Hormone-sensitive lipase is structurally related to acetylcholinesterase, bile salt-stimulated lipase, and several fungal lipases. Building of a three-dimensional model for the catalytic domain of hormone-sensitive lipase.
Hormone-sensitive lipase is the key enzyme in the mobilization of fatty acids from adipose tissue, thereby playing a crucial role in the overall energy homeostasis in mammals. Its activity is stimulated by catecholamines through cAMP-dependent phosphorylation of a single serine, a process that is prevented by insulin. This regulatory property is unique to this enzyme among all known lipases and has been acquired during evolution through insertion of a regulatory module into an ancestral lipase. Sequence alignments have failed to detect significant homology between hormone-sensitive lipase and the rest of the mammalian lipases and esterases, to which this enzyme is only very distantly related. In the present work, we report the finding of a remarkable secondary structure homology between hormone-sensitive lipase and the enzymes from a superfamily of esterases and lipases that includes acetylcholinesterase, bile salt-stimulated lipase, and several fungal lipases. This finding, based on the identification of the secondary structure elements in the hormone-sensitive lipase sequence, has allowed us to construct a three-dimensional model for the catalytic domain of hormone-sensitive lipase. The model reveals the topological organization, predicts the components of the catalytic triad, suggests a three-dimensional localization of the regulatory module, and provides a valuable tool for the future study of structural and functional aspects of this metabolically important enzyme.
Contreras
J A
JA
Department of Cell and Molecular Biology, Lund University, Lund S-221 00, Sweden. cecilia.holm@medkem.lu.se
Karlsson
M
M
Osterlund
T
T
Laurell
H
H
Svensson
A
A
Holm
C
C
D000110:Acetylcholinesterase / Q000737:chemistry*; D000595:Amino Acid Sequence; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001665:Binding Sites; D008049:Lipase / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D002787:Sterol Esterase
D001647:Bile Acids and Salts; D002787:Sterol Esterase; D008049:Lipase; D000110:Acetylcholinesterase