Omecamtiv Mecarbil modulates the kinetic and motile properties of porcine β-cardiac myosin.

Autor:	Liu Y; †Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, United States., White HD; †Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, United States., Belknap B; †Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, United States., Winkelmann DA; ‡Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey 08854, United States., Forgacs E; †Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, Virginia 23507, United States.
Jazyk:	angličtina
Zdroj:	Biochemistry [Biochemistry] 2015 Mar 17; Vol. 54 (10), pp. 1963-75. Date of Electronic Publication: 2015 Mar 04.
DOI:	10.1021/bi5015166
Abstrakt:	We determined the effect of Omecamtiv Mecarbil, a novel allosteric effector of cardiac muscle myosin, on the kinetic and "in vitro" motility properties of the porcine ventricular heavy meromyosin (PV-HMM). Omecamtiv Mecarbil increases the equilibrium constant of the hydrolysis step (M-ATP ⇄ M-ADP-Pi) from 2.4 to 6 as determined by quench flow, but the maximal rates of both the hydrolysis step and tryptophan fluorescence increase are unchanged by the drug. OM also increases the amplitude of the fast phase of phosphate dissociation (AM-ADP-Pi → AM-ADP + Pi) that is associated with force production in muscle by 4-fold. These results suggest a mechanism in which hydrolysis of M-ATP to M-ADP-Pi occurs both before and after the recovery stroke, but rapid acceleration of phosphate dissociation by actin occurs only on post-recovery stroke A-M-ADP-Pi. One of the more dramatic effects of OM on PV-HMM is a 14-fold decrease in the unloaded shortening velocity measured by the in vitro motility assay. The increase in flux through phosphate dissociation and the unchanged rate of ADP dissociation (AM-ADP → AM + ADP) by the drug produce a higher duty ratio motor in which a larger fraction of myosin heads are strongly bound to actin filaments. The increased internal load produced by a larger fraction of strongly attached crossbridges explains the reduced rate of in vitro motility velocity in the presence of OM and predicts that the drug will produce slower and stronger contraction of cardiac muscle.
Databáze:	MEDLINE
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