosyl residue. This seemingly minor modification to the tyrosyl residue results in profound physiological effects, as AzaTyr has been shown to promote permanent reversion of ras-dependent transformed cells to the normal phenotype in culture and to inhibit chemical induction of carcinogenesis in transgenic mice bearing oncogenic human ras. The mechanisms underlying these effects are not known, however ras-pathways involve an intricate balance between both protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). The present study was undertaken to examine the general utility of AzaTyr as a structural motif for PTP inhibitor design by examining the phospho-azatyrosine (pAzaTyr)-containing peptide Ac-Asp-Ala-Asp-Glu-pAzaTyr-Leu-amide (8) in a PTP1 enzyme system. Kinetic analysis indicated that 8 binds with a Km value of 210 μM and a catalytic turnover rate, kcat of 52 s-1. This represents a greater than 50-fold reduction in binding affinity relative to the parent phosphotyrosine-containing peptide, indicating that the aryl nitrogen adversely affects binding affinity. The much lower PTP affinity of the pAzaTyr-containing peptide reduces the potential utility of the AzaTyr pharmacophore for PTP inhibitor design. These results are discussed from the point of view that incorporation of AzaTyr residues into proteins could result in perturbation of protein-tyrosine phosphorylation/dephosphorylation cascades that control signal transduction processes, including ras-dependent pathways.

Original languageEnglish (US)
Pages (from-to)1265-1268
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume11
Issue number10
DOIs
StatePublished - May 21 2001
Externally publishedYes

Fingerprint

Phosphotyrosine
Protein Tyrosine Phosphatases
Substrates
Peptides
Bearings (structural)
Nitrogen
Signal transduction
Phosphorylation
Streptomyces
Biological Products
Amides
Protein-Tyrosine Kinases
Transgenic Mice
Tyrosine
Signal Transduction
Carcinogenesis
Proteins
Phenotype
Atoms
Kinetics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Phospho-azatyrosine, a less effective protein-tyrosine phosphatase substrate than phosphotyrosine. / Burke, Terrence R.; Yao, Zhu Jun; Ye, Bin; Miyoshi, Kengo; Otaka, Akira; Wu, Li; Zhang, Zhong-Yin.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 11, No. 10, 21.05.2001, p. 1265-1268.

Research output: Contribution to journalArticle

Burke, Terrence R. ; Yao, Zhu Jun ; Ye, Bin ; Miyoshi, Kengo ; Otaka, Akira ; Wu, Li ; Zhang, Zhong-Yin. / Phospho-azatyrosine, a less effective protein-tyrosine phosphatase substrate than phosphotyrosine. In: Bioorganic and Medicinal Chemistry Letters. 2001 ; Vol. 11, No. 10. pp. 1265-1268.
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