The amide moiety belongs to the most common motives in
pharmaceutical
chemistry, present in many prescribed small-molecule pharmaceuticals.
Methods for its manufacture are still in high demand, especially using
water/buffer as a solvent and avoiding stoichiometric amounts of activation
reagents. Herein, we identified from a library of lipases/esterases/acyltransferases
and variants thereof a lipase originating from Sphingomonas sp. HXN-200 (SpL) able to form amides in aqueous solution starting
from a broad scope of sterically demanding heteroaromatic ethyl esters
as well as aliphatic amines, reaching isolated yields up to 99% on
preparative scale and space time yields of up to 864 g L–1 d–1; thus, in selected cases, the amide was formed
within minutes. The enzyme features an aspartate next to the canonical
serine of the catalytic triad, which was essential for amide formation.
Furthermore, the enzyme structure revealed two tunnels to the active
site, presumably one for the ester and one for the amine, which permit
the bringing together of the sterically demanding heteroaromatic esters
and the amine in the active site. This work shows that biocatalytic
amide formation starting from various five- and six-membered heteroaromatic
ethyl esters in the buffer can serve as a platform for preparative
amide synthesis.