title: Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke.
abstract: Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin's prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin's ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin's mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455.
authors.forename: John A
authors.initials: JA
authors.lastname: Rohde
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455 muret003@umn.edu ddt@umn.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: Thomas
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455 muret003@umn.edu ddt@umn.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Muretta
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D024722:Cardiac Myosins / Q000737:chemistry / Q000187:drug effects* / Q000302:isolation & purification; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000737:chemistry; D002417:Cattle; D002645:Chickens; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D007700:Kinetics; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009218:Myosins / Q000737:chemistry / Q000187:drug effects*; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D002317:Cardiovascular Agents; D010710:Phosphates; C547293:omecamtiv mecarbil; D014508:Urea; D024722:Cardiac Myosins; D009218:Myosins
keywords: FRET; heart failure; myosin; omecamtiv mecarbil; phosphate release