Bioorganic Chemistry of Sphingolipids: Pore Formation and Anion Transport
Bioorganic Chemistry of Sphingolipids: Pore Formation and Anion Transport
Files
Publication or External Link
Date
2011
Authors
Harrell, Jr., William A.
Advisor
Davis, Jeffery T.
Citation
DRUM DOI
Abstract
Ceramide is an amphiphilic natural product that plays important roles in multiple cellular processes. Ceramide also is known to self-assemble into transmembrane pores under physiologically relevant concentrations. In order to study the role of ceramide's 1,3-diol functionality in the stabilization of transmembrane pores, ceramide analogs were prepared using protecting groups to block the 1,3-diol unit. Blocking the 1,3-diol with an acetal protecting group led to a drastic decrease in membrane-activity. Surprisingly, blocking the -OH groups of C2-ceramide 2 with simple esters yielded a C2-diacetate 16 analog with increased pore-forming activity.
Additionally, a new function of C2-ceramide 2 has been discovered that has important biological implications. Working below concentrations in which it self-assembles into transmembrane pores, C2-ceramide 2 facilitated the transmembrane transport of biologically relevant anions such as Cl<super>-</super> and HCO<sub>3</sub><super>-</super> via an anion exchange mechanism. The 1,3-diol functionality of the C2-ceramide 2 headgroup was found to play an integral role in the binding and transport of anions, as the isopropylidene C2-ceramide 18 analog was unable to facilitate transmembrane anion transport.
D-erythro-Sphingosine 3, produced naturally by the metabolism of ceramide, lacks the amide functionality in its hydrophilic head-group. Unlike C2-ceramide 2, sphingosine 3 does not facilitate transmembrane Cl<super>-</super>/HCO<sub>3</sub><super>-</super> exchange. Possible reasons for this failure to facilitate the transmembrane transport of anions are discussed, namely that sphingosine 3 does not bind HCO<sub>3</sub><super>-</super> in a non-covalent manner. Instead, sphingosine 3 forms carbamates in the presence of HCO<sub>3</sub><super>-</super> and CO<sub>2</sub> in a solvent dependent manner.