Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase.

Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase. Research Abstract Details 

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Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase. Abstract Text:

Kathryn M Johnson,Joanne Cleary,Carol A Fierke,Anthony W Opipari,Gary D Glick,

Altered cellular bioenergetics are implicated in many disease processes, and modulating the F 1 F o -ATPase, the enzyme responsible for producing the majority of ATP in eukaryotic cells, has been proposed to have therapeutic utility. Bz-423 is a 1,4-benzodiazepine that binds to the oligomycin sensitivity-conferring protein subunit of the mitochondrial F 1 F o -ATPase and inhibits the enzyme. In response to Bz-423, cells moderately decrease ATP synthesis and significantly increase superoxide, resulting in redox-regulated apoptosis. Administering Bz-423 to autoimmune mice leads to apoptosis of pathogenic cells and potent attenuation of disease progression. To determine if a mechanism of action distinguishes Bz-423 from toxic F 1 F o -ATPase inhibitors like oligomycin, we studied how both compounds inhibit the enzyme. Oligomycin is a high-affinity mixed inhibitor, displaying time-dependent inhibition, resulting in severe depletion of ATP. In contrast, Bz-423 is an allosteric inhibitor with lower affinity that rapidly dissociates from the enzyme. Our data support a model in which the interplay of these features underlies the favorable properties of Bz-423. They also represent key criteria for the development of therapeutic F 1 F o -ATPase inhibitors, which should have utility across a range of areas.

Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase. Publishing Authors By Initials

KM Johnson,J Cleary,CA Fierke,AW Opipari,GD Glick,

For similar organic chemicals: lactones: macrolides: oligomycins research abstracts see: organic chemicals: lactones: macrolides: oligomycins research

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Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: ACS chemical biology

VOLUME: 1

Page Numbers: 304-8

Journal Abbreviation: ACS Chem. Biol.

ISSN: 1554-8937

DAY: 20

MONTH: Jun

YEAR: 2006

Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101282906

Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase. Keywords Mesh Terms:

KEYWORDS: Oligomycins

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase. Information

Substance Name: Mitochondrial Proton-Translocating ATPas

Registry Number: EC 3.6.3.-

Grant and Affiliation Information for Mechanistic basis for therapeutic targeting of the mitochondrial F1F0-ATPase.

AFFILIATION:

Country: United States

AGENCY: United States NIAID

GRANT: AI-47450

ACRONYM: AI

MEDLINETA: ACS Chem Biol

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