Digestive lipases: From three-dimensional structure to physiology

Human gastric lipase (HGL) is a lipolytic enzyme that is secreted by the ch ief cells located in the fundic part of the stomach. HGL plays an important role in lipid digestion, since it promotes the subsequent hydrolytic actio n of pancreatic lipase in duodenal lumen. Physiological studies have shown that HGL is able of acting not only in the highly acid stomach environment but also in the duodenum in synergy with human pancreatic lipase (HPL). Rec ombinant HGL (r-HGL) was expressed in the baculovirus/insect cell system in the form of an active protein with a molecular mass of 45 kDa. The specifi c activities of r-HGL were found to be similar to that of the native enzyme when tested on various triacylglycerol (TG) substrates. The 3-D structure of r-HGL was the first solved within the mammalian acid lipase family. This globular enzyme (379 residues) shows a new feature, different from the oth er known lipases structures, which consists of a core domain having the cli p hydrolase fold and a cap domain including a putative 'lid' of 30 residues covering the active site of the Lipase (closed conformation). HPL is the m ajor lipolytic enzyme involved in the digestion of dietary TG. HPL is a 50 kDa glycoprotein which is directly secreted as an active enzyme. HPL was th e first mammalian lipase to be solved structurally, and it revealed the pre sence of two structural domains: a large N-terminal domain (residues 1-336) and a smaller C-terminal domain (residues 337-449). The large N-terminal d omain belongs to the alpha/beta hydrolase fold and contains the active site . A surface loop called the lid domain (C237-C261) covers the active site i n the closed conformation of the lipase. The 3-D structure of the lipase-pr ocolipase complex illustrates how the procolipase might anchor the lipase a t the interface in the presence of bile salts: procolipase binds to the C-t erminal domain of HPL and exposes the hydrophobic tips of its fingers at th e opposite site of its lipase-binding domain. These hydrophobic tips help t o bring N-terminal domain into close conformation with the interface where the opening of the lid domain probably occurs. As a result of all these con formational changes, the open lid and the extremities of the procolipase fo rm an impressive continuous hydrophobic plateau, extending over more than 5 0 Angstrom. This surface might able to interact strongly with a lipid-water interface. The biochemical, histochemical and clinical studies as well as the 3-D structures obtained will be a great help for a better understanding of the structure-function relationships of digestive lipases. (C) 2000 Soc iete francaise de biochimie et biologie moleculaire / Editions scientifique s et medicales Elsevier SAS.