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are generally well-conserved across species. HSL is composed of two main structural domains, consisting of a slightly variable N-terminus that is thought to contribute to numerous factors including activity, specificity, regioselectivity, thermophilicity, and thermostability. The second, highly conserved, domain of HSL is the C-terminal catalytic domain, which contains the catalytic triad, viewed , a charge relay network that is characteristic of many hydrolases. Size-exclusion chromatography studies have shown that HSL has a ligand pocket that is approximately 16Å deep, suggesting that HSL primarily hydrolyzes shorter chained molecules. ^[3]

The catalytic triad 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°. 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 covalent binding to . Return to default view, .

Inhibition of hormone-sensitive lipase

Hormone-Sensitive Lipase Complex with PMSF from 3h17

Hormone-sensitive lipase can be inhibited by phenylmethylsufonyl flouride (PMSF) entering into the . The experiments performed to test this inhibition used different strains of bacteria, which had a different order of residues but the same catalytic effect. This experiment tested the Ser144 residue rather than the Ser157 residue seen in other HSL proteins. PMSF inhibits enzymes by binding to the Ser144 residue of the serine protease active sites so that the normal catalytic activity cannot be carried out. This inhibitor will only bind to the active site Ser144 because of its participation in the charge relay of the . This hyper activity allows the sulfonyl group of PMSF to to the Ser144 residue to disrupt its activity. Because of this Ser144 residue specificity, PMSF does not inhibit all kinds of lipases, just those dependent on Ser144 residues in the active site. PMSF is highly degradable in aqueous solutions so it does not inhibit for very long periods of time in its natural environment. PMSF binding induces only a minor conformational change from the native protein.^[4]

Inhibition or decreased activity of hormone-sensitive lipases can possibly lead to disorders such as atherosclerosis, obesity, and type 2 diabetes. Inability to break down fatty acid molecules due to inactive hormone-sensitive lipases has been reported in many cases of obesity and type 2 diabetes. Increased inhibition of HSL by PMSF could, in theory, also be a possible cause of these diseases.^[5]