Cellular Signalling 79 (2021) 109890

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Cellular Signalling
journal homepage: www.elsevier.com/locate/cellsig

The noncanonical chronicles: Emerging roles of sphingolipid

structural variants
Brenda Wan Shing Lam a, Ting Yu Amelia Yam a, Christopher P. Chen a, b, Mitchell K.P. Lai a, b,
Wei-Yi Ong c, Deron R. Herr a, d, e, *
a
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
b
Memory Aging and Cognition Centre, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
c
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
d
Department of Biology, San Diego State University, San Diego, CA, USA
e
American University of Health Sciences, Long Beach, CA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Sphingolipids (SPs) are structurally diverse and represent one of the most quantitatively abundant classes of
Chain-length variation lipids in mammalian cells. In addition to their structural roles, many SP species are known to be bioactive
Lipidomics mediators of essential cellular processes. Historically, studies have focused on SP species that contain the ca­
Neuroinflammation
nonical 18‑carbon, mono-unsaturated sphingoid backbone. However, increasingly sensitive analytical technol­
Phytosphingosine
Sphingadiene
ogies, driven by advances in mass spectrometry, have facilitated the identification of previously under-
Sphingoid backbone appreciated, molecularly distinct SP species. Many of these less abundant species contain noncanonical back­
bones. Interestingly, a growing number of studies have identified clinical associations between these nonca­
nonical SPs and disease, suggesting that there is functional significance to the alteration of SP backbone
structure. For example, associations have been found between SP chain length and cardiovascular disease, pain,
diabetes, and dementia. This review will provide an overview of the processes that are known to regulate
noncanonical SP accumulation, describe the clinical correlations reported for these molecules, and review the
experimental evidence for the potential functional implications of their dysregulation. It is likely that further
scrutiny of noncanonical SPs may provide new insight into pathophysiological processes, serve as useful bio­
markers for disease, and lead to the design of novel therapeutic strategies.

1. Introduction to noncanonical SPs
Sphingolipids (SPs), including ceramides, sphingomyelins, ganglio­
sides, cerebrosides, sulfatides, and others, represent a highly diverse
class of lipids that are abundant in virtually all membranes of eukaryotic
cells [1]. All SPs are built on an essential core structure; a sphingoid base
that serves as the scaffold for SPs of varying complexity [2]. The vast
diversity of SPs is due to the potential for the scaffold to be modified at
two positions (Fig. 1A). Thousands of unique functional groups may be
added to the hydroxylated carbon at position 1, and dozens of struc­
turally distinct acyl chains may be added to the amine group at carbon 2.
This results in hundreds of empirically confirmed variants and tens of
thousands of additional species that are presumed or are necessary
metabolic intermediates. This diversity is widely appreciated and has
been scrutinized by mass spectrometry-based lipidomics studies for
several decades. However, one additional aspect of SP diversity that is
often overlooked involves variations of the structure of the sphingoid
backbone itself. In mammals, the majority of SPs contain a canonical
18‑carbon, dihydroxy, monounsaturated backbone, or “d18:1”. (See
Fig. 1 for nomenclature.) As a result, most studies into SP functions
disregard the quantitatively minor noncanonical species, and many
lipidomics studies do not discriminate canonical from noncanonical SPs.
This is particularly conspicuous regarding the widely studied signaling
SP, sphingosine 1-phosphate (S1P). Despite the fact that “S1P” typically
refers to the aggregate mixture of several different S1P variants, func­
tional studies almost uniformly address the canonical d18:1 without
acknowledging potential roles of the quantitatively minor structural
variants. For the purpose of this review, the term “noncanonical” refers
to any SPs that contain a sphingoid backbone other than d18:1 (Fig. 1B).
In Section 2, we first review the fundamentals of SP metabolism and the

* Corresponding author at: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
E-mail address: phcdrh@nus.edu.sg (D.R. Herr).

https://doi.org/10.1016/j.cellsig.2020.109890
Received 13 October 2020; Received in revised form 15 December 2020; Accepted 16 December 2020
Available online 28 December 2020
0898-6568/© 2020 Elsevier Inc. All rights reserved.
B.W.S. Lam et al.
processes that provide structural diversity outside of the sphingoid
backbone. Section 3 describes the metabolic sources of noncanonical SPs
and emerging data that underscore their physiological and pathophys­
iological importance.
2. Sphingolipid metabolism
2.1. De novo synthesis of the sphingoid backbone
The fundamental structural element of all sphingolipids is a sphin­
goid base with an acyl chain that has some variation in length and
saturation. This makes up the sphingoid backbone which is formed by de
novo synthesis in the endoplasmic reticulum (ER). Once produced in the
ER membrane, sphingolipids can be transported to the Golgi apparatus
for further packaging and processing, or to the plasma membrane where
they participate in the maintenance of membrane architecture.
The first and rate-limiting step of de novo synthesis is catalyzed by the
enzyme complex serine palmitoyltransferase (SPT), localized to the ER
membrane [3]. Initially characterized as a heterodimer [4], studies in
yeast have since demonstrated that SPT is made up of a heterotrimer of
main catalytic subunits, Lcb1p and Lcb2p, along with an additional
regulatory subunit, Tsc3p [5]. Human SPT is similarly made up of the
Lcb1p ortholog, SPTLC1, and two Lcb2p orthologs, SPTLC2 and SPTLC3
[6] (Fig. 2). Additionally, although there was no subunit found similar to
Tsc3p in mammals, two small short-membrane proteins were identified
to be functional orthologous, namely SPTssa and SPTssb [7]. These two
proteins share the same function as Tsc3p, where their presence expo­
nentially increases the activity of the SPT complex [8].
SPT is dependent on pyridoxal 5′ -phosphate (PLP) for activity, where
PLP is bound to the lysine on the SPTLC2/SPTLC3 subunits [4,9]. The
lack of a PLP-binding motif in the SPTLC1 subunit [10] suggests that SPT
needs to exist as a complex of SPTLC1 with either SPTLC2 or SPTLC3 for
SPT to carry out its function. Thus, SPT, as a heterotrimer, facilitates the
condensation reaction between an amino acid and an acyl-CoA to form
3-ketosphinganines, which are rapidly reduced by ketosphinganine
reductase to “sphinganines,” representing the simplest SPs consisting
only of a naked sphingoid backbone. As described below, this step is the
sole determinant of the sphingoid backbone acyl chain length. On
average, the most common substrates for SPT are serine and the
16‑carbon palmitoyl-CoA, catalyzing the formation of the canonical
sphingoid backbone and leading to the abundance of d18:1
sphingolipids.
Fig. 1. Structure and variation of canonical and noncanonical mammalian SPs. A) This structure, showing the canonical d18:1 sphingoid backbone, indicates the
positions of the headgroup and N-acyl modifications that generate diversity among the canonical SPs. B) Using the canonical SP d18:1 sphingosine as a reference, this
structure shows where modifications occur within the sphingoid backbone to produce noncanonical variants. C1P, ceramide 1-phosphate; S1P, sphingosine
1-phosphate.
2
Cellular Signalling 79 (2021) 109890
2.2. Generating diversity of canonical SPs
Dihydroceramides are formed by combining sphinganine with acyl-
CoAs of varying chain lengths, which are then desaturated by dihy­
droceramide desaturase to form ceramides (Fig. 2). Ceramides can then
act as a precursor to “higher-order” ceramides, such as glucosylcer­
amides, sphingomyelins and ceramide 1-phosphates, forming a meta­
bolic “hub” with ceramides at the center [11].
2.2.1. Ceramides
As mentioned above, a major source of variation of canonical SPs
occurs during the synthesis of ceramides, where acyl-CoAs are combined
with sphinganines, producing ceramides with different N-acyl chain
lengths (Fig. 1). This diversity is facilitated by the diversity of ceramide
synthase (CerS) enzymes, 6 in total (CerS1-6), that vary in substrate
preference [11,12]. Namely, Cer5/6 prefer C14-C18 acyl-CoAs, CerS1/4
prefer C18-C20 acyl-CoAs, and CerS2/3 prefer C18-C24 acyl-CoAs [11].
As a result, the human complement of ceramides contains N-linked acyl
chains that vary from 14 to 24 carbons, typically with 0 to 2 double
bonds, resulting in several dozen ceramide variants containing the same
canonical d18:1 SP backbone. Derangement from the “normal” com­
plement of ceramide chain length has been associated with a number of
human diseases including cardiovascular disease, neurodegenerative
diseases, diabetes, and cancer [11,13–15], suggesting that acyl chain
length is an important determinant of the pathological effects of cer­
amide [16,17].
Ceramides can be further acylated at the 1-O-position or by
ω-esterification to form acylceramides [18]. These ultra-long chain SPs
are abundant in the skin and are known to be important for skin barrier
function [19]. Due in large part to pioneering studies by Lina Obeid’s
group and others [20], modulation of acylceramides has been proposed
as a mechanism of regulating the pro-apoptotic effects of ceramides.
Acylceramides are produced from ceramides on lipid droplets by the
action of diacylglycerol acyltransferase 2 (DGAT2) to prevent an
excessive accumulation of ceramides [20]. Thus, the generation of
acylceramides provides a protective effect against pro-apoptotic
ceramides which, when dysregulated, can give rise to a wide range of
pathologies, such as non-alcoholic fatty liver disease [21] and obesity
induced insulin resistance [22].
2.2.2. Hexosylceramides
Once formed by the acylation of the sphingoid backbone, ceramides
B.W.S. Lam et al. Cellular Signalling 79 (2021) 109890

Fig. 2. Metabolic pathways producing noncanonical SPs in mammals. Variations in SP chain length and hydroxylation are due to differences in substrate use by the
SPT enzyme complex in the first step of de novo synthesis. The combination of SPT subunit combinations determines substrate preference. Resulting sphingoid
backbones enter the SP metabolic pathway and are converted to ceramides and higher-order ceramides. SDs are generated when FADS3 desaturates ceramides at
carbon position 14. SDs, sphingadienes; SP, sphingolipid; SPT, serine palmitoyltransferase.

then serve as scaffolds for the generation of a class of higher-order
ceramides known as the hexosylceramides. These are formed with the
attachment of a hexose sugar, glucose or galactose, to the primary hy­
droxyl group of ceramides by glucosylceramide synthase. These mono­
hexosylceramides can be further modified with the additional hexose
sugars (glucose, galactose, mannose, fucose), other monosaccharides
(xylose), or amino sugars (sialic acid). The incorporation of up to a
dozen monosaccharides in straight-chain or branched configurations
results in the generation of hundreds of confirmed species [2] and
thousands of theoretical variants and metabolites. SP diversity increases
by orders of magnitude when hundreds to thousands of unique hexosyl
headgroups are paired with the dozens of N-acyl ceramide variants.
Hexosylceramides can be further diversified by the addition of a sulfate
to form sulfatides, known to be involved in neuronal differentiation and
myelination [23]. Functionally, hexosylceramides localize in lipid rafts
where they participate in the regulation of cell signaling [24] and cell
differentiation [25].
2.2.3. Sphingomyelins
Another class of higher-order SPs, the sphingomyelins, are formed
from ceramide by the addition of a phosphocholine headgroup. Sphin­
gomyelins are the most abundant phospholipid present in most
mammalian membranes, where they provide structural stability [26]
and contribute to the ordering of lipid rafts [27]. Ceramide is trans­
ported from the ER lumen to the Golgi by a ceramide transfer protein,
CERT [28], where sphingomyelin is synthesized by sphingomyelin
synthase 1 (SMS1) at the trans-Golgi lumen. Sphingomyelin can also be
produced by sphingomyelin synthase 2 (SMS2) at the plasma membrane
[29], using ceramides produced locally at the membrane [30]. Since
sphingomyelins are formed from ceramides by a single headgroup
modification, the generation of sphingomyelins makes a relatively
minor impact on overall SP diversity. However, the structural variation
within the class of sphingomyelins is likely to be functionally mean­
ingful [31,32].
2.3. Degradation and recycling of the sphingoid backbone
Ceramides, either from de novo synthesis or from degradation of
higher-order ceramides, can be readily hydrolyzed back into sphingo­
sine in what is known as the salvage pathway [33]. This pool of salvaged
sphingosine can be re-acylated into ceramides and thus recycled back
into the hub of SP metabolism. This recycling contributes an estimated
50–90% of sphingolipid biosynthesis [34] and has been demonstrated to
be active in important cell signaling processes such as PKC signaling
[35]. Interestingly, it is known that ceramides produced by the salvage
pathway are functionally distinct from those generated by de novo syn­
thesis [36]. Although the mechanism underlying this difference is un­
clear, it is likely the result of differences in subcellular localization.
Sphingosines formed from the degradation of ceramides are phos­
phorylated by two isoforms of sphingosine kinase (SPHK1 and SPHK2)
to form sphingosine 1-phosphate (S1P). This process exists in dynamic
equilibrium, where S1P can be converted back to sphingosines by

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B.W.S. Lam et al.
selective S1P phosphatases (SGPP1 and SGPP2) [37–39] or by promis­
cuous lipid phosphate phosphatases [40]. S1P can also be catabolized by
S1P lyase (SGPL1) to hexadecanal and ethanolamine 1-phosphate,
which feed into phospholipid biosynthesis [41]. It is important to note
that hydrolysis of S1P by SGPL1 is the only known enzymatic process
that irreversibly degrades the sphingoid backbone, thus making S1P a
key intermediate in SP degradation [42] and positioning SGPL1 as a
critical regulator of homeostatic SP content [43]. In addition to this
metabolic role, the biological roles of S1P have been extensively studied
since its identification as a potent cognate ligand of a family of G
protein-coupled receptors (S1P1 – S1P5). The effects of S1P receptor
signaling are highly pleotropic and are reviewed in detail elsewhere
[44–46].
3. Formation and biological roles of SPs with noncanonical
sphingoid backbones
The preceding sections describe mechanisms by which the canonical
d18:1 sphingoid backbone is decorated to generate the structural di­
versity of SPs. However, there are several variations of the backbone
structure itself that have been known for decades, but whose signifi­
cance has been largely neglected. This is due, in large part, to their
relatively low abundance and the technical challenges of quantification,
purification, and synthesis. However, due to improvements in analytical
techniques [47] and the formation of metabolomics consortia [48],
emerging data suggest that these noncanonical SPs are precisely regu­
lated and that they play functional roles in physiology and disease
(Table 1).
Table 1
Reported biological functions of noncanonical SPs.
Species Biological effect
Variations in sphingoid backbone chain length
d20:1 GM1 Neuronal differentiation and senescence
d16:1 S1P Inhibits cytokine expression in astrocytes
d20:1 S1P Inhibits COX-2 expression in glioblastoma
cells
Variations in sphingoid backbone saturation
d18:2 HexCer Inhibit viability of colon cancer and
(plant- neuroblastoma cells through suppression of
derived) AKT and WNT signaling
d18:2 SPH
(plant-
derived)
d18:2 Cer Inhibits neurite outgrowth
(plant-
derived)
Variations in sphingoid backbone hydroxylation
m18:0 SPH Disrupt mitochondrial dysfunction and
m17:0 SPH promote neurodegeneration
m18:1 Cer Neurotoxic via inhibition of SPHK and
m18:1 SPH disruption of S1P receptor signaling
m18:0 SPH Cytotoxic to pancreatic β islet cells and
inhibits glucose-stimulated insulin secretion
t20:0 Cer Promotes chemotaxis and viability in dermal
fibroblasts via JNK and Akt signaling
t18:0 S1P Promotes survival and maturation of oocytes
18:0 SPH Inhibits EMT and depletes cancer stem cells
18:0 SPH Inhibits melanin production in melanocytes
Cer, ceramide; GM1, GM1 ganglioside; HexCer, hexosylceramide; S1P, sphin­
gosine 1-phosphate, SPH, sphingosine.
Cellular Signalling 79 (2021) 109890
3.1. Variations in sphingoid backbone chain length
Mammalian SPs largely contain backbones with a canonical
18‑carbon, dihydroxy, monounsaturated acyl chain (d18:1), represent­
ing >60% of total SPs [49,50]. However, there is significant variation in
the backbone structures of quantitatively minor species [1]. The
following section will discuss variations in chain length, which in
mammals, typically ranges from 14 to 22 carbons but species ranging
from 12 to 26 carbons have been reported [1]. Although most of these
SPs have even-numbered chain lengths, odd-chain lengths are known to
be present as well [50]. These odd-chain SPs will not be addressed in this
review since their metabolic origins [51] and their structures (straight-
chain or branched) have not been confirmed [52] with one notable
exception, namely the 17‑carbon deoxymethylsphinganine, which is
discussed in Section 3.3.
3.1.1. Metabolism of noncanonical chain lengths
As mentioned above, SPT catalyzes the first step in de novo SP syn­
thesis with the generation of the basic building block for SPs: the
sphingoid backbone. There are four typical configurations of the SPT
enzyme complex (Fig. 2), where each configuration has a different
preference for the length of acyl-CoA substrate [7]. The complex must
contain SPTLC1 and one of two major non-obligatory subunits, SPTLC2
or SPTLC3 [4,6,10]. In addition, the incorporation of one of two small
subunits, SPTSSA (ssSPTa) and SPTSSB (ssSPTb), is necessary for full
enzymatic activity [7]. In general, complexes containing SPTLC2 prefer
a 16‑carbon substrate (palmitoyl-CoA) while SPTLC3 is more promis­
cuous [53,54], and SPTSSB prefers longer chain substrates, while
SPTSSA prefers shorter chains [7] (Fig. 2). The ability of the small
subunits to discriminate among acyl-CoA substrates of different chain
lengths is due to a single amino acid difference between SPTSSA and
SPTSSB [8], where at the 25th amino acid position, SPTSSA has
methionine while SPTSSB has valine. Although the SPT complex is
References present in all tissues, its three large subunits have differential but
overlapping patterns of expression [6]. Notably, SPTLC3 expression is
[67–70] more restricted with highest expression in placental tissue [53]. This
suggests that 16‑carbon sphingolipids, made almost exclusively by
[71]
SPTLC3 [54], require tissue-specific regulation but may be particularly
[72] important during fetal development.
Numerous studies have demonstrated that the length of the N-linked
acyl chain of ceramides and sphingomyelins affects their biophysical
properties. This influences the rigidity/fluidity, permeability, and
[89,100,101]
thickness of resulting membranes, and alters membrane-protein in­
teractions [55,56]. For example, membrane order is increased by the
incorporation of ceramides with longer N-acyl chains [57]. Interest­
[102]
ingly, similar positive correlations were observed between membrane
order and the length of the ceramide sphingoid base [58]. In fact, it
[105]
appears that the impact of sphingoid base length is more significant than
the length of the N-acyl chain with respect to biophysical properties of
SPs [59].
3.1.2. Known functions of SPs with noncanonical chain lengths
[110,120–122]
3.1.2.1. Aging/neurodegeneration. Gangliosides, a class of higher-order
[124,125] hexosylceramides, localize within the outer layer of the plasma mem­
brane and are mainly found in the central nervous system (CNS). They
[129] confer structural rigidity to cells and form membrane microdomains
which mediate cell adhesion [60]. Additionally, they have many regu­
[142–144] latory roles in the CNS, including the regulation of neurotrophic and
neuroprotective properties pathways [61–64]. For example, the inter­
[146] action of GM1, a member of the ganglioside family, with TrkA can
protect against neurotoxic stimuli and promote cell differentiation via
[147]
activation of the ERK1/2 pathway [62]. GM1 has also been shown to
[148,149] exert a protective effect against MPTP-induced oxidative stress and cell
death in Neuro-2a neuroblastoma cells [63]. This could be due to the
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B.W.S. Lam et al. Cellular Signalling 79 (2021) 109890

role of GM1 as a mitochondrial regulator, whereby it promotes mito­
chondriogenesis and enhances mitochondrial activity [65].
Interestingly, both d18:1 and d20:1 GM1 are abundant in the CNS
[66]. Currently, whilst there are no reports directly demonstrating
functional difference between the two naturally occurring GM1 species,
correlation studies have nevertheless suggested functional relevance.
For example, d18:1 and d20:1 GM1 are distributed non-homogenously
in the brain [67,68]. Although the absolute content of d18:1 GM1 is
higher throughout the cortical regions, the relative enrichment of d20:1
GM1 is highest in the molecular layer of the dentate gyrus and lowest in
the amygdala, and the cerebral cortex has a gradient of d20:1 GM1
distribution, with the highest concentrations in the superficial layers
[67,69]. Interestingly, in the aforementioned rat studies, d20:1 GM1
content increased markedly from postnatal day 0 to 3 months, and to a
lesser extent from 3 months to 20 months, suggesting a role in both
neuronal differentiation and senescence. This is consistent with a pre­
vious study reporting that d20:1 gangliosides were detectable in adult
brain, but were undetectable in embryonic brain tissues from multiple
species including human [70].
To determine whether specific, noncanonical S1P species correlate
with neurodegenerative disease, we evaluated the four most abundant
S1P species in plasma from patients with Alzheimer’s disease (AD) or
vascular dementia (VaD) relative to cognitively normal controls [71].
We found that specific decreases in d16:1 S1P were associated with VaD,
while no associations were found with AD. We further demonstrated
Cumulatively, these studies suggest that perturbations of SP metabolism,
rather than total ceramide content, may be particularly relevant to the
pathophysiology of CAD.
3.1.2.3. Insulin resistance. Several studies have drawn clinical and
functional correlations between ceramides and insulin resistance, a
major risk factor for T2DM (Table 2). For example, ceramide production
mediates TLR4-dependent induction of insulin resistance in vivo [86].
Moreover, ceramides are shown be increased in a rat model of high-fat
diet-induced non-alcoholic fatty liver disease (NAFLD), an insulin
resistance-related hepatic disorder, and inhibition of ceramide synthesis
reduces NAFLD-induced insulin resistance and hepatic lipid accumula­
tion [87]. Similarly, decreasing the concentration of ceramides was
shown to improve glucose tolerance and insulin sensitivity in mice fed a
high fat diet [88]. Interestingly, a recent study demonstrated that the
Table 2
Reported clinical correlations between noncanonical SPs and disease or de­
mographic characteristics.
Species Clinical correlation References
Variations in sphingoid backbone chain length
d16:1 S1P ↓ Vascular dementia [71]
d16:1 S1P ↑ Oxaliplatin treatment [74]

that d16:1 S1P correlated negatively with inflammatory cytokines while d20:0 SPH ↑ Cardiovascular event [83]
canonical d18:1 S1P correlated positively. Surprisingly, in vitro studies d16:1/16:0 Cer ↑ HOMA-IR [15]
demonstrated that both d16:1 and d18:1 S1P induce cytokine expression d16:1/18:0 Cer
in astrocytic cells. However, the efficacy of d16:1 S1P was lower, and d16:1/20:0 Cer
was able to attenuate the inflammatory effect of d18:1 S1P when both d16:1/18:0 SM
d16:1/20:0 SM
species were administered simultaneously. It remains unclear whether d16:1 SPH
this phenomenon occurs in vivo, since endogenous levels of d16:1 S1P d16:1 S1P
are low to undetectable in the brain [49]. However, another group re­ d17:1 S1P
ported a similar finding for d20:1 S1P, which is present in significant d16:1/18:0 SM ↑ Type 2 Diabetes Mellitus [15]
quantities in the brain [72]. That study demonstrates that d18:1 S1P-
mediated induction of inflammatory COX-2 expression in glioblastoma Variations in sphingoid backbone saturation
cells can be attenuated by co-administration of d20:1 S1P, also sup­ d18:2/24:1 Cer ↑ Aging [152]
porting a model that noncanonical S1Ps may play a role in “fine tuning” d18:2/16:0 SM
S1P-mediated inflammation. d18:2/23:0 Cer ↓ HOMA-IR [15,152]
The different inflammomodulatory effects of individual S1P species d18:2/24:0 Cer
are likely to be the result of differential interactions with their cognate d18:2/24:1 Cer
receptors. Indeed, although all S1P species tested have been shown to d18:2/25:0 Cer
d18:2/26:0 Cer
interact with cognate S1P receptors, they display differences in their
d18:2/18:1 SM
potencies and efficacies [73]. For example, shortening the S1P acyl d18:2/23:0 SM
chain (<18 carbons) increases its efficacy toward S1P4, but decreases its d18:2/24:0 SM
efficacy toward all other cognate receptors. Our previous study supports d18:2/16:0 Hex2Cer
this model by demonstrating that patients receiving cisplatin exhibited a d18:2/22:0 HexCer
d18:2/23:0 HexCer
specific increase in plasma d16:1 S1P content, but not other S1P species d18:2/24:0 HexCer
[74]. We further show that activation of receptor S1P2 attenuates d18:2/24:1 HexCer
cisplatin-mediated neuropathy and that d16:1 S1P is selectively less
d18:2/18:0 SM ↑ HOMA-IR [15]
potent toward S1P2. We hypothesize that elevation of d16:1 S1P pref­ d18:2 SPH
erentially activates pro-neuropathic S1P1 [75–78] at the expense of d18:2 S1P
neuroprotective S1P2. m18:2 SPH ↓ Cardiovascular Event [83]

3.1.2.2. Cardiovascular disease. SPs have been shown to act as car­ Variations in sphingoid backbone hydroxylation
dioprotectants at physiological concentrations, but an increase in SP m18:0 SPH ↑ HSN Type I (A and C) [111]
content, particularly ceramides, can be toxic to many cell types m17:0 SPH
including cardiomyocytes [79–82]. Interestingly, a study published in m18:1 Cer ↑ CIPN [123]
2015 has shown that only elevated d20:1 sphingosine, but not canonical m18:1 SPH
d18:1 sphingosine, was associated with an increased risk of coronary m18:0 SPH ↑ Type II Diabetes Mellitus [107,127,128]
artery disease (CAD) [83]. In addition, another recent study identified
m18:1 SPH
positive correlations between d16:1/18:1 ceramide and both large artery
atherosclerosis and cerebrovascular disease [84]. Due to the relative high t20:0 Cer ↓ Psoriasis [137,153]
expression of SPTLC3 in myocardium [85], it is likely that these non­ ↓ Atopic dermatitis

canonical SPs are produced by pathological conditions in the heart itself. Cer, ceramide; HexCer, hexosylceramide; Hex2Cer, dihexosylceramide; S1P,
sphingosine 1-phosphate; SM, sphingomyelin; SPH, sphingosine.

5
B.W.S. Lam et al.
protective effect of sulforaphane against insulin resistance is likely to be
the result of inhibition of SPTLC3 [88]. Although this study demon­
strated only that SPTLC3 inhibition reduced total ceramide content and
did not evaluate individual species, it is likely that noncanonical
ceramides were preferentially depleted due to SPTLC3’s broad substrate
specificity. This is consistent with a large scale clinical study conducted
by our group that demonstrated that d16:1 ceramide species, have
stronger positive correlations with both insulin resistance and body
mass index compared to canonical d18:1 ceramides [15].
3.2. Variations in sphingoid backbone saturation
The canonical d18:1 sphingoid backbone contains a trans double
bond between carbons 4 and 5 (4E-d18:1 or d18:1∆4t), but naturally
occurring species contain 0 to 2 double bonds. Fully saturated SPs
(d18:0) are common and are, in fact, a necessary intermediate in the
production of d18:1 species (Fig. 2). Sphingoid backbones containing
two double bonds (d18:2), the sphingadienes (SDs), are present in many
mammalian tissues but at a relatively low abundance. Interestingly, the
existence of SDs has been shown in many species, but the position of the
second double bond demonstrates characteristic phylogenetic differ­
ences. Plants, such as soy, are characterized by an abundance of ∆4,∆8
SDs [89] while insects contain an unusual conjugated ∆4,∆6 configu­
ration [90]. To date, the only specific SD species reported in humans
contain a 4E,14Z-d18:2 backbone [1].
Fatty acid saturation has a marked effect on the behavior of SPs in a
fluid membrane, which consequently impacts membrane properties. It
has been previously established that introduction of cis double bonds
into the N-linked acyl chain of ceramide reduces membrane order and
rigidity [91]. More recently, a similar effect was seen with the sphingoid
backbone in that 4E,14Z-d18:2 ceramides destabilized membrane gel
phases relative to that of canonical d18:1 ceramides [92]. This raises the
possibility that accumulation of SP dienes results in the dispersion of SP-
rich membrane microdomains, potentially disrupting signaling protein
complexes [93].
3.2.1. Metabolism of sphingadienes
Although the existence of d18:2 SPs in humans has been known since
the 1960’s [94,95], the metabolic source of this backbone structure
remained elusive until 2019. Two independent groups reported that the
enzyme fatty acid desaturase 3 (FADS3) can catalyze the formation of
4E,14Z-d18:2 SDs [96,97]. Although the precise substrate preference
has not been described in detail, it is likely that FADS3 desaturates d18:1
ceramides rather than sphingosines. The resulting d18:2 ceramides enter
the SP metabolic pathway leading to the accumulation of higher-order
d18:2 ceramides. d18:2 sphingosine can be efficiently phosphorylated
by both SPHK1 and SPHK2 to form d18:2 S1P [98,99]. However, d18:2
S1P is less susceptible to terminal degradation by SGPL1 relative to
d18:1 [97], suggesting increased metabolic stability of SDs.
3.2.2. Known functions of SPs with sphingadiene backbones
Although the functional roles of SDs in mammalian physiology/
pathophysiology are not yet clear, their asymmetric tissue distribution
suggests the potential significance of maintaining SD homeostasis.
Notably, an analysis of mouse tissues demonstrated that SD ceramides
are particularly abundant in the kidney and brain, where they represent
68% and 30% of total ceramides, respectively [97]. Furthermore, clin­
ical studies implicate their potential role in the pathophysiology of
cardiovascular and metabolic disease (Table 2). The study described
above that identified a positive relationship between d20:1 sphingosine
and CAD also identified a negative association between d18:2 sphingo­
sine and subsequent cardiovascular event (HR = 0.79) [83]. This sug­
gests that SDs may play a protective role in cardiovascular disease. In
addition, our large-scale lipidomics analysis [15] demonstrated that
d18:2 SD species correlate negatively with obesity and insulin resis­
tance, or in some cases, showed weaker positive correlations relative to
6
Cellular Signalling 79 (2021) 109890
their d18:1 counterparts. Interestingly, women demonstrated signifi­
cantly higher concentrations of SDs compared to men [15], suggesting
that a protective effect of SDs may contribute to the lower incidence of
CAD in women.
In addition to the clinical correlations, a number of preclinical
studies demonstrated that SDs have significant biological effects on
mammalian cells. For example, soy-based 4E,8E-d18:2 hexosylceramide
was shown to inhibit colon tumorigenesis and reduce gene expression of
cancer-related transcription factors in two different murine cancer
models [100]. Similarly, 4E,8Z-d18:2 sphingosine (soy) and 4E,6E-d18:2
sphingosine (insect) were shown to reduce the viability of colon cancer
cells in vitro and in vivo [89] and can downregulate tumorigenic Wnt
signaling [101]. Similar antiproliferative effects of soy-based SDs were
demonstrated in cultured neuroblastoma cells and in a neuroblastoma
xenograft model [102]. Coupled with the demonstration that soy-based
SDs can be absorbed though the gut and enter peripheral circulation
[103,104], these data suggest that dietary plant-based SDs may be
broadly chemopreventive.
SDs have also been shown to exert effects on neural cells. For
example, d18:2 ceramides derived from the edible tuber konjac can
inhibit nerve growth factor-mediated neurite outgrowth via an Sema3A-
dependent mechanism [105]. Interestingly, konjac contains both 4E,8Z-
d18:2 and 4E,8E-d18:2 ceramides. While both confirmations can inhibit
neurite outgrowth, only 4E,8E-d18:2 ceramide can bind Sema3A,
providing evidence for mechanistically distinct functions of different
noncanonical backbones.
3.3. Variations in sphingoid backbone hydroxylation
The third known backbone modification that results in noncanonical
SPs involves the number of hydroxyl moieties. Canonical dihydroxy
d18:1 SPs contain two hydroxyl groups at carbon positions 1 and 3, but
monohydroxy (m18:1) and trihydroxy (t18:0) species are known to exist
in mammals. The most common of these noncanonical variants is
“phytosphingosine” (t18:0), which, although detectable in mammals, is
much more abundant in plants and fungi.
3.3.1. Metabolism of hydroxylation variants of the sphingoid backbone
Although SPT largely uses the amino acid serine as a preferred sub­
strate for condensation with acyl-CoA, it is also able to utilize other
amino acids such as alanine and glycine (Fig. 3), resulting in the rela­
tively inefficient formation of deoxy-SPs [106]. Condensation of L-
alanine with palmitoyl-CoA forms deoxysphinganine (m18:0) and the
condensation of glycine with palmitoyl-CoA forms deoxymethyl­
sphinganine (m17:0) [107]. Deoxysphinganines and deoxymethyl­
sphinganines then serve as substrates for ceramide synthase to form
deoxyceramides and deoxymethylceramides, respectively [108]. It is
suggested that the utilization of alternative amino acids occurs due to a
serine deficiency in the extracellular environment [109,110], leading to
elevated levels of deoxysphingolipids [111,112]. In addition, poly­
morphisms within the SPTLC1 and SPTLC2 subunits of SPT have been
shown to result in substrate promiscuity leading to increased production
of deoxysphingolipids [113–116]. Although it is not clear whether the
small subunits of SPT participate in specificity of the amino acid sub­
strate, it has been reported that, relative to SPTSSA, SPTSSB is a more
efficient activator of a mutant form of SPTLC1 (SPTLC1S331F) that
demonstrates substrate promiscuity [8]. Furthermore, a yeast study
demonstrated that the functional homolog of SPT small subunits (Tsc3),
in addition to activating SPT, also plays an important role in amino acid
selectivity [114] allowing yeast SPT to use alanine as a substrate.
Interestingly, instead of the trans- 4E double bond present in ca­
nonical sphingolipids, 1-deoxysphingosines possess a cis- 14Z double
bond [117], potentially affecting the metabolism and functional activity
of m18:1 SPs relative to that of d18:1 species. As described above, 14Z is
the position and confirmation of the second double bond in the more
abundant d18:2 SD species (see Section 3.2), and it was confirmed that
B.W.S. Lam et al.
Fig. 3. Metabolic pathways producing deoxy-SPs in mammals. The generation of deoxy-SPs is typically rare in mammals, but certain mutations of SPT result in
increased preference for alanine or glycine substrates, resulting in the absence of hydroxylation at carbon position 1. HSAN1, hereditary sensory and autonomic
neuropathy type 1.
this desaturation reaction is catalyzed by the SD-producing enzyme
FADS3 [96]. The absence of 4E-m18:1 SPs suggests that m18:0 SPs
cannot serve as substrates for dihydroceramide desaturase. Due to the
absence of the C1 hydroxyl group, m18:1 SPs also cannot serve as sub­
strates for glucosylceramide synthases or sphingomyelin synthases and
thus cannot be metabolized into higher-order ceramides [107]. Simi­
larly, they cannot serve as substrates for sphingosine kinases to form
S1Ps for their subsequent degradation by S1P lyase [106]. As a result,
these deoxysphingolipids are metabolically stable and accumulate in
tissues as ceramides or free sphingoid bases, lending to their neurotox­
icity (see below).
The metabolic origin of t18:0 phytosphingosine in mammals is less
well characterized and may be obtained primarily through dietary
sources [118]. However, is has been demonstrated that ∆4-sphingolipid
desaturate (DEGS2), the enzyme responsible for introducing the 4E
double bond, is also able to instead hydroxylate the same position [119],
resulting in t18:0–1,3,4-triol phytosphingosine. The relative contribu­
tion of DEGS2 to the accumulation of t18:0 SPs in mammals in unclear.
3.3.2. Known functions of deoxy-SPs
The clearest evidence that deoxy-SPs have functional relevance in
human pathophysiology is their known associations with disease, most
notably, hereditary sensory and autonomic neuropathy type I (HSAN I).
Certain forms of this hereditary syndrome are associated with missense
mutations of SPTLC1 or SPTLC2 resulting in the accumulation of deoxy-
SPs [120]. Persistent elevation of these noncanonical SP species results
in neurotoxicity, resulting in Ca2+ mishandling and neurodegeneration
[121], likely through disruption of mitochondrial function
[111,120,122]. In HSN1 patients, accumulation of deoxy-SPs and
resultant disease severity can be attenuated by dietary supplementation
7
Cellular Signalling 79 (2021) 109890
with L-serine, thus favoring production of canonical d18:1 SPs [109].
Deoxy-SPs may be involved in other, non-hereditary forms of neu­
ropathy. For example, an association between deoxy-SPs and CIPN was
identified in a cohort of 27 breast cancer patients treated with paclitaxel,
where it was found that several species of m18:1 ceramides correlated
positively with the incidence and severity of neuropathy [123]. Mech­
anistically, it was demonstrated that m18:1 ceramides and m18:1
sphingosine were elevated in the dorsal root ganglia (DRGs) of mice
treated with docetaxel in a model for chemotherapy-induced peripheral
neuropathy (CIPN) [124]. The resulting m18:1 sphingosine-induced
neurotoxicity (neurite swelling) could be ameliorated by co-
administration of canonical d18:1 S1P, suggesting that the mechanism
underlying m18:1 SP-induced neurotoxicity may, in part, be the result of
the disruption of S1P receptor signaling. Interestingly, it was shown that
derivatives of deoxy-sphinganine (m18:0 sphingosine) selectively
inhibit SPHK1 [125,126], offering a potential pharmacophore for the
development of SPHK1-targeted drugs. It is likely, therefore, that
disruption of S1P signaling due to accumulation of deoxy-SPs is the
result of the direct inhibition and proteasomal degradation of SPHK1,
leading to local and intracellular depletion of S1P.
Elevated plasma deoxy-SPs are also found to be associated with pa­
tients with type 2 diabetes mellitus (T2DM) but not with T1DM
[127,128]. m18:0 and m18:1 sphingosine improved the predictive value
of blood glucose for incident diabetes, but their predictive power
declined with increasing BMI and was only significant for non-obese
individuals with BMI <30 [127]. It is likely that accumulation of
deoxy-SPs contributes mechanistically to the progression of T2DM since
m18:0 sphingosine has been shown to be cytotoxic to pancreatic β islet
cells and inhibited glucose-stimulated insulin secretion [129]. It is
notable, however, that HSAN1 patients, who present with chronic
B.W.S. Lam et al.
elevation of m18:0 sphingosine, are not characterized by overt T2DM
[130]. This suggests that, although deoxy-SPs probably contribute to
T2DM progression, they are not sufficient for disease onset. Considering
that deoxy-SPs are positively associated with T2DM and are neurotoxic,
it is tempting to speculate whether they play a functional role in the
development of diabetic neuropathy. However, a study of 39 patients
with diabetic distal sensorimotor polyneuropathy showed an expected
increase in plasma m18:1 sphingosine relative to healthy non-diabetic
controls, but this study showed no correlation between deoxy-SP con­
tent and clinical severity of neuropathy [131].
Although the causal relationships between deoxy-SPs and diabetes or
non-hereditary neuropathy are not known, it is worth noting that
metabolic perturbance can favor deoxy-SP production. Specifically,
experimental serine deficiency was shown to induce the elevation of
deoxy-SPs in vitro and in vivo [110], and in humans, plasma deoxy-SP
content correlates negatively with serine concentration [112]. Inter­
estingly, in some cancers, a source of exogenous serine is required to
prevent the endogenous production of cytotoxic deoxy-SPs [132]. One
source of exogenous serine may be sensory neurons innervating the
tumor [133]. It is tempting to speculate, therefore, that depletion of
serine by highly metabolic cancer cells may result in local conditions
that favor neuronal deoxy-SP production, contributing to cancer-related
neuropathy.
3.3.3. Known functions of t18:0 “phyto” SPs
Phyto-SPs are particularly abundant in the skin and are likely to play
significant roles in barrier integrity and skin homeostasis [134]. For
example, treatment of human keratinocytes with t18:0 phytosphingo­
sine has been shown to cause an increase in t18:0 phytoceramides [135].
This is likely to be functionally relevant since it has been shown that
t18:0 phytoceramides are significantly lower in skin lesions associated
with psoriasis [136] and atopic dermatitis [137], and that increasing the
skin content of t18:0 phytoceramides improves the symptoms of atopic
dermatitis [138]. This is likely to be mediated by the production of
natural moisturizing factor, possibly due to the activation of the
filament-associated protein filaggrin [139].
Accumulation of phytoceramides will result in the production of
t18:0 phyto-S1P, therefore, it is likely that many of the effects of phyto-
SPs on the skin are mediated by this signaling molecule. Although its
ability to activate the entire S1P receptor family is assumed, it remains
incompletely characterized. t18:0 phyto-S1P has been shown to bind at
least to both S1P1 and S1P4 [140], and can activate S1P4 with ~50-fold
greater potency compared to S1P [141]. t18:0 phyto-S1P promoted
chemotaxis in murine dermal fibroblasts in pertussis toxin-sensitive
manner, presumably via the activation of either S1P2 or S1P4 [142]. In
human dermal fibroblasts, t18:0 phyto-S1P was shown to increase cell
viability through the regulation of JNK and AKT signaling [143]. Since
these cells express S1P1, S1P2, and S1P3, but not S1P4, the effects of
phyto-t18:0 S1P are presumably mediated via the activation of one or
more of these S1P receptors. Cumulatively, these two studies suggest the
potential importance of S1P2 in t18:0 phyto-S1P signaling, although this
has yet to be confirmed. Interestingly, phyto-t18:0 S1P synergizes
epidermal growth factor (EGF) signaling, and their combined topical use
has been shown to improve moisture content, dermal thickness, and skin
elasticity in a human clinical study [144].
Since these noncanonical SPs are abundant in certain bacteria and
fungi, and appear to be produced only in small quantities by mammalian
cells, it is likely that the skin microbiome is the primary source of
bioactive t18:0 SPs, and that these “postbiotics” are relevant mediators
of the activity of commensal skin microorganisms [145].
Phyto-SPs have been shown to have roles in tissues other than the
skin. For example, t18:0 phyto-S1P promoted survival and maturation of
porcine oocytes in vitro, likely though the SOD3-mediated attenuation of
oxidative stress, and the activation of ERK and AKT survival pathways
[146]. Furthermore, there is evidence that phyto-SPs may be chemo­
protective. t18:0 phyto-sphingosine was shown to inhibit epithelial-
8
Cellular Signalling 79 (2021) 109890
mesenchymal transition in breast cancer cells and reduce cancer stem
cell proliferation in a spheroid assay, likely by binding and antagonizing
EGF receptor [147]. Interestingly, t18:0 phyto-sphingosine was also
shown to inhibit melanin production in human skin cells, presumably
though the inhibition of microphthalmia-associated transcription factor
[148]. Although this study was performed in the context of cosmetic
applications, it suggests that t18:0 phyto-sphingosine may potentially be
protective against melanoma [149].
Although there are no reports implicating t18:0 phyto-SPs as direct
regulators of neurophysiological responses, it is notable that one recent
study found that plasma t18:0 phyto-sphingosine was identified as a
potential biomarker for clinical depression using a bioinformatics
approach [150]. While this does not define a causal relationship, it is
intriguing to speculate whether this may involve gut-brain axis in­
teractions [151].
4. Forward looking statement
Although the marked structural diversity of SPs has been understood
since the mid-20th century, the functional significance of the quantita­
tively minor noncanonical species has only been addressed within the
last 20 years. Variation of the sphingoid backbone will necessarily affect
the biophysical properties of membrane bilayers, but in addition,
emerging data demonstrate that the diversity of backbone structure also
influences cell signaling. Perhaps the clearest example of this is
demonstrated by the differences in receptor selectivities among the S1Ps
[72–74,141], and the fact that these differences affect meaningful
changes in cell behavior [71,72,146]. Moving forward, it is likely that
increasingly sensitive mass spectrometry technologies will allow routine
evaluation of noncanonical SPs, resulting in the identification of new
clinical correlations, and thus, leading to the identification of novel
biological functions. We, the authors, hope that this review helps to
draw attention to the potential roles of noncanonical SPs and that future
studies will place increased emphases on these often-overlooked mo­
lecular mediators.
Acknowledgements
This work was supported by grants from the Ministry of Education,
Singapore (R-181-000-183-114, WYO and DRH), the National Univer­
sity Health System, Singapore (NUHSRO/2019/051/T1/Seed-Mar/04,
WYO and DRH), and the National Medical Research Council, Singapore
(NMRC/CSA-SI/007/2016, CPC, MKPL, and DRH).
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