Lipases and their inhibitors in health and disease

Abstract

Lipids play diverse and important biological roles including maintaining cellular integrity, storing fat for energy, acting as signaling molecules, and forming microdomains to support membrane protein signaling. Altering the levels of specific lipid species through activating or inactivating their biosynthetic or degradative pathways has been shown to provide either therapeutic benefit or cause disease. This review focuses on the functional, therapeutic, and (patho)physiological roles of lipases within the serine hydrolase superfamily and their inhibitors, with particular emphasis on the pharmacological tools, drugs, and environmental chemicals that inhibit these lipases.

LIPG‐promoted lipid storage mediates adaptation to oxidative stress in breast cancer

“…f ). Blockage of LIPG activity with the LIPG inhibitor GSK264220A significantly reduced intracellular TAG levels (Fig. g ) and LD accumulation (Fig.…”

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

“…The known thieno [1,3]oxazines-4-ones 29 and 30 previously described as alternate substrate inhibitors of bCEase were found to exhibit high species-specific differences in their inhibitory potency, decreasing the activityo ft he human CEase to a much lesser extent than that of the murinea nd bovines isoenzymes owing to higherd issociation constants K i and the formation of catalytically active enzyme-inhibitor complexes. In the search for potent ands elective inhibitors of CEase, we applied an ew assay using the fluorogenic substrate 4-MUB on the recombinantly expressed murinea nd human isoenzymes, leadingt ot he identification of w-phthalimidoalkyl aryl ureas 2, 21,a nd 22.S tructure-activity relationship studies revealed that the urea moiety with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic charactero ft he terminal phthalimide residue on the alkyl chain are crucial for the inhibitory activity of these compounds.…”

“…[1][2][3] In this context, we are particularly interested in the bile salt-activated cholesterol esterase (CEase;E C3.1.1.13), a nonspecific serine hydrolase with variouss ubstrates including cholesteryl esters;t ri-, di-, and monoacylglycerols;p hospholipids;v itaminA esters; [4] and lipid amides. [1][2][3] In this context, we are particularly interested in the bile salt-activated cholesterol esterase (CEase;E C3.1.1.13), a nonspecific serine hydrolase with variouss ubstrates including cholesteryl esters;t ri-, di-, and monoacylglycerols;p hospholipids;v itaminA esters; [4] and lipid amides.…”

“…[7,8] Furthermore, plasma CEase may contributet oC HD by converting "larger andl ess atherogenic LDL to smaller and more atherogenic LDL subspecies" [8] and by being involved in the generation of cholesterol crystals in LDL aggregates, which are thought of as ah allmark of atherosclerotic plaques and represent ap ossible source of inflammation. [12][13][14][15][16] Most of the initially developed CEase inhibitor classes contain electrophilic sites that are attacked by the active site serine residue (e.g.,b oronic acids, [17] carbamates, [17][18][19][20][21] phosphoisocoumarines, [22] andt hieno [1,3]oxazin-4ones 29 and 30; [23] Figure 1), whereas recently reported rhodanine [24] and thiazolidinedione [24] inhibitors as well as 2-(1 Hindol-3-yl)-4-phenylquinolines [25] do not appear to modify the catalytic triad (Ser-His-Asp). [12][13][14][15][16] Most of the initially developed CEase inhibitor classes contain electrophilic sites that are attacked by the active site serine residue (e.g.,b oronic acids, [17] carbamates, [17][18][19][20][21] phosphoisocoumarines, [22] andt hieno [1,3]oxazin-4ones 29 and 30; [23] Figure 1), whereas recently reported rhodanine [24] and thiazolidinedione [24] inhibitors as well as 2-(1 Hindol...…”

“…The crude product was purified by column chromatography (100 %M TBE), yielding aw hite solid (556 mg, 1.05 mmol, 35 %): R f = 0.48 (100 %M TBE);m p: 152 8C; 1 HNMR (300 MHz, [D 6 ]DMSO): d = 7.84 (m, 4H), 7.47 (s, 2H), 7.29 (s, 1H), 6.65 (t, J = 5.2 Hz, 1H), 3.59 (t, J = 7.1 Hz, 2H), 3.39 (m, 8H),3.08 (dd, J = 12.5, 6.5 Hz, 2H), 1.77 ppm (m, 2H);13 CNMR (75 MHz, [D 6 ]DMSO): d = 167.90, 157.28, 151.56, 134.31, 131.63, 131.05 (q, J = 33.0 Hz), 123.58 (q, J = 273.1 Hz), 122.94, 114.37, 110.12, 46.82, 42.89, 37.84, 35.55, 28.74 ppm;I R( neat): urea(21):T he reaction was performed according to the general procedure with 5-(1,3-dioxoisoindolin-2-yl)pentanoic acid (0.74 g, 3mmol), SOCl 2 (1.09 mL, 1.78 g, 15 mmol), NaN 3 (0.20 g, 3mmol), and 3,5-bis(trifluoromethyl)aniline (0.469 mL, 0.687 g, 3mmol). The crude product was purified by column chromatography (100 %M TBE), yielding aw hite solid (556 mg, 1.05 mmol, 35 %): R f = 0.48 (100 %M TBE);m p: 152 8C; 1 HNMR (300 MHz, [D 6 ]DMSO): d = 7.84 (m, 4H), 7.47 (s, 2H), 7.29 (s, 1H), 6.65 (t, J = 5.2 Hz, 1H), 3.59 (t, J = 7.1 Hz, 2H), 3.39 (m, 8H),3.08 (dd, J = 12.5, 6.5 Hz, 2H), 1.77 ppm (m, 2H);13 CNMR (75 MHz, [D 6 ]DMSO): d = 167.90, 157.28, 151.56, 134.31, 131.63, 131.05 (q, J = 33.0 Hz), 123.58 (q, J = 273.1 Hz), 122.94, 114.37, 110.12, 46.82, 42.89, 37.84, 35.55, 28.74 ppm;I R( neat): urea(21):T he reaction was performed according to the general procedure with 5-(1,3-dioxoisoindolin-2-yl)pentanoic acid (0.74 g, 3mmol), SOCl 2 (1.09 mL, 1.78 g, 15 mmol), NaN 3 (0.20 g, 3mmol), and 3,5-bis(trifluoromethyl)aniline (0.469 mL, 0.687 g, 3mmol).…”