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The PNPLA family of enzymes: characterisation and biological role

Ana-Marija Lulić
Ana-Marija Lulić
 y 
Maja Katalinić
Maja Katalinić
   | 26 jun 2023
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Article Category: Review
Publicado en línea: 26 jun 2023
Páginas: 75 - 89
Recibido: 01 feb 2023
Aceptado: 01 may 2023
DOI: https://doi.org/10.2478/aiht-2023-74-3723
© 2023 Ana-Marija Lulić et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Figure 1

3D illustration of the patatin structure (PDB: 1OXW) (created with PyMol). α-helices are coloured red and β-helices green (top). The crystal structure of patatin was solved in 2003 and its core consists of the α/β fold with about three layers of the α/β/α sandwiches, in which the β-sheet is sandwiched between two α-helices front and back. In the active site (bottom), patatin contains the catalytic dyad serine-aspartic acid. Catalytic serine is situated at a nucleophilic elbow following a β-sheet and preceding an α-helix. Serine is part of the classical lipase Gly-Thr-Ser-Thr-Gly motif, and aspartic acid is part of the Asp-Gly-Ala motif. Close to the active site is an oxyanion hole characterised by the Gly-Gly-Gly-Arg motif, whose function is to stabilise the transition state. Yellow dashed lines represent hydrogen bonds between serine and water and aspartic acid and water (molecule of water is marked with a red sphere)
3D illustration of the patatin structure (PDB: 1OXW) (created with PyMol). α-helices are coloured red and β-helices green (top). The crystal structure of patatin was solved in 2003 and its core consists of the α/β fold with about three layers of the α/β/α sandwiches, in which the β-sheet is sandwiched between two α-helices front and back. In the active site (bottom), patatin contains the catalytic dyad serine-aspartic acid. Catalytic serine is situated at a nucleophilic elbow following a β-sheet and preceding an α-helix. Serine is part of the classical lipase Gly-Thr-Ser-Thr-Gly motif, and aspartic acid is part of the Asp-Gly-Ala motif. Close to the active site is an oxyanion hole characterised by the Gly-Gly-Gly-Arg motif, whose function is to stabilise the transition state. Yellow dashed lines represent hydrogen bonds between serine and water and aspartic acid and water (molecule of water is marked with a red sphere)

Figure 2

Substrates of the PNPLA enzymes. Some PNPLAs can hydrolyse sn-1, sn-2 or ester bonds on both positions in phospholipids and lysophospholipids (R1 represents examples of modified phosphate groups; R2, R3 represent alkyl groups which can contain 6–22 carbon atoms and one or more double bonds). Certain members can hydrolyse ester bonds of triacylglycerol, cholesteryl ester, and retinyl ester
Substrates of the PNPLA enzymes. Some PNPLAs can hydrolyse sn-1, sn-2 or ester bonds on both positions in phospholipids and lysophospholipids (R1 represents examples of modified phosphate groups; R2, R3 represent alkyl groups which can contain 6–22 carbon atoms and one or more double bonds). Certain members can hydrolyse ester bonds of triacylglycerol, cholesteryl ester, and retinyl ester

Figure 3

Simplified representation of lipolysis on lipid droplets (created courtesy of Biorender.com). PNPLA2, activated by CGI-58, hydrolyses triacylglycerol (TG) generating diacylglycerol (DG) and non-esterified fatty acid (NEFA). Then, hormone-sensitive lipase (HSL) hydrolases diacylglycerol (DG) generating monoacylglycerol (MG) and non-esterified fatty acid (NEFA) and finally, monoacylglyceride lipase (MGL) hydrolyses monoacylglycerol (MG) generating non-esterified fatty acid (NEFA) and glycerol
Simplified representation of lipolysis on lipid droplets (created courtesy of Biorender.com). PNPLA2, activated by CGI-58, hydrolyses triacylglycerol (TG) generating diacylglycerol (DG) and non-esterified fatty acid (NEFA). Then, hormone-sensitive lipase (HSL) hydrolases diacylglycerol (DG) generating monoacylglycerol (MG) and non-esterified fatty acid (NEFA) and finally, monoacylglyceride lipase (MGL) hydrolyses monoacylglycerol (MG) generating non-esterified fatty acid (NEFA) and glycerol

Figure 4

Simplified representation of autophagy (created courtesy of Biorender.com). It starts with the formation of a phagophore which develops into an autophagosome. Autophagosome fuses with a lysosome and degrades it. Blue and purple circles and curved blue dashes in represent proteins and cytoplasmic content that will be eventually degrade in the lysosome. Red and pink Pac-Man-like structures represent hydrolytic enzymes that degrade the autophagosome content
Simplified representation of autophagy (created courtesy of Biorender.com). It starts with the formation of a phagophore which develops into an autophagosome. Autophagosome fuses with a lysosome and degrades it. Blue and purple circles and curved blue dashes in represent proteins and cytoplasmic content that will be eventually degrade in the lysosome. Red and pink Pac-Man-like structures represent hydrolytic enzymes that degrade the autophagosome content

Figure 5

Simplified scheme of PNPLA6 inhibition with organophosphate compounds (OP). It starts with a nucleophilic attack of the hydroxyl group of the serine on the phosphorus atom from the OP, which leads to the formation of a tetrahedral intermediate. R1, R2 – acyl groups, L – leaving group. a) Reaction with OPs which does not undergo aging and does not cause OPIDN and the enzyme can be reactivated. b) Reaction with OPs containing the P-O-R or P-NH-R bond that undergoes aging, in which the R-group spontaneously leaves the intermediate. As a result, the phosphate group is negatively charged and stays covalently bound to the serine in the active site. The enzyme cannot be reactivated because of the negative charge. The negatively charged phosphate group is stabilised through hydrogen bonds in the oxyanion hole. OP compounds that undergo the aging reaction can cause neuropathy and OPIDN
Simplified scheme of PNPLA6 inhibition with organophosphate compounds (OP). It starts with a nucleophilic attack of the hydroxyl group of the serine on the phosphorus atom from the OP, which leads to the formation of a tetrahedral intermediate. R1, R2 – acyl groups, L – leaving group. a) Reaction with OPs which does not undergo aging and does not cause OPIDN and the enzyme can be reactivated. b) Reaction with OPs containing the P-O-R or P-NH-R bond that undergoes aging, in which the R-group spontaneously leaves the intermediate. As a result, the phosphate group is negatively charged and stays covalently bound to the serine in the active site. The enzyme cannot be reactivated because of the negative charge. The negatively charged phosphate group is stabilised through hydrogen bonds in the oxyanion hole. OP compounds that undergo the aging reaction can cause neuropathy and OPIDN

Figure 6

3D illustration of the PNPLA9 dimer (PDB: 6AUN) (created with PyMol). Top: catalytic domains of monomer one and monomer two are coloured yellow and pink, respectively. Active sites represented by spheres and sticks. Ankyrin repeats of monomer one and monomer two are coloured dark and light blue, respectively. The binding site of CaM kinase is in red. Bottom: the active site of PNPLA9 contains the catalytic dyad serine-aspartic acid, with the catalytic serine situated on a nucleophilic elbow following a β-sheet and preceding an α-helix. Serine is part of the lipase Gly-Thr-Ser-Thr-Gly motif and aspartic acid is a part of the Asp-Gly-Gly motif. Close to the active site is an oxyanion hole characterised by the Gly-Gly-Gly-Arg motif, whose function is to stabilise the transition state. Yellow dashed line represents a hydrogen bond formed between serine and aspartic acid
3D illustration of the PNPLA9 dimer (PDB: 6AUN) (created with PyMol). Top: catalytic domains of monomer one and monomer two are coloured yellow and pink, respectively. Active sites represented by spheres and sticks. Ankyrin repeats of monomer one and monomer two are coloured dark and light blue, respectively. The binding site of CaM kinase is in red. Bottom: the active site of PNPLA9 contains the catalytic dyad serine-aspartic acid, with the catalytic serine situated on a nucleophilic elbow following a β-sheet and preceding an α-helix. Serine is part of the lipase Gly-Thr-Ser-Thr-Gly motif and aspartic acid is a part of the Asp-Gly-Gly motif. Close to the active site is an oxyanion hole characterised by the Gly-Gly-Gly-Arg motif, whose function is to stabilise the transition state. Yellow dashed line represents a hydrogen bond formed between serine and aspartic acid
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