Novel molecular interactions of acylcarnitines and fatty acids with myoglobin

Sree V. Chintapalli, Srinivas Jayanthi, Prema L. Mallipeddi, Ravikumar Gundampati, Thallapuranam Krishnaswamy Suresh Kumar, Damian B. Van Rossum, Andriy Anishkin, Sean H. Adams

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8 Scopus citations

Abstract

Previous research has indicated that long-chain fatty acids can bind myoglobin (Mb) in an oxygen-dependent manner. This suggests that oxy-Mb may play an important role in fuel delivery in Mb-rich muscle fibers (e.g. type I fibers and cardiomyocytes), and raises the possibility that Mb also serves as an acylcarnitine-binding protein. We report for the first time the putative interaction and affinity characteristics for different chain lengths of both fatty acids and acylcarnitines with oxy-Mb using molecular dynamic simulations and isothermal titration calorimetry experiments. We found that short- to medium-chain fatty acids or acylcarnitines (ranging from C2:0 to C10:0) fail to achieve a stable conformation with oxy-Mb. Furthermore, our results indicate that C12:0 is the minimum chain length essential for stable binding of either fatty acids or acylcarnitines with oxy-Mb. Importantly, the empirical lipid binding studies were consistent with structural modeling. These results reveal that: (i) the lipid binding affinity for oxy-Mb increases as the chain length increases (i.e. C12:0 to C18:1), (ii) the binding affinities of acylcarnitines are higher when compared with their respective fatty acid counterparts, and (iii) both fatty acids and acylcarnitines bind to oxy-Mb in 1:1 stoichiometry. Taken together, our results support a model in which oxy-Mb is a novel regulator of long-chain acylcarnitine and fatty acid pools in Mb-rich tissues. This has important implications for physiological fuel management during exercise, and relevance to pathophysiological conditions (e.g. fatty acid oxidation disorders and cardiac ischemia) where long-chain acylcarnitine accumulation is evident.

Original languageEnglish (US)
Pages (from-to)25133-25143
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number48
DOIs
StatePublished - Nov 25 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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