Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
The importance of post-translational modifications
in systems biology approaches to identify
therapeutic targets in cancer metabolism
Alfonso Martín-Bernabé1,2,3,4,5, Cristina Balcells1,5,
Josep Tarragó-Celada1,5, Carles Foguet1,5,
Sandrine Bourgoin-Voillard2,3,4, Michel Seve2,3,4 and
Marta Cascante1
Abstract
Cancer metabolism is reprogrammed to fulfill the needs of
proliferation and migration, which is accomplished through
different levels of regulation. In recent years, new advances in
protein post-translational modifications (PTMs) research have
revealed a complex layer of regulatory mechanisms through
which PTMs control cell signaling and metabolic pathways,
contributing to the diverse metabolic phenotypes found in
cancer. Despite the efficacy of current modeling approaches
to study cancer metabolism they still lack the capacity to inte-
grate PTMs in their predictions. Here we will review the impor-
tance of PTMs in cancer metabolic reprogramming and
suggest ways in which computational predictions could be
enhanced through the integration of PTMs.
Addresses
1
Department of Biochemistry and Molecular Biomedicine, Universitat
de Barcelona and Institute of Biomedicine of Universitat de Barcelona
(IBUB), Barcelona, Spain
2
Univ. Grenoble Alpes, LBFA et BEeSy, PROMETHEE Proteomic
Platform, Grenoble, France
3
Inserm, U1055, PROMETHEE Proteomic Platform, Grenoble, France
4
CHU de Grenoble, Institut de Biologie et de Pathologie, PROM-
ETHEE Proteomic Platform, Grenoble, France
Corresponding author: Cascante, Marta (martacascante@ub.edu)
Email addresses: alf.martin@gmail.com (A. Martín-Bernabé),
crisgatsu@gmail.com (C. Balcells), jtarragocelada@ub.edu
(J. Tarragó-Celada), cfoguet@ub.edu (C. Foguet),
sandrine.bourgoin@univ-grenoble-alpes.fr (S. Bourgoin-Voillard),
michel.seve@univ-grenoble-alpes.fr (M. Seve)
5
These authors contributed equally to this work.
Current Opinion in Systems Biology 2017, 3:161–169
This review comes from a themed issue on Clinical and translational
systems biology (2017)
Edited by Jesper Tegnér and David Gomez-Cabrero
For a complete overview see the Issue and the Editorial
Available online 19 May 2017
http://dx.doi.org/10.1016/j.coisb.2017.05.011
2452-3100/© 2017 Elsevier Ltd. All rights reserved.
www.sciencedirect.com
Systems Biology
Introduction
Cancer is a complex and heterogeneous disease, which
involves alteration of multiple biological processes.
Some of these alterations are geared towards metabolic
reprogramming, which provides advantages to cancer
cells in terms of energy production and synthesis of
biomolecules and is essential for tumor progression.
Understanding metabolic reprogramming in heteroge-
neous tumor cell populations is key to identify meta-
bolic vulnerabilities in cancer that can be exploited in
therapy [1].
Metabolism is a complex network of biochemical re-
actions that requires a systemic view. Computational
models have emerged as platforms to integrate multi-
omics data (genomics, transcriptomics, proteomics,
metabolomics, etc.), and therefore to understand the
underlying metabolic phenotype. However current
modeling approaches have a limited capacity to inte-
grate modifications that occur at a post-translational
level hence limiting their usefulness at analyzing
cancer metabolic reprogramming.
Here, we review recent studies regarding the role of
post-translational modifications (PTMs) in cancer
metabolic reprogramming, mainly focusing on central
carbon metabolism. In this context, we assess how
computational predictions through genome-scale meta-
bolic models (GSMMs) and kinetic models could be
enhanced through the integration of PTMs.
Metabolic reprogramming in cancer
The most common metabolic adaptation in cancer is the
Warburg effect, consisting of high glucose uptake,
glycolytic activity, and lactate production even under
aerobic conditions [2]. However, metabolic reprogram-
ming is not limited to the Warburg effect and usually
involves the enhancement of other essential metabolic
pathways including pentose phosphate pathway (PPP),
glutaminolysis, and amino acid and lipid metabolisms [3].
Tumor cells display metabolic flexibility, which allows
them to undergo metabolic switches and use different
energy and carbon sources depending on their
Current Opinion in Systems Biology 2017, 3:161–169
162 Clinical and translational systems biology (2017)
availability. Moreover, the metabolic phenotype is
influenced by the interplay between tumor cells and the
surrounding stroma, resulting in distinct metabolic sig-
natures, as an adaptation to a particular microenviron-
ment [4].
Post-translational modifications
Post-translational modifications (PTMs) can directly
regulate metabolic enzymes employing different
mechanisms such as leading to proteineprotein in-
teractions that can result in the formation of multi-
protein complexes, triggering conformational changes
between active and inactive states, causing translocation
to a different cellular compartment or targeting for
degradation. The signal transduction effectors respon-
sible for these modifications, such as kinases/phospha-
tases or acetylases/deacetylases are also regulated at the
same level generating a complex signaling circuitry that
responds quickly to cellular needs or external stimuli
(Figure 1) [5].
Furthermore, metabolites can also alter signal trans-
duction pathways, inducing metabolically sensitive
PTMs, which in turn can modulate the activities of
signaling proteins, metabolic enzymes and transcrip-
tional regulators [6]. This constitutes an important
mechanism by which signal transduction pathways are
modulated through feedback control of multiple types
of metabolite-derived PTMs acting as “nutritional sen-
sors” [7,8].
Recent advances in post-translational
modifications in cancer metabolic
reprogramming
Phosphorylation
Protein phosphorylation is a well-studied regulatory
mechanism of metabolism with an important role in
most cellular processes, and its dysfunction is a major
contributor to cancer. Protein kinases and phosphatases
modulate the capability of a protein to perform its
function in the cellular metabolic and signaling net-
works, by covalently binding or hydrolyzing phosphate
groups from the hydroxyl-containing residues of pro-
teins, serine, tyrosine and threonine. In particular,
different signaling cascades of phosphorylation regulate
central carbon metabolism in a direct manner [9]. For
instance, crosstalk between insulin receptor tyrosine
kinase (IRTK) and PI3K/AKT serine/threonine kinase
pathways regulates insulin-stimulated metabolism.
Insulin-driven glucose uptake is regulated by insulin
receptor substrates IRS1 and IRS2 that rely on PI3K
activation and, besides, glucose transporter GLUT4 is
regulated via AS160 phosphorylation by AKT [10].
Moreover, AKT is also responsible for phosphofructoki-
nase 2 (PFK2) phosphorylation, an enzyme that directly
regulates glycolysis through fructose-2,6-bisphosphate
levels, as found in HeLa cells [11].
Current Opinion in Systems Biology 2017, 3:161–169
In addition to AKT signaling, both AS160 and PFK2 also
receive signaling inputs through phosphorylation by
AMP-activated protein kinase (AMPK). AMPK con-
tributes to achieve a fine-tuned control over the glyco-
lytic rate as a response to low energy levels. On the one
hand, enhancing glucose uptake via AS160 [12] and, on
the other, balancing the glycolysis/gluconeogenesis ratio
by regulating PFK2, promoting energy homeostasis and
survival in lung and breast cancer [13]. Moreover, AMPK
is also an important regulator of lipid metabolism,
targeting acetyl-CoA carboxylase (ACC), responsible for
the synthesis of the lipid precursor malonyl-CoA [14].
Indeed, the interplay between AKT pathway and AMPK
in driving central energy metabolism is complex, as is
their contribution to oncogenic metabolic reprogram-
ming. As described recently for HeLa cells, PI3K/AKT
pathway is also responsible for the regulation of trans-
ketolase (TKT), one important node of the non-
oxidative branch of PPP. AKT directly phosphorylates
TKT, increasing its activity and the carbon flow through
the non-oxidative branch of PPP, thus having a direct
impact on purine synthesis [15].
Another prominent family of kinases with direct impact
on cancer metabolic reprogramming is the pyruvate
dehydrogenase kinase (PDHK) family. Phosphorylation,
and thereby inactivation, of pyruvate dehydrogenase by
PDHKs certainly contributes to maintaining an
increased glycolytic rate by redirecting pyruvate to
lactate production, consequently supporting the
Warburg effect. An increased relative abundance of
phosphorylated pyruvate dehydrogenase (PDH) has
been linked to higher metastatic and proliferative ca-
pabilities in a prostate cancer model of increased and
suppressed metastatic capacity of PC-3 [16].
Another phosphorylation event that promotes the
Warburg effect has been elucidated recently. This new
mechanism involves the enhancement of hexokinases 1
and 2 (HK1/2) activities by tyrosine kinase c-Src phos-
phorylation, thus activating mechanisms that lead to
tumorigenesis and metastasis in different cancer cell
types such as lung, ovarian, breast or colon, among others
(Figure 2A) [17]. Since phosphorylation has such a
profound impact on the regulation of metabolic en-
zymes, the addition of this layer of data is crucial. In this
fashion, some examples are already available in the
literature using phosphoproteomic approaches, focusing
on the signaling pathways mentioned above that exert
control over metabolism [18e20].
Acetylation
Protein lysine acetylation is another well-studied PTM,
which consists on transferring or removing an acetyl
group from acetyl-CoA to an ε-N-lysine. The responsible
enzymes for this PTM are lysine acetyltransferases
(KATs) and lysine deacetylases (KDACs). It was first
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 Post-translational modifications as therapeutic targets in cancer metabolism Martín-Bernabé et al. 163

Figure 1

Simplified diagram of central carbon metabolism depicting some of the metabolic enzymes directly regulated by post-translational modifica-
tions (PTMs) and involved in the cancer metabolic reprogramming. Each metabolic enzyme is regulated by different PTMs: phosphorylation (P),
acetylation (+Ac), deacetylation (−Ac), glycosylation (G), hydroxylation (OH), oxidation (Ox), ubiquitination (+Ub), deubiquitination (−Ub) and SUMOylation
(SU). The modifications are represented in boxes next to the metabolic enzymes of the following pathways: glycolysis/gluconeogenesis (blue), pentose
phosphate pathway (orange), lactate metabolism (purple), TCA cycle (green) and lipid metabolism (yellow). Each box is split in three: left box indicates the
type of PTM, right box indicates the effect on the metabolic enzyme and the responsible effectors are enclosed between them. 6PGD, 6-phosphogluconate
dehydrogenase; ACAT1, acetyl-CoA acetyltransferase 1; ACAT2, acetyl-CoA acetyltransferase 2; ACC1, acetyl-CoA carboxylase 1; ACC2, acetyl-CoA
carboxylase 2; ACLY, ATP citrate lyase; AMPK, AMP-activated protein kinase; c-Src, proto-oncogene tyrosine-protein kinase; CK2, casein kinase 2;
DLAT, dihydrolipoamide S-acetyltransferase; ENO1/2, enolase 1/2; ERK1/2, extracellular signal-regulated kinase 1/2; FASN, fatty acid synthase;
FGFR1, fibroblast growth factor receptor 1; G6PD, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase;
GLUT1, glucose transporter 1; HK1/2, hexokinase 1/2; LDHA, lactate dehydrogenase A; IDH2, isocitrate dehydrogenase 2; KDAC3, histone deacetylase
3; KAT, lysine acetyltransferase; LCAD, long chain fatty acid acyl-CoA dehydrogenase; MDH, malate dehydrogenase; OGDH, 2-oxoglutarate dehydroge-
nase; OGT, O-linked N-acetylglucosamine (GlcNAc) transferase; PCAF, p300/CBP-associated factor; PDH, pyruvate dehydrogenase; PDH3, prolyl hy-
droxylase 3; PEPCK1, phosphoenolpyruvate carboxykinase; PFK1/2, phosphofructokinase1/2; PGAM1, phosphoglycerate mutase 1; PGI,
phosphoglucose isomerase; PIAS3, protein inhibitor of activated STAT (signal transducer and activator of transcription); PI3K/AKT,
phosphatidylinositol-3 kinase, serine/threonine protein kinase; PKA, protein kinase A; PKM2, pyruvate kinase M2; ROS, reactive oxygen species;
SDH, succinate dehydrogenase; SIRT1, sirtuin 1; SIRT2, sirtuin 2; TKT, transketolase; USP13, ubiquitin-specific peptidase 13; USP20, ubiquitin-
specific peptidase 20.

discovered in histones, but it is now known to act on
other proteins, including metabolic enzymes [21]. Since
its discovery, acetylation has been extensively explored,
and new methods to detect and quantify it have been
developed [22,23] and virtually, almost every enzyme
from the central carbon metabolism is susceptible to be
acetylated [24].
Among the most relevant enzymes in cancer meta-
bolism, the case of pyruvate kinase isoform M2 (PKM2)
is widely studied: acetylation at K305 decreases its
enzyme activity and chaperone-mediated degradation
[25] while acetylation at K433 promotes its nuclear
translocation [26]. In both cases, cancer cell prolifera-
tion is favored through glycolytic intermediates accu-
mulation. Another well characterized example of direct
acetylation of an enzyme is LDH isoform A. In contrast
with the previous example, in this case acetylation at K5
impairs tumor growth by inhibiting LDHA enzyme ac-
tivity [27]. Fatty acid synthesis is another important

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164 Clinical and translational systems biology (2017)

Figure 2

Schematic examples of recent post-translational modifications involved in cancer metabolic reprogramming with potential therapeutic
implications. (A) Phosphorylation. Hexokinases (HK1/2) catalyze the rate-limiting step of glycolysis. Zhang et al. found that s-Src promotes glycolytic
flux by phosphorylating and activating HK, which stimulates the Warburg effect, cell proliferation, and metastasis [17]. (B) Acetylation. Cluntun et al.
proved that the glycolytic rate correlates with histone acetylation sites leading to transcriptional activation of glycolytic and TCA enzymes, which in
turn enhances the Warburg effect [29]. This is mediated by the high levels of Acetyl-CoA induced by glycolysis that can be reverted in a caloric restriction
diet, which can be a complement to cancer treatment [33]. (C) Glycosylation. The redirection of glucose from glycolysis through the pentose phosphate
pathway (PPP) provides a growth advantage to tumors. Rao et al. identified a new mechanism by which O-GlcNAcylation of glucose-6-phosphate de-
hydrogenase (G6PD) promotes the PPP, which has clear therapeutic implications [41]. (D) Ubiquitination. ATP citrate lyase (ACLY) and oxoglutarate
dehydrogenase (OGDH) are key metabolic enzymes involved in mitochondrial respiration, glutaminolysis, and fatty acid synthesis. Han et al. found a
positive correlation between up-regulation of ACLY and OGDH and USP13 (ubiquitin specific peptidase 13) overexpression which, is frequently amplified
in human ovarian cancer [48].

pathway for cancer metabolism affected by acetylation:
It has been recently reported that FASN proteasome
degradation is promoted by KAT8 acetylation while
HDAC3 deacetylation prevents FASN degradation,
promoting tumor cell growth by de novo lipogenesis [28].
Protein acetylation is highly sensitive to acetyl-CoA
levels, the substrate for lysine acetyltransferases. A pos-
itive correlation has been found between acetyl-CoA
levels and histone acetylation which results in
increased expression of glycolytic enzymes in HCT-116
colon cancer cells (Figure 2B) [29]. Another effect of
high acetyl-CoA levels is found in glioblastoma cells
where acetylation of a component of the mTORC2
signaling complex, Rictor, occurs in a glucose-dependent
manner. This allows cells to proliferate even under the
inhibition of the epidermal growth factor receptor VIII
(EGFRVIII) unveiling a new mechanism for targeted
therapy resistance [30].
However, the levels of acetyl-CoA are not only depen-
dent on glycolysis but also on synthesis from acetate or
fatty acid and amino acid catabolism. In certain cancers,
where cells that are usually glucose-deprived or suffer
from acidosis, fatty acids and acetate constitute signifi-
cant energetic substrates [31]. In this context, mito-
chondrial proteins such as components of the respiratory
complex I are down-regulated by hyperacetylation,
while histones in the nucleus are deacetylated to
maintain high acetate levels [32]. Additionally, reduced

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 Post-translational modifications as therapeutic targets in cancer metabolism Martín-Bernabé et al.
acetylation associated with low acetyl-CoA levels has
been shown to drive autophagy, evidencing caloric re-
striction as a potential complement to cancer therapy
[33]. Therefore, it is clear that acetylation links nutrient
status with gene expression and metabolic regulation.
Lysine deacetylases are also possible targets for cancer
treatment. The inhibitors of lysine deacetylases have
been broadly studied, and some of them are even clin-
ically approved. In HeLa and A549 cells, one of the ef-
fects of these inhibitors is the acetylation of
mitochondrial proteins [34,35]. It is also observed that
ketogenic diets maintain high acetylation levels due to
the inhibitory effect of beta-hydroxybutyrate to lysine
deacetylases [36].
Glycosylation
Protein glycosylation is another widespread PTM, which
involves the addition of glycans to proteins. This
modification is mostly associated with membrane pro-
teins but also occurs at intracellular level. It is now well
established that protein glycosylation modulates tumor
growth and malignant transformation and glycans might
play a role in every well-recognized cancer hallmark
[37]. Among the various forms of protein glycosylations,
intracellular O-GlcNAcylation (O-GlcNAc), which is
abundant in proteins involved in cell signaling, stress
responses and energy metabolism, plays a relevant role
in cancer development by regulating signaling pathways
[38]. In addition, O-GlcNAc glycosylation and expres-
sion of O-GlcNAc-cycling enzymes have also been
widely described as being dysregulated in many types of
cancer, activating multiple transcription factors and key
metabolic enzymes [39]. In lung cancer, for example,
the O-GlcNAcylations of PFK1 and glucose-6-
phosphate dehydrogenase (G6PD), enzymes catalyzing
rate-limiting steps in glycolysis and PPP, respectively,
are dynamically controlled in response to different
cellular conditions including hypoxia and nutrient
levels. The inhibition of PFK1 and activation of G6PD
by O-GlcNAc control directly the flux of PPP which may
represent a potential therapeutic target in cancer
(Figure 2C) [40,41].
Other protein post-translational modifications
Metabolic enzymes are also regulated through other
PTMs such as hydroxylation, which is the transfer of
hydroxyl groups to proline or lysine residues. Hydrox-
ylation of proline, mostly catalyzed by prolyl hydroxylase
domain (PHD) enzymes, has a prominent role in cancer
[42]. For instance, the metabolic adaptation of cancer
cells to hypoxia is predominantly executed through the
activation of the hypoxia-induced factor-1 (HIF-1)
pathway, which is degraded and inactivated in the
presence of oxygen through hydroxylation. In hypoxia,
HIF-1 activity enhances glycolysis through the up-
regulation of almost all glycolytic genes and glucose
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165
and lactate transporters. Besides the post-translational
regulation of HIF-1, PKM2 and PDH and, more
recently acetyl-CoA carboxylase 2 (ACC2) have also
been found to be susceptible to hydroxylation [43e45].
Certainly, due to the high importance of hypoxia and
ROS in cancer metabolism, hydroxylation will probably
attract more attention in the future.
Ubiquitination and SUMOylation are also worth
mentioning, since they are important regulators of pro-
tein function and fate. They involve the attachment of
the polypeptides ubiquitin or SUMO (small ubiquitin-
like modifier) to lysine residues. In the context of
cancer, increasing evidence has linked dysregulation of
these two PTMs with cancer development and meta-
bolic reprogramming [46e48]. There is a recent example
where Parkin, a ubiquitin E3 ligase, has an important role
in cancer metabolism by inhibiting glycolysis through
ubiquitination of PKM2 and therefore, suppressing
tumor growth [49]. Another example is given by the
upregulation of ATP citrate lyase (ACLY) and oxogluta-
rate dehydrogenase (OGDH), which control mitochon-
drial function, lipid metabolism, and glutaminolysis. In
this case, the event responsible of the metabolic rewiring
is the overexpression of the ubiquitin-specific peptidase
13 (USP13), a deubiquitination enzyme activating both
metabolic enzymes, thereby conferring a tumor growth
advantage (Figure 2D) [48]. Additionally, the nuclear
receptor Nur77 has been shown to activate gluconeo-
genesis through an attenuation of the SUMOylation of
phosphoenolpyruvate carboxykinase 1 (PEPCK1) in he-
patocellular carcinoma [50].
However, the scope of PTMs is rapidly expanding with
the identification of new PTMs, and this is the case of
protein lysine acylations such as malonylation, succiny-
lation, and glutarylation. They are believed to modify
metabolic enzymes using intermediates of energy
metabolism, but their roles in the regulation of cellular
metabolism remain largely unknown [51e55].
Finally, it is important to mention that PTMs are rarely
single independent events and they likely occur in a
coordinated manner through various and abundant
PTMs crosstalks, but this will not be discussed here.
PTMs in metabolic modeling
PTMs in genome-scale metabolic models
GSMMs are mathematical representations of the entire
metabolic reaction complement encoded by an organ-
ism’s genome. An essential part of GSMMs is the Gene
Protein Reaction (GPR) associations, a set of rules that
define the gene products needed to catalyze each of the
reactions included in the model. The GPR rules allow
GSMMs to serve as platforms where transcriptomics and
proteomics can be integrated to construct condition-
specific metabolic models. There are several algorithms
Current Opinion in Systems Biology 2017, 3:161–169
166 Clinical and translational systems biology (2017)

capable of integrating these omics data, but mostly, they
are all based on the assumption that a reaction catalyzed
by a highly expressed enzyme is most likely to be active
than a reaction catalyzed by a lowly expressed one [56].
These algorithms have been extensively used to
generate cancer-specific metabolic reconstructions with
the goal of identifying vulnerabilities that can be
exploited in therapy [57,58].
However, PTMs are one of the major limitations of the
current generation of algorithms as highly expressed
enzymes can be inactivated due to PTMs, which may
lead to errors on the resulting metabolic reconstructions.
Therefore, a major challenge in the coming years will be
to overcome this limitation and improve their predictive
capacity through the integration of PTM measure-
ments. To achieve this, GSMMs will firstly need to be
expanded to include annotations about PTMs. Such
annotation should provide the following information: 1)
which residues of a given enzyme can be modified, 2)
the specific PTMs that are possible at each residue and
3) a set of rules capable of predicting the likely effect of
possible combinations of PTMs on enzyme activity.
Secondly, we must develop a new generation of algo-
rithms capable of predicting flux distributions using not
only transcriptomic or proteomic data but also the
relative abundances of the modified and unmodified
forms for each enzyme (Figure 3). As not all PTMs
might be characterized in a given study and some PTMs
might be undetectable (e.g. due to low abundance or
short half-life), such algorithm should be robust enough
to deal with incomplete PTM experimental data.
PTMs in kinetic modeling
Kinetic modeling is based on using a system of ordinary
differential equations to predict the evolution of a

Figure 3

Example of condition-specific reconstructions performed with a current and a hypothetical next generation algorithms. Consider three metabolic pathways
(P1, P2, and P3) in which a set of enzymes (E1, E2, …, E9) catalyze the conversion of a series of metabolites (M1, M2, …, M8). Additionally, assume that
E7 can be completely inhibited by a PTM. Furthermore, consider that the heatmap summarizes gene expression evidence of the enzymes in the system
(green = lowly expressed, red = highly expressed) and the relative abundance of E7 post-translationally modified (red = 100% abundance compared to
the total E7). A current generation algorithm would only be able to integrate gene expression data and might predict that P1 is inactive (as its reactions are
catalyzed by lowly expressed enzymes) and that pathway P2 and P3 can be active. A hypothetical next generation algorithm would also integrate gene
expression, but would also be able to integrate PTM data (E7-PTM) predicting that P3 is inactive as E7 is inactivated by PTMs. Should production of M8
be necessary for cell proliferation/survival, the reliance on P2 to produce M8 would be a vulnerability that could be exploited in cancer therapy.

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 Post-translational modifications as therapeutic targets in cancer metabolism Martín-Bernabé et al. 167

metabolic network in time. A key part of kinetic Conclusions

modeling is kinetic laws, mathematical representations
of the kinetic properties of enzymes in the network (i.e.
substrate affinity, maximal velocity, cooperativity, etc.).
Consequently, the effect of a PTM that alters the ki-
netic properties of an enzyme can be modeled by using
different kinetic laws for the modified and unmodified
enzymes. Then, the apparent kinetic law of the enzyme
can be formulated as the linear combination of kinetic
laws using the fraction of modified and unmodified
enzyme as coefficients (Figure 4). This approach was
successfully used by König et al. [59] to build a kinetic
model of hepatic metabolism with hormonal control
represented as changes in the phosphorylation state of
key enzymes.
The main challenge to simulating PTMs in kinetic
models is that the effect of PTMs on kinetic properties
has only been characterized on a very small subset of
enzymes.
Nevertheless, the development of genome-scale kinetic
models [60,61] is sparking a renewed interest in kinetic
modeling, and it is likely that we will see the kinetic
characterization of many PTMs in the coming years.
Oncogenic activation alters post-translational signaling
cascades that contribute, together with changes in
transcription and epigenetics, to a complete reprog-
ramming of metabolism. However, limited information
is available on post-translational events and their precise
contribution to metabolic reprogramming.
Understanding the roles of the diverse PTMs governing
cancer metabolism is still challenging due to the com-
plex and heterogeneous nature of tumors. Thus, further
research and PTM data integration are necessary to
develop more accurate modeling strategies, which may
offer new approaches to target cancer metabolism. In
the horizon, a high-throughput characterization of
PTMs and its integration in genome-scale modeling
approaches is likely to help to identify novel personal-
ized diagnostic and therapeutic applications.
Acknowledgements
This work was supported by grants to M.C. from the “Agència de Gestió
d’Ajuts Universitaris i de Recerca (AGAUR)” e Generalitat de Catalunya,
(2014SGR1017), ICREA Foundation (ICREA Acadèmia 2015), the
“Ministerio de Economı́a y Competitividad” from the Spanish Government
and FEDER funds from the European Union “una manera de hacer
Europa” (SAF2014-56059-R, SAF2015-70270-REDT). A.M.B. acknowl-
edges the “Ministère de l’Enseignement supérieur et de la Recherche”
from the French Government. C.B. acknowledges the AGAUR. J.T.C. ac-
knowledges the “Ministerio de Educación, Cultura y Deporte”. C.F. ac-
knowledges “La Caixa” Foundation.

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