THE MECHANISMS OF ACTION AND INHIBITION OF PANCREATIC LIPASE AND ACETYLCHOLINESTERASE - A COMPARATIVE MODELING STUDY

Pancreatic lipase and acetylcholinesterase are both serine esterases. Their X-ray structures reveal a similar overall fold, but no sequence homology can be detected. A catalytic triad like in the trypsin family of serine proteases consisting of serine, histidine and aspartate (gl utamate in acetylcholinesterase) suggests mechanistic similarities. Mo dels of the transition states of the substrate cleavage have been buil t and possible catalytic pathways were examined. The model that could produce a consistent pathway throughout the reactions had a transition state of the opposite handedness compared to trypsin. These models co uld be used to rationalise binding modes of inhibitors of both enzymes . The lipase inhibitor tetrahydrolipstatin (THL) contains a gamma-lact one which is opened by the catalytic serine; the alcohol leaving group prohibits deacylation by locking the pathway for incoming water and t hus inactivates the enzyme. Carbamate inhibitors of acetylcholinestera se transfer a carbamoyl group to the serine-OH which deacylates slowly . These observations can be used as a starting point for the discovery of new classes of inhibitors.