G protein-coupled receptor 55 (GPR55) is highly expressed in brain and peripheral nervous system. Originally deorphanized as a cannabinoid receptor, recently GPR55 has been described as a lysophospholipid-responsive receptor, specifically toward lysophosphatidylinositol and lysophosphatidyl-β-D-glucoside (LysoPtdGlc). To characterize lysolipid-GPR55 interaction, synthetic access to LysoPtdGlc and selected analogues was established utilizing a phosphorus(III)-based chemical approach. The biological activity of each synthetic lipid was assessed using a GPR55-dependent chemotropism assay in primary sensory neurons. Combined with molecular dynamics simulations the potential ligand entry port and binding pocket specifics are discussed. These results highlight the preference for gluco-over inositol-and galacto-configured headgroups.

Secretory proteins and lipids are biosynthesized in the endoplasmic reticulum (ER). The “protein quality control” system (PQC) monitors glycoprotein folding and supports the elimination of terminally misfolded polypeptides. A key component of the PQC system is Uridine diphosphate glucose:glycoprotein glucosyltransferase 1 (UGGT1). UGGT1 re-glucosylates unfolded glycoproteins, to enable the re-entry in the protein-folding cycle and impede the aggregation of misfolded glycoproteins. In contrast, a complementary “lipid quality control” (LQC) system that maintains lipid homeostasis remains elusive. Here, we demonstrate that cytotoxic phosphatidic acid derivatives with saturated fatty acyl chains are one of the physiological substrates of UGGT2, an isoform of UGGT1. UGGT2 produces lipid raft-resident phosphatidylglucoside regulating autophagy. Under the disruption of lipid metabolism and hypoxic conditions, UGGT2 inhibits PERK-ATF4-CHOP-mediated apoptosis in mouse embryonic fibroblasts. Moreover, the susceptibility of UGGT2 KO mice to high-fat diet-induced obesity is elevated. We propose that UGGT2 is an ER-localized LQC component that mitigates saturated lipid-associated ER stress via lipid glucosylation.

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Lyso-phosphatidyl β-D-glucoside (lysoPtdGlc) is during embryonic development a neurite growth cone guidance cue associated with G-protein coupled receptor 55, and has been found to be involved in a variety of physiological and pathological events, including inflammatory pain, and cancer. Hence, the ability to prepare large quantities of lysoPtdGlc is an important objective. Herein, we report the convergent chemical synthesis of lysoPtdGlc and its glyceryl epimer (S-lysoPtdGlc).High stereocontrol during β-glycosyl H-phosphonate construction was achieved using a microfluidic approach, and common but undesirable regioisomerization due to acyl migration on the glyceryl subunit was successfully suppressed during deprotection. Purification of the final product was optimized to obtain sufficiently large amounts of lysoPtdGlc and S-lysoPtdGlc for biological assaying purposes.

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