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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #348527

Title: Exploring the entry route of palmitic acid and palmitoylcarnitine into myoglobin

Author
item CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC)
item ANISHKIN, ANDRIY - University Of Maryland
item Ferruzzi, Mario

Submitted to: Archives of Biochemistry and Biophysics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/31/2018
Publication Date: 8/6/2018
Citation: Chintapalli, S.V., Anishkin, A., Adams, S.H. 2018. Exploring the entry route of palmitic acid and palmitoylcarnitine into myoglobin. Archives Of Biochemistry and Biophysics. https://doi.org/10.1016/j.abb.2018.07.024.
DOI: https://doi.org/10.1016/j.abb.2018.07.024

Interpretive Summary: Heart muscle and many skeletal muscles rely heavily on fat combustion to generate energy and function properly. Yet, when fat delivery to tissues is excessive, as can occur in certain metabolic conditions such as pre-diabetes and type 2 diabetes, fatty acids and their metabolic by-products (acylcarnitines) can contribute to increase resistance to the blood sugar-regulating hormone insulin in muscle cells. However, it is still unclear regarding the storage and transportation of both fatty acids and acylcarnitines in muscle. Experimental evidence suggested that the abundant muscle protein myoglobin binds to both fatty acids and acylcarnitines strongly when myoglobin is in the oxygenated state. Oxygen is stored and transported in both heart and skeletal muscle by myoglobin, which is analogous to hemoglobin in red blood cells. This leads to a speculation that myoglobin may help move oxygen and fuel (fatty acids and acylcarnitines) to the mitochondria (the power house of a cell) to help produce energy, and the protein may even help regulate the accumulation of excessive fat in the cells. To further understand how fatty acids and acylcarnitines bind to myoglobin, we conducted computer modeling studies which indicate that fatty acids binds to myoglobin when in the oxygenated state, and releases fatty acids when myoglobin is converted to the deoxygenated state. This binding appears to be quite specific to the oxygen-containing region of the myoglobin protein, based on our observations from 80 different independent computer models using molecular dynamic simulations. Computational structural analysis reveals the importance of critical hydrophobic (lipid-attracting) residues in the crevice, which (along with heme) may play a significant role in the entry mechanism. These results point to muscle myoglobin—long believed to simply ferry oxygen to working cardiac- and skeletal muscle—as an important regulator of fat metabolism in the body.

Technical Abstract: Myoglobin, besides its role in oxygen turnover, has gained recognition as a potential regulator of lipid metabolism. Previously, we confirmed the interaction of fatty acids and acylcarnitines with Oxy-Myoglobin, using both molecular dynamic simulations and Isothermal Titration Calorimetry studies. However, those studies were limited to testing only the binding sites derived from homology to fatty acid binding proteins and predictions using automated docking. To explore the entry mechanisms of the lipid ligands into myoglobin, we conducted molecular dynamic simulations of murine Oxy- and Deoxy-Mb structures with palmitate or palmitoylcarnitine starting at different positions near the protein surface. The simulations indicated that both ligands readily (under ~10–20 ns) enter the Oxy-Mb structure through a dynamic area ("portal region") near heme, known to be the entry point for small molecule gaseous ligands like O2, CO and NO. The entry is not observed with Deoxy-Mb where lipid ligands move away from protein surface, due to a compaction of the entry portal and the heme-containing crevice in the Mb protein upon O2 removal. The results suggest quick spontaneous binding of lipids to Mb driven by hydrophobic interactions, strongly enhanced by oxygenation, and consistent with the emergent role of Mb in lipid metabolism.