Table Of ContentAdvances in Experimental Medicine and Biology 1274
Yasuyuki Kihara Editor
Druggable
Lipid Signaling
Pathways
Advances in Experimental Medicine
and Biology
Volume 1274
Series Editors
Wim E. Crusio, Institut de Neurosciences Cognitives et Intégratives
d’Aquitaine, CNRS and University of Bordeaux, Pessac Cedex, France
Haidong Dong, Departments of Urology and Immunology,
Mayo Clinic, Rochester, MN, USA
Heinfried H. Radeke, Institute of Pharmacology & Toxicology,
Clinic of the Goethe University Frankfurt Main, Frankfurt am
Main, Hessen, Germany
Nima Rezaei, Research Center for Immunodeficiencies, Children’s Medical
Center, Tehran University of Medical Sciences, Tehran, Iran
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Cardiovascular Sciences, School of Life Science, Shanghai
University, Shanghai, China
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Yasuyuki Kihara
Editor
Druggable Lipid
Signaling Pathways
Editor
Yasuyuki Kihara
Sanford Burnham Prebys Medical
Discovery Institute
La Jolla, CA, USA
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-030-50620-9 ISBN 978-3-030-50621-6 (eBook)
https://doi.org/10.1007/978-3-030-50621-6
© Springer Nature Switzerland AG 2020
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Contents
1 Introduction: Druggable Lipid Signaling Pathways . . . . . . . . . 1
Yasuyuki Kihara
2 Biosynthetic Enzymes of Membrane
Glycerophospholipid Diversity as Therapeutic
Targets for Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
William J. Valentine, Tomomi Hashidate-Yoshida,
Shota Yamamoto, and Hideo Shindou
3 Druggable Prostanoid Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Liudmila L. Mazaleuskaya and Emanuela Ricciotti
4 Targeting Leukotrienes as a Therapeutic Strategy
to Prevent Comorbidities Associated
with Metabolic Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Theresa Ramalho, Nayara Pereira, Stephanie L. Brandt,
and C. Henrique Serezani
5 Epoxy Fatty Acids Are Promising Targets
for Treatment of Pain, Cardiovascular Disease
and Other Indications Characterized
by Mitochondrial Dysfunction,
Endoplasmic Stress and Inflammation . . . . . . . . . . . . . . . . . . . . 71
Cindy McReynolds, Christophe Morisseau, Karen Wagner,
and Bruce Hammock
6 Druggable Sphingolipid Pathways:
Experimental Models and Clinical Opportunities . . . . . . . . . . . 101
Victoria A. Blaho
7 Druggable Lysophospholipid Signaling Pathways . . . . . . . . . . . 137
Keisuke Yanagida and William J. Valentine
8 Druggable Targets in Endocannabinoid Signaling . . . . . . . . . . 177
Ann M. Gregus and Matthew W. Buczynski
v
vi Contents
9 Drugging the Phosphoinositide 3-Kinase (PI3K)
and Phosphatidylinositol 4-Kinase (PI4K)
Family of Enzymes for Treatment of Cancer,
Immune Disorders, and Viral/Parasitic Infections . . . . . . . . . . 203
Jacob A. McPhail and John E. Burke
10 Druggable Lipid GPCRs: Past, Present, and Prospects . . . . . . 223
Hirotaka Mizuno and Yasuyuki Kihara
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
1
Introduction: Druggable Lipid
Signaling Pathways
Yasuyuki Kihara
Abstract fatty acids, sphingolipids, lysophospholipids,
endocannabinoids, and phosphoinositides) and
Lipids are essential for life. They store energy, lipid signaling proteins (lysophospholipid acyl-
constitute cellular membranes, serve as signal- transferases, phosphoinositide 3-kinase, and G
ing molecules, and modify proteins. In the long protein-coupled receptors (GPCRs)). Drugs
history of lipid research, many drugs targeting targeting lipid signaling pathways promise to
lipid receptors and enzymes that are responsi- be life changing magic for the future of human
ble for lipid metabolism and function have been health and well-being.
developed and applied to a variety of diseases.
For example, non-steroidal anti-i nflammatory Keywords
drugs (NSAIDs) are commonly prescribed
medications for fever, pain, and inflammation. Lipid mediator · Drug discovery ·
The NSAIDs block prostaglandin production Pharmacology · Biochemistry · Molecular
by inhibiting cyclooxygenases. A recent inno- biology
vative breakthrough in drug discovery for the
lipid biology field was the development of the
sphingosine 1-phosphate receptor modulators
(fingolimod, siponimod and ozanimod) for the The lipid bilayer membrane that protects DNA
treatment of multiple sclerosis, which were from external stress is essential for DNA inheri-
approved by the United States Food and Drug tance and cell survival [1]. Membrane lipids con-
Administration in 2010, 2019 and 2020, respec- tain glycerophospholipids (phosphatidylcholine,
tively. This review series of “Druggable Lipid phosphatidylethanolamine, phosphatidylserine,
Signaling Pathways” provides 9 outstanding phosphatidylinositol), glycerolipids (mono-, di-
reviews that summarize the currently available tri-acyl-glycerols), sphingolipids, and sterol lip-
drugs that target lipid signaling pathways and ids [2–4]. Membrane glycerophospholipids are
also outlines future directions for drug discov- de novo synthesized from glycerol-3-phosphate
ery. The review chapters include lipid signaling (known as the Kennedy pathway), which pro-
pathways (prostanoids, leukotrienes, epoxy duces phosphatidic acid (PA) via lysophospha-
tidic acid (LPA) by the sequential actions of
Y. Kihara (*) glycerol-3-phosphate acyltransferase and LPA
Sanford Burnham Prebys Medical Discovery acyltransferase (LPAAT). Phospholipases liber-
Institute, La Jolla, CA, USA
ate fatty acyls from the glycerophospholipids,
e-mail: [email protected]
© Springer Nature Switzerland AG 2020 1
Y. Kihara (ed.), Druggable Lipid Signaling Pathways, Advances in Experimental Medicine and
Biology 1274, https://doi.org/10.1007/978-3-030-50621-6_1
2 Y. Kihara
whose diversity is generated by lysophospholipid A. Blaho reviewed drug discoveries in the sphin-
acyltransferases (known as Land’s cycle) [5–8]. golipid pathways (Chap. 6).
Liberated fatty acyls are further metabolized by Lysophospholipid biology is expanding rap-
cyclooxygenases (COXs), lipoxygenases (LOs), idly by finding receptors for each lysophospho-
and cytochrome P450, resulting in the generation lipid (LPA, lysophosphatidic acid; LPI,
of prostanoids, leukotrienes, and epoxy fatty lysophosphatidylinositol; lysoPS, lysophosphati-
acids, respectively [9–11]. Drug discoveries for dylserine; LPGlc, lysophosphatidylglucoside)
lysophospholipid acyltransferases are summa- [26, 27]. LPA receptor antagonists and the LPA
rized by Dr. Hideo Shindou (Chap. 2). metabolic enzyme, autotaxin, inhibitors are
The first NSAID, acetylsalicylic acid expected to treat pulmonary fibrosis, pain, car-
(Aspirin®), was commercialized in 1897 before diovascular, and neurological diseases [29–32],
the finding of prostanoids including the prosta- which was summarized by Dr. Keisuke Yanagida
glandins (PGs: PGD, PGE, PGF , PGI) and (Chap. 7).
2 2 2α 2
thromboxane (TXA ) [12]. Prostanoids are Endocannabinoids (anandamide and
2
derived from arachidonic acid and play important 2- arachidonoylglycerol) are essential lipid medi-
roles in pain, fever, inflammation, cardiovascular ators in the central nervous system and immune
diseases, the reproductive system, and others [9, system [33]. The endocannabinoid receptors
13, 14]. Dr. Emanuela Ricciotti summarizes the were originally discovered as receptors for can-
prostanoid pathways and drugs targeting this nabis components before endocannabinoids were
pathway (Chap. 3). Leukotrienes are also derived found. Cannabinoids are clinically and recre-
from arachidonic acid, whose receptor antago- ationally used worldwide. Dr.
nists such as pranlukast, montelukast, and zafiru- Matthew W. Buczynski provides an overview of
lukast are prescribed for treating asthma and endocannabinoid biology and drug discovery
rhinitis [9, 15–19]. Dr. C. Henrique Serezani pro- (Chap. 8).
vided a review of leukotriene pathways, particu- Phosphoinositides (phosphatidylinositol
larly focusing on metabolic and cardiovascular 3-phosphate (PI3P), phosphatidylinositol
diseases (Chap. 4). Polyunsaturated fatty acids 4- phosphate (PI4P), phosphatidylinositol
including arachidonic acid, docosahexaenoic 5- phosphate (PI5P), phosphatidylinositol
acid, and eicosapentaenoic acid are metabolized 3,4-biphosphate (PI(3,4)P), phosphatidylinosi-
2
by CYP P450 to produce epoxy fatty acids that tol 3,5-biphosphate (PI(3,5)P ), phosphatidylino-
2
are further metabolized to hydroxy fatty acids by sitol 3,4-biphosphate (PI(3,4)P), and
2
soluble epoxide hydrolases (sEHs) [20]. Cindy phosphatidylinositol 3,4,5-triphosphate (PIP))
3
McReynolds et al. introduced novel drugs are essential intracellular signaling molecules
targeting sEH for the treatment of neuropathic downstream of a variety of cell surface receptors
pain and cardiovascular diseases (Chap. 5). [34, 35]. These are derived from phosphati-
Sphingolipids (sphingoid bases, ceramides, dylinositol by the actions of phosphoinositide
sphingomyelins, cerebrosides) are also essential kinases. Dr. John E. Burke provided a compre-
components of membranes that have a sphingo- hensive summary of this pathway with particular
sine backbone with N-acyl chains and/or head focus on the phosphoinositide 3-kinase (PI3K)
groups [21, 22]. Sphingosine 1-phosphate (S1P) and phosphatidylinositol 4-kinase (PI4K) family
is a lipid mediator that controls lymphocyte traf- (Chap. 9).
ficking and is responsible for immune diseases All the lipid mediators introduced above bind
[23, 24]. Fingolimod is a pro-drug that is metabo- to their cognate GPCRs that are the most attrac-
lized to fingolimod-phosphate by endogenous tive targets for drug discovery. This book’s editor,
sphingosine kinases [25]. Fingolimod is the first Dr. Yasuyuki Kihara, provided a review of drug-
FDA-approved orally available drug for the treat- gable lipid GPCRs that summarizes the histories
ment of relapsing-remitting multiple sclerosis, of lipid GPCR identification, drugs targeting
which targets S1P receptors [26–28]. Dr. Victoria
1 Introduction: Druggable Lipid Signaling Pathways 3
lipid GPCRs, and striking drug designs for future phospholipids generated by the remodeling pathway
in mammalian cells. J Lipid Res 55:799–807
GPCR drug discovery (Chap. 10).
6. Kita Y, Shindou H, Shimizu T (2019) Cytosolic
Taken together, the book contains 10 chapters
phospholipase A2 and lysophospholipid acyltrans-
that provide a historical overview as well as the ferases. Biochim Biophys Acta Mol Cell Biol Lipids
recent advances in studies of lipid signaling path- 1864:838–845
7. Shindou H, Hishikawa D, Harayama T, Eto M,
ways with particular emphasis on “druggable”
Shimizu T (2013) Generation of membrane diver-
targets. The book is aimed at a broad audience
sity by lysophospholipid acyltransferases. J Biochem
from academic to industry researchers and was 154:21–28
authored by the next generation of lipid research- 8. Shindou H, Shimizu T (2009) Acyl-
CoA:lysophospholipid acyltransferases. J Biol Chem
ers who were trained and mentored by presti-
284:1–5
gious lipid scientists including Drs. Frank
9. Funk CD (2001) Prostaglandins and leukotri-
K. Austen, Charles R. Brown, Jerold Chun, enes: advances in eicosanoid biology. Science
Edward A. Dennis, Garret A. FitzGerald, Timothy 294:1871–1875
10. Inceoglu B, Schmelzer KR, Morisseau C, Jinks
Hla, Bruce D. Hammock, Loren H. Parsons,
SL, Hammock BD (2007) Soluble epoxide hydro-
Marc Peters-Golden, Takao Shimizu, Gabor
lase inhibition reveals novel biological functions of
Tigyi, Roger L. Williams, and more. epoxyeicosatrienoic acids (EETs). Prostaglandins
Other Lipid Mediat 82:42–49
11. Smith WL, Urade Y, Jakobsson PJ (2011) Enzymes of
Acknowledgements Thanks to all the authors who con-
the cyclooxygenase pathways of prostanoid biosyn-
tributed to this book, Dr. Inês Alves (Springer Nature) for
thesis. Chem Rev 111:5821–5865
inviting me to edit this book, Ms. Ilse Kooijman (Springer
12. Vane JR, Botting RM (2003) The mechanism of
Nature), and Ms. Danielle Jones (SBP) for editorial assis-
action of aspirin. Thromb Res 110:255–258
tance. This work was supported by a grant from NIH/
13. Ricciotti E, FitzGerald GA (2011) Prostaglandins
NINDS R01NS103940 (Y.K.). The content is solely the
and inflammation. Arterioscler Thromb Vasc Biol
responsibility of the authors and does not necessarily rep-
31:986–1000
resent the official views of the National Institutes of
14. Smyth EM, Grosser T, Wang M, Yu Y, FitzGerald GA
Health.
(2009) Prostanoids in health and disease. J Lipid Res
50(Suppl):S423–S428
Conflict of Interest Y.K. declares no competing finan- 15. Austen KF (2005) The mast cell and the cysteinyl
cial interests. leukotrienes. Novartis Found Symp 271:166–175;
discussion 176-168, 198-169
16. Austen KF, Maekawa A, Kanaoka Y, Boyce JA
(2009) The leukotriene E4 puzzle: finding the missing
pieces and revealing the pathobiologic implications. J
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