Walden-inversion-enforced transition-state stabilization in a protein tyrosine phosphatase

Cristobal Alhambra, Li Wu, Zhong-Yin Zhang, Jiali Gao

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

The initial step of the dephosphorylation reaction of a tyrosine phosphate substrate catalyzed by the low molecular weight bovine protein tyrosine phosphatase (BPTP) has been studied, making use of a combined quantum mechanical and molecular mechanical approach in molecular dynamics simulations. It was found that the enzyme favors a dianion substrate in the dephosphorylation reaction, which is consistent with experiments but in contrast to a recent mechanistic proposal involving a monoanion phosphate. The computed activation free energy is ca. 14 kcal/mol, in accord with the activation parameters determined in the present study from stopped-flow kinetics experiments. Structural analyses support the finding that BPTP catalyzes dephosphorylation reactions by stabilizing the transition state through Walden-inversion-enforced hydrogen-bonding interactions during the S(N)2 process.

Original languageEnglish (US)
Pages (from-to)3858-3866
Number of pages9
JournalJournal of the American Chemical Society
Volume120
Issue number16
DOIs
StatePublished - Apr 29 1998
Externally publishedYes

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Protein Tyrosine Phosphatases
Phosphatases
Phosphates
Stabilization
Chemical activation
Proteins
Substrates
Molecular Dynamics Simulation
Hydrogen Bonding
Free energy
Tyrosine
Molecular dynamics
Hydrogen bonds
Enzymes
Molecular Weight
Experiments
Molecular weight
Kinetics
Computer simulation

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Walden-inversion-enforced transition-state stabilization in a protein tyrosine phosphatase. / Alhambra, Cristobal; Wu, Li; Zhang, Zhong-Yin; Gao, Jiali.

In: Journal of the American Chemical Society, Vol. 120, No. 16, 29.04.1998, p. 3858-3866.

Research output: Contribution to journalArticle

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