Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates.

Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates. Research Abstract Details 

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Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates. Abstract Text:

A Draganescu,S C Hodawadekar,K R Gee,C Brenner,

Fhit, a member of the histidine triad superfamily of nucleotide-binding proteins, binds and cleaves diadenosine polyphosphates and functions as a tumor suppressor in human epithelial cancers. Function of Fhit in tumor suppression does not require diadenosine polyphosphate cleavage but correlates with the ability to form substrate complexes. As diadenosine polyphosphates are at lower cellular concentrations than mononucleotides, we sought to quantify interactions between Fhit and competitive inhibitors with the use of diadenosine polyphosphate analogs containing fluorophores in place of one nucleoside. Appp-S-(7-diethylamino-4-methyl-3-(4-succinimidylphenyl)) coumarin (ApppAMC), Appp-S-(4-4-difluoro-5,7-dimethyl-4-bora-3a, 4a-diaza-s-indacine-3-yl) methylaminoacetyl (ApppBODIPY), and GpppBODIPY, synthesized in high yield, are effective Fhit substrates, producing AMP or GMP plus fluorophore diphosphates. GpppBODIPY cleavage is accompanied by a 5.4-fold increase in fluorescence because BODIPY fluorescence is quenched by stacking with guanine. Titration of unlabeled diadenosine polyphosphates, inorganic pyrophosphate, mononucleotides, and inorganic phosphate into fluorescent assays provided values of K(m) and K(I) as competitive inhibitors. The data indicate that Fhit discriminates between good substrates via k(cat) and against cellular competitors in equilibrium binding terms. Surprisingly, pyrophosphate competes better than purine mononucleotides.

Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates. Publishing Authors By Initials

A Draganescu,SC Hodawadekar,KR Gee,C Brenner,

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Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: The Journal of biological chemistry

VOLUME: 275

Page Numbers: 4555-60

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 18

MONTH: Feb

YEAR: 2000

Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985121

Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates. Keywords Mesh Terms:

KEYWORDS: Proteins

MESH TERMS: metabolism

Chemical & Substance for Abstract: Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates. Information

Substance Name: Acid Anhydride Hydrolases

Registry Number: EC 3.6.-

Grant and Affiliation Information for Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates.

AFFILIATION: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Country: UNITED STATES

AGENCY: United States NCI

GRANT: R01 CA075954-03

ACRONYM: CA

MEDLINETA: J Biol Chem

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