HORMONE-SENSITIVE LIPASE IS STRUCTURALLY RELATED TO ACETYLCHOLINESTERASE, BILE SALT-STIMULATED LIPASE, AND SEVERAL FUNGAL LIPASES - BUILDING OF A 3-DIMENSIONAL MODEL FOR THE CATALYTIC DOMAIN OF HORMONE-SENSITIVE LIPASE

Hormone-sensitive Lipase is the key enzyme in the mobilization of fatt y acids from adipose tissue, thereby playing a crucial role in the ove rall energy homeostasis in mammals, Its activity is stimulated by cate cholamines through cAMP-dependent phosphorylation of a single serine, a process that is prevented by insulin, This regulatory property is un ique to this enzyme among all known Lipases and has been acquired duri ng evolution through insertion of a regulatory module into an ancestra l Lipase, Sequence alignments have failed to detect significant homolo gy between hormone-sensitive lipase and the rest of the mammalian lipa ses and esterases, to which this enzyme is only very distantly related , In the present work, Fee report the finding of a remarkable secondar y structure homology between hormone-sensitive Lipase and the enzymes from a superfamily of esterases and lipases that includes acetylcholin esterase, bile salt-stimulated lipase, and several fungal lipases. Thi s finding, based on the identification of the secondary structure elem ents in the hormone-sensitive lipase sequence, has allowed us to const ruct a three-dimensional model for the catalytic domain of hormone-sen sitive Lipase, The model reveals the topological organization, predict s the components of the catalytic triad, suggests a three-dimensional localization of the regulatory module, and provides a valuable tool fo r the future study of structural and functional aspects of this metabo lically important enzyme.