Chemical modulation of glycerolipid signaling and metabolic pathways

Abstract

Thirty years ago, glycerolipids captured the attention of biochemical researchers as novel cellular signaling entities. We now recognize that these biomolecules occupy signaling nodes critical to a number of physiological and pathological processes. Thus, glycerolipid-metabolizing enzymes present attractive targets for new therapies. A number of fields—ranging from neuroscience and cancer to diabetes and obesity—have elucidated the signaling properties of glycerolipids. The biochemical literature teems with newly emerging small molecule inhibitors capable of manipulating glycerolipid metabolism and signaling. This ever-expanding pool of chemical modulators appears daunting to those interested in exploiting glycerolipid-signaling pathways in their model system of choice. This review distills the current body of literature surrounding glycerolipid metabolism into a more approachable format, facilitating the application of small molecule inhibitors to novel systems.

Phospholipase D Signaling Pathways and Phosphatidic Acid as Therapeutic Targets in Cancer

“…Until 2007, small molecules employed to study PLD function (Fig. 3) were either indirect inhibitors, such as resveratrol and honokiol (compounds 1 and 2, respectively); direct inhibitors, such as tungstate (compound 3); lipid mimetics such as (Z)-PSDP, the (Z)-isomer of presqualene diphosphate (compound 4); selective estrogen receptor modulators, such as raloxifene (compound 5); or alternative substrates to inhibit the ability of PLD to make the lipid product PtdOH, such as n-butanol (compound 6), which leads to the formation of phosphatidylbutanol [reviewed in Selvy et al (2011) andScott et al (2014)]. Indeed, the lack of small-molecule ligands to use as tools to probe both the cellular and the in vivo roles of each PLD isoform has arguably hindered the target validation for PLD because these ligands do not discriminate between the PLD isoforms.…”

The status of the lysophosphatidic acid receptor type 1 (LPA1R)

“…LPA 5 (GPR92) was identied by two independent groups in 2005 from the receptor gene data bank. This receptor is structurally different to LPA [1][2][3] , but shares 35% homology with LPA 4 . Lpar5 is relatively broadly expressed in murine and human tissues.…”

“…The LPA 4 receptor is structurally distinct from classical LPA [1][2][3] and S1P receptors that share signicant homology, and is more closely related to P2Y purinergic receptors. It does not, however, respond to any nucleotide or nucleoside tested.…”

“…Phospholipids are usually divided into two broad families: (i) glycerophospholipids, 3 which are structurally based on the glycerol scaffold (Fig. 1A) and (ii) sphingophospholipids, which are derivatives of the amino alcohol sphingosine (Fig.…”

“…30,31 This latter group is more closely related to the family of P2Y purinergic receptor genes, indicating that LPA receptors have evolved via two distinct lineages in the rhodopsin GPCR family. To date, a total of eleven receptors have been described, six for LPA (LPA [1][2][3][4][5][6] ) and ve for S1P (S1P [1][2][3][4][5] ). The current nomenclature includes the cognate ligand and the chronological order of identication.…”