title: Novel Molecular Interactions of Acylcarnitines and Fatty Acids with Myoglobin.
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.
authors.affiliation: From the Arkansas Children's Nutrition Center and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, svchintapalli@uams.edu.
authors.forename: Sree V
authors.initials: SV
authors.lastname: Chintapalli
authors.affiliation: the Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Jayanthi
authors.affiliation: the Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204.
authors.forename: Prema L
authors.initials: PL
authors.lastname: Mallipeddi
authors.affiliation: the Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Gundampati
authors.affiliation: the Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701.
authors.forename: Thallapuranam Krishnaswamy
authors.initials: TK
authors.lastname: Suresh Kumar
authors.affiliation: the Center for Computational Proteomics and.|the Department of Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, and.
authors.forename: Damian B
authors.initials: DB
authors.lastname: van Rossum
authors.affiliation: the Department of Biology, University of Maryland, College Park, Maryland 20742.
authors.forename: Andriy
authors.initials: A
authors.lastname: Anishkin
authors.affiliation: From the Arkansas Children's Nutrition Center and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202, shadams@uams.edu.
authors.forename: Sean H
authors.initials: SH
authors.lastname: Adams
mesh_terms: D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry*; D006736:Horses; D008956:Models, Chemical; D009211:Myoglobin / Q000737:chemistry*
chemical_list: D005227:Fatty Acids; D009211:Myoglobin; C116917:acylcarnitine; D002331:Carnitine
keywords: isothermal titration calorimetry (ITC); lipid binding protein; lipotoxicity; molecular docking; molecular dynamics; myoglobin; polyunsaturated fatty acid (PUFA)