Novel Molecular Interactions of Acylcarnitines and Fatty Acids with Myoglobin

Abstract

Edited by George CarmanPrevious 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 acylcarnitinebinding 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 oxyMb. 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 longchain 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.

Mass Spectrometry-Based Chemical Cartography of a Cardiac Parasitic Infection

“…2i), with an increased representation of higher molecular weight lipids in non-fatal outcomes. Long and short-chain acylcarnitines and fatty acids play differential roles in cardiac muscle energy metabolism, stress response, and oxidative damage management 34 . Phosphatidylcholines are major membrane components, but also play important roles in immune regulation 35,36 .…”

“…Long and short-chain acylcarnitines and fatty acids play differential roles in cardiac muscle energy metabolism, stress response, and oxidative damage management. 35 Phosphatidylcholines are not only major membrane components but also play important roles in immune regulation. 36,37 Furthermore, modulations of serum phosphatidylcholine levels have been detected in coronary heart disease and noninfectious heart failure.…”

Carnitine palmitoyltransferase 2 knockout potentiates palmitate-induced insulin resistance in C2C12myotubes

“…37,41). Another caveat to characterizing potential effects of acylcarnitines in muscle and cardiac tissue is that oxygenated myoglobin avidly binds palmitoylcarnitine (9,10), which may lead to cellular sequestration. Finally, it is intriguing to consider that lipid intermediates synergize or interact to modify insulin sensitivity: palmitoylcarnitine, for instance, is thought to activate some PKC isoforms and caspase 3 (see Ref.…”

Structural and Energetic Insights Into the Interaction of Niacin With the GPR109A Receptor

“… 23 By allowing the torsional degrees of freedom for the ligand, we intended to facilitate the exploration of the conformational space of the niacin and the binding region. 40 , 41 Polar hydrogen atoms and Kollman’s united atom partial charges were assigned for the protein using AutoDock tools. 35 , 39 The grid size was set to 70X70X70 points with a grid spacing of 0.375 Å.…”