Suramin is an active site-directed, reversible, and tight-binding inhibitor of protein-tyrosine phosphatases

Yan Ling Zhang, Yen Fang Keng, Yu Zhao, Li Wu, Zhong-Yin Zhang

Research output: Contribution to journalArticle

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Abstract

The effect of suramin, a well known antitrypanosomal drug and a novel experimental agent for the treatment of several cancers, on protein-tyrosine phosphatases (PTPases) has been examined. Suramin is a reversible and competitive PTPase inhibitor with K(is) values in the low μM range, whereas the K(is), for the dual specificity phosphatase VHR is at least 10-fold higher. Although suramin can also inhibit the activity of the potato acid phosphatase at a slightly higher concentration, it is 2-3 orders of magnitude less effective against the protein Ser/Thr phosphatase 1α and the bovine intestinal alkaline phosphatase. Suramin binds to the active site of PTPases with a binding stoichiometry of 1:1. Furthermore, when suramin is bound to the active site of PTPases, its fluorescence is enhanced approximately by 10- fold. This property has allowed the determination of the binding affinity of suramin for PTPases and several catalytically impaired mutant PTPases by fluorescence titration techniques. Thus, the active site Cys to Ser mutants bind suramin with similar affinity as the wild type, while the active site Arg to Ala mutant exhibits a 20-fold reduced affinity toward suramin. Interestingly, the general acid deficient Asp to Ala mutant PTPases display an enhanced affinity toward suramin, which is in accord with their use as improved 'substrate-trapping' agents. That suramin is a high affinity PTPase inhibitor is consistent with the observation that suramin treatment of cancer cell lines leads to an increase in tyrosine phosphorylation of several cellular proteins. Given the pleiotropic effects of suramin on many enzyme systems and growth factor-receptor interactions, the exact in vivo actions of suramin require further detailed structure-activity investigation of suramin and its structural analogs.

Original languageEnglish (US)
Pages (from-to)12281-12287
Number of pages7
JournalJournal of Biological Chemistry
Volume273
Issue number20
DOIs
StatePublished - May 15 1998
Externally publishedYes

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Suramin
Protein Tyrosine Phosphatases
Catalytic Domain
Carrier Proteins
Mutant Proteins
Fluorescence
Dual-Specificity Phosphatases
Phosphorylation
Growth Factor Receptors
Solanum tuberosum
Acid Phosphatase
Titration
Phosphoric Monoester Hydrolases
Stoichiometry

ASJC Scopus subject areas

  • Biochemistry

Cite this

Suramin is an active site-directed, reversible, and tight-binding inhibitor of protein-tyrosine phosphatases. / Zhang, Yan Ling; Keng, Yen Fang; Zhao, Yu; Wu, Li; Zhang, Zhong-Yin.

In: Journal of Biological Chemistry, Vol. 273, No. 20, 15.05.1998, p. 12281-12287.

Research output: Contribution to journalArticle

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