The origins of enzyme specificity are well established. However, the molecular details
underlying the ability of a single active site to promiscuously bind different substrates and
catalyze different reactions remain largely unknown. To better understand the molecular
basis of enzyme promiscuity, we studied the mammalian serum paraoxonase 1 (PON1)
whose native substrates are lipophilic lactones. We describe the crystal structures of PON1
at a catalytically relevant pH and of its complex with a lactone analogue. The various PON1 …

… In particular, we sought for a detailed description of the complexes and catalytic
mechanisms for the native substrate of an enzyme and for its different alternative substrates
and promiscuous reactions. Our case study discusses the mammalian serum paraoxonase
1 (PON1). This enzyme comprises the most-studied member of a family of calciumdependent
hydrolases. As it turns out, the name …