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Review
. 2014 Aug;1841(8):1060-84.
doi: 10.1016/j.bbalip.2014.01.009. Epub 2014 Jan 15.

Chemical modulation of glycerolipid signaling and metabolic pathways

Sarah A Scott  1 , Thomas P Mathews  2 , Pavlina T Ivanova  1 , Craig W Lindsley  3 , H Alex Brown  4
Affiliations
Review

Chemical modulation of glycerolipid signaling and metabolic pathways

Sarah A Scott et al. Biochim Biophys Acta. 2014 Aug.

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. This article is part of a Special Issue entitled Tools to study lipid functions.

Keywords: Autotaxin; Fatty acyltransferase; Glycerolipid; Inhibitor; Lipase; Lipid kinase; Lipin; Metabolism; Phospholipase.

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Figures

Figure 1
Figure 1
Molecular trafficking and small molecule inhibitors of phospholipase C (PLC). A. The catalytic activity of PLC regulates cellular concentrations of PIP2, DAG and IP3. PIP2 is a minor component of cellular membranes but servers as an anchor for protein recruitment and subsequent activation. PLC degrades PIP2 into DAG, a second messenger at PKC, and IP3, which stimulates Ca2+ release. PLCs regulation of these three signaling nodes makes it an important drug target. B. U73122 is a modest inhibitor of PI-PLC and the most widely used, although has never been identified as a direct inhibitor of enzymatic activity. 3013 and 3017 are more recently identified mid-micromolar inhibitors of PI-PLC and empirical evidence suggests they directly inhibit PLC catalytic activity.
Figure 2
Figure 2
Molecular trafficking and small molecule inhibitors of phospholipase D (PLD). A. PLD hydrolyzes phosphatidic esters, like phosphatidylcholine (PC), yielding phosphatidic acid (PA) and choline. PC is the primary component of cellular membranes while the PA is a vital second messenger within the cell regulating a number of downstream targets. Since PC is readily available within the cell, PLD plays a central role in rapid production of signaling PA. B. Small molecule inhibitors of PLD. Structural analogues of halopemide such as FIPI, VU0359595, VU0155056, and VU0364739 are potent, direct, and isoform-specific inhibitors of PLD activity while SERMs such as raloxifene are much less potent but provide a second structural scaffold for PLD inhibitor development. Primary alcohols limit PA production by PLD by competing with water as an enzymatic substrate and are thus not accurately described as PLD inhibitors.
Figure 3
Figure 3
Molecular trafficking and small molecule inhibitors of autotaxin (ATX). A. ATX is a lyso-PLD hydrolyzing lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA) and choline. Like PC, LPC is a membrane component and readily available in cells. The product of ATX catalytic activity, LPA, is an agonist at membrane-bound GPCRs known as the LPA receptors. The activity of LPA at its receptors grants the lipid an exceptional status as a mitogenic and survival signaling molecule. B. Inhibitors of ATX catalysis are thought to be ideal drug targets for hyper-proliferative diseases such as cancer. S32826 is a low-nanomolar inhibitor of ATX but its poor bioavailability limits its use in vivo. PF8380 is a commercially-available non-lipid ATX inhibitor developed by Pfizer. Along with the boronic acid HA130, both compounds inhibit ATX in whole blood and directly inhibit the enzyme at nanomolar IC50 values.
Figure 4
Figure 4
Molecular trafficking and small molecule inhibitors of diacylglycerol kinase (DGK). A. DGK phosphorylates DAG to produce PA. DAG is a vital second messenger and PA is a prominent activator of several signaling proteins including mTOR. The DGKs are broadly expressed and regulate a host of physiological processes. B. Two synthetic inhibitors of DGK have been identified: R59022 and R59949. Both inhibitors only target the Ca2+-dependent type I DGKs at low-micromolar concentrations.
Figure 5
Figure 5
Molecular trafficking and small molecule inhibitors of DAGL and MGLL. A. DAGL and MGLL regulate the production of 2AG and AA in cells. 2AG is a potent agonist at the EC receptors granting the lipid important signaling roles in the nervous system. In addition, DAGL and MGLL also regulate AA production in tissues in which they are expressed. The important signaling roles of both 2AG and AA have made DAGL and MGLL important targets for small molecule inhibitors. B. Small molecule inhibitors of MGLL are a short list. JZL-184 has been used extensively both in vitro and in vivo for the characterization of MGLL in the CNS and cancer models. C. Several DAGL inhibitors have been reported. The 1,2,3-triazoleureas KT172 and KT109 were recently used in vitro and in vivo to characterize the DAGLβ isoform and its role in inflammation.
Figure 6
Figure 6
Mechanisms of serine hydrolase inhibition. Serine hydrolases are major regulators of lipid metabolism. MGLL, DAGL, HSL and ATGL all utilize a serine hydrolase catalytic motif to metabolize glycerolipids. Several classes of inhibitors of serine hydrolases have been developed to irreversibly bind to the active site of hydrolases by acting as electrophiles. Carbamates, β-lactones, fluorophosphonates and 1,2,3-triazole ureas are structurally distinct scaffolds but mechanistically inhibit serine hydrolases identically.
Figure 7
Figure 7
Differential regulation of HSL and ATGL for TAG metabolism. A. HSL sits downstream of the β-adrenergic receptor where hormonal cues activate PKA which stimulates HSL activity after phosphorylation. B. Due to their central role in TAG metabolism, small molecule inhibitors of HSL have been developed. Aventis’ 7600 and 9368 compounds inhibit HSL at nanomolar concentrations C. AGTL relies on its association with a catalytically-inactive serine hydrolase, CGI-58, to increase hydrolytic activity. ATGL displays a basal level of TAG hydrolysis which increases dramatically upon CGI-58 binding. D. Atglistatin is a recently reported ATGL inhibitor.
Figure 8
Figure 8
De novo TAG biosynthetic pathway and inhibitors. A. TAG biosynthesis is derived from sequential acylation of glycerol-3-phosphate by a series of acyltransferases and dephosphorylation by lipin. B. FSG67 is the only reported inhibitor of GPAT activity with an IC50 value of 25 μM. C. CT32228 is one of a small number of LPAAT inhibitors with a mid-nanomolar IC50 but off target toxicity limits its use in vivo. D. DGAT inhibitors are well-represented in the literature because of DGATs position in the TAG biosynthetic pathway.
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