Can lipases cleave fatty acids linked with amides instead of the usual esters?

The typical substrate for lipases are esters, such as triglycerides where fatty acids are linked to the glyerol through ester linkages. I'm interested in whether lipases (such as pancreatic lipase) can cleave fatty acids linked to proteins by amide linkages. In lipopeptides, fatty acids are often conjugated to peptides at the N-terminal amine or lysine side chain, yielding an amide (also known as a peptide) linkage.


I have found [some examples](https://doi.org/10.1016/j.tetlet.2018.04.049) where some lipases can be used to catalyze the opposite reaction (forming an amide between a fatty acid and an amine of a polypeptide). So it seems like such cleavage might be possible. Does any one know of work demonstrating cleavage of amide bonds between fatty acids and amines?




Yes they can, but they have higher specificity for esters. Here is part of the abstract of a [paper](https://academic.oup.com/peds/article/18/2/93/1545211) using directed evolution to increase the activity:



> 
> A double mutant F207S/A213D gave the highest molecular activity of 1.1 min−1 for the amide, corresponding to a 2-fold increase compared with that of the wild-type lipase. A structural model of the lipase indicated that the mutations occurred at the sites near the surface and remote from the catalytic triad, but close to the calcium binding site. This study is a first step towards understanding why lipases do not hydrolyze amides despite the similarities to serine proteases in the active site structure and the reaction mechanism and towards the preparation of a general acyl transfer catalyst for the biotransformation of amides.
> 
> 
> 


Note that the abstract is a bit self-contradictory, first saying that they increased the activity two-fold, then saying lipases have no amide hydrolysis activity. It is possible that a turnover of $\pu{1.1 min-1}$ is considered not active, considering the much faster turnover for the lipase reaction. The introduction, which has lots of references, clarifies this.


I found this in a search for "lipase specificity amide" on google scholar. I did not look for the specific substrate you had in mind because that feels like giving out fish instead of hints on fishing.


 6