Hormone sensitive lipase

are generally well-conserved across domains, including prokaryotes, showing 29, 26, and 22% residue overlap in Alicyclobacillus acidocaldarius, Archaeoglobus fulgidus, and Bacillus subtilis, respectively.^[4] HSL is composed of two main structural domains, consisting of a slightly variable N-terminus (shown in blue in the ) that is thought to contribute to numerous factors including activity, specificity, regioselectivity, thermophilicity, and thermostability.^[4] Research speculates that the N-terminal domain, consisting of about 300 residues, mediates protein-protein interactions, and possibly subsequent lipid binding.^[3] The second domain of HSL is the C-terminal catalytic domain (colors other than blue), which contains serine residue phosphorylation sites as well as the catalytic triad, viewed with ligand β-mercaptoethanol, a charge relay network that is characteristic of many hydrolases, such as chymotrypsin.^[3] With respect to sequence conservation across species, it has been shown that the catalytic domain, including the triad, is conserved across domains, but the domain containing the N-terminus shows little conservation.^[4] HSL has a that is approximately 16Å deep. Kinetic studies with substrates of varying lengths suggest that HSL primarily hydrolyzes shorter chained molecules.^[4]

Catalytic triad

The catalytic triad with β-mercaptoethanol toward the middle of HSL. The catalytic triad is composed of residues . The Ser157 residue sits at a site deemed the "nucleophilic elbow," that models an approximate torsion of Φ = 60° and Ψ =-120°.^[4] This nucleophilic elbow is stabilized by a hydrogen bond between the proximal nitrogen and oxygen atoms of His281 and Glu251, respectively. This model also shows the strong nucleophilic character of Ser157, portraying the interaction and subsequent covalent bonding (not shown) to . Return to default view, .^[3]

Inhibition of hormone-sensitive lipase

Surface image of Hormone-Sensitive Lipase Complex with PMSF from 3h17. Green indicates carbon atoms, blue indicates nitrogen atoms, red indicates oxygen atoms, and orange indicates sulfur atoms.

Hormone-sensitive lipase can be inhibited by phenylmethylsufonyl flouride (PMSF) covalently bound to the . PMSF is a general, covalent inhibitor of serine hydrolases, which has been co-crystallized bound to hormone-sensitive lipases. The experiments performed to test this inhibition used different lipases obtained from Bacillus coagulans as well as lipases from different areas of the human body.^[5] PMSF inhibits hydrolase by binding to the catalytic serine residue of the serine protease active site which disrupts the nucleophilic activity of the catalytic serine. The sulfur of PMSF binds to the oxygen of the hydroxyl group on the serine residue to form this covalent bond. This inhibitor will only bind to the active site of the catalytic serine because of its participation in the charge relay of the catalytic triad. This hyper activity, indicated by increased temperature (shown in red) around the active site , allows the sulfonyl group of PMSF to covalently bind to the catalytic serine residue to disrupt its activity.^[6] Because of this catalytic serine residue specificity, PMSF does not inhibit all kinds of lipases, such as pancreatic lipase and lipolase.^[5] induces only a minor conformational change from the .^[6]

Increased activity of HSL is also linked to disorders such as atherosclerosis, obesity, and type 2 diabetes. High concentration of free fatty acids (FFA) in skeletal muscles has been reported in many cases of obesity and type 2 diabetes. Increased inhibition of HSL through synthetic inhibitors could be a possible route for decreasing FFA concentration.^[7]