Deuterated hetero-acyl phospholipids via enzymatic modification

Phospholipids are a major component of all cell membranes. They are amphiphilic and can form a variety of structures which find applications in nanotechnology and materials science. Deuterated analogues are useful for neutron experiments and have been used to investigate drug-membrane interactions, for instance. However, deuterated analogues of these molecules generally contain two of the same acyl chain (homo-acyl), when in reality they most often contain different acyl chains (hetero-acyl) (Figure 1). This is because synthesis of phospholipids containing different chains, using standard chemical techniques, is much more challenging than the synthesis of phospholipids containing the same chain.

Figure 1. POPC, a hetero-acyl phospholipid, and DPPC, a homo-acyl analogue.

We recently synthesised POPC-d64 using a lipase enzyme to complete key steps; the regiospecificity of the enzyme allowed us to replace a single acyl chain, leaving the other intact (Scheme 1). Both of the chains are perdeuterated, meaning the bulk of the hydrogen in the lipid is 2H, deuterium, rather than 1H, protium. POPC-d64 will be used as a model skin lipid to investigate transdermal drug delivery mechanisms via neutron reflectometry experiments at ISIS (UK) later this year.

Scheme 1. Synthesis of POPC-d64 using a regiospecific lipase enzyme.

DOI: 10.1021/acsomega.0c02823