Partitioning of Catechol Derivatives in Lipid Membranes: Implications for Substrate Specificity to Catechol- O-methyltransferase

Abstract

We have utilized multiparametric surface plasmon resonance and impendance-based quartz crystal microbalance instruments to study the distribution coefficients of catechol derivatives in cell model membranes. Our findings verify that the octanol-water partitioning coefficient is a poor descriptor of the total lipid affinity for small molecules which show limited lipophilicity in the octanol-water system. Notably, 3-methoxytyramine, the methylated derivative of the neurotransmitter dopamine, showed substantial affinity to the lipids despite its nonlipophilic nature predicted by octanol-water partitioning. The average ratio of distribution coefficients between 3-methoxytyramine and dopamine was 8.0. We also found that the interactions between the catechols and the membranes modeling the cell membrane outer leaflet are very weak, suggesting a mechanism other than the membrane-mediated mechanism of action for the neurotransmitters at the postsynaptic site. The average distribution coefficient for these membranes was one-third of the average value for pure phosphatidylcholine membranes, calculated using all compounds. In the context of our previous work, we further theorize that membrane-bound enzymes can utilize membrane headgroup partitioning to find their substrates. This could explain the differences in enzyme affinity between soluble and membrane-bound isoforms of catechol-O-methyltransferase, an essential enzyme in catechol metabolism.

Keywords: Catechols; distribution coefficient; multiparametric surface plasmon resonance; partition coefficient; quartz crystal microbalance; supported lipid bilayer.

Figure 1

Chemical structures of the studied catechol derivative compounds. Formal charges are indicated at pH = 7.4. The nitrite group in tolcapone and entacapone has a net negative charge.

Figure 2

Depiction of the analysis process performed on the surface plasmon resonance data for the extraction of the binding parameters.

Figure 3

Average surface-mass densities as a function of time for the deposition of SLBs and different catechol compounds (N = 4). Dashed lines show the kinetic fits using the one-site kinetic model, and shaded areas represent the standard error of the mean.

Figure 4

Logarithm of the membrane partition cofficient (log D_m) plotted against log Y where Y = D_m,pred, the predicted membrane distribution coefficient calculated using the linear regression analysis (blue circles); Y = P_oct/w, the partition coefficient (red squares); and Y = D_oct/w, the distribution coefficient at pH = 7.4 (green triangles). Open markers represent the membrane partitioning data from Osanai et al., and closed markers correspond to the studied catechol derivatives. The dashed black line shows where the parameters in horizontal and vertical axes are equal.