BIOPHYSICAL THEORY AND MODELING |
Modeling of Spatial Metabolite Distributions in the Cardiac Sarcomere
Vitaly Selivanov 1*, Stephen Krause 2, Josep Roca 3 and Marta Cascante 1
1 University of Barcelona
2 Merck Research Laboratories
3 IDIBAPS
* To whom correspondence should be addressed. E-mail: selivanov{at}ub.edu.
Submitted on November 21, 2006
Revised on December 19, 2006
Accepted on 29 January 2007
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Abstract |
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Although the high ATP diffusion rate implies homogeneous distribution of this principal energetic currency in the cytosol, local diffusion barriers represented by macromolecular structures can render ATP concentrations to be inhomogeneous. A method, which provides apparent diffusion coefficient values in local intracellular regions and allows estimating spatial metabolite distribution, is present here. The apparent local diffusion coefficient for ATP in cardiac myofibrils was determined from the analysis of diffusion-dependent rightward shift of the substrate dependence for acto-myosin ATPase activity using the reaction-diffusion model, which accounted for the properties of phosphotransfer reactions. This functional analysis, which took into account the local diffusional ATP delivery to the active sites, provided an apparent value that was three orders of magnitude lower than that defined by direct methods for the cytosol. The low value of the diffusion coefficient was shown to define unusual properties of the intracellular space in working heart, where small reductions in ATP levels in the surrounding cytosol result in a large drop of [ATP] inside myofibrils. This drop is critical for vital cellular functions and the present analysis defines its physical basis. The diffusion barriers thus defined explain the coexistence of pathological energy deficit with almost normal average ATP levels.
Key Words:
ATP diffusion limitation, ATP gradients, diffusion-defined compartmentalization, myofibrils, reaction-diffusion model
