© 2021 IJRAR January 2021, Volume 8, Issue 1 www.ijrar.

org (E-ISSN 2348-1269, P- ISSN 2349-5138)

Glycolytic Pyruvate Kinase Isoform PKM2 in

Cancer
Jaspreet Singh* and Balwinder Singh
P.G. Department of Biotechnology, Khalsa College, Amritsar – 143002, Punjab

Abstract :
Pyruvate kinase a glycolytic enzyme that catalyses the dephosphorylation of phosphoenolpyruvate into
pyruvate exists in four isoforms in mammals ie. PKL in the liver, PKR in erythrocytes, PKM1 in somatic cells
and PKM2 in cancer cells. PKM2 has potential to revive cellular homeostatic state to proliferative state,
thereby, converting normal cell to cancerous cell. PKM2 activity is regulated by various metabolites
contributing towards elevated levels of glycolytic intermediates which are to be utilized in anabolic reactions
leading to nucleic acid biosynthesis. Fructose-1,6-bisphosphate and triiodothyronine are allosterically
modulating the activity of PKM2. In cancer cells all other Pyruvate kinase isoforms are replaced by PKM2
which is encoded by alternative splicing of the PKM gene. Cancer cells appreciate PKM2 isoform because of
its uniqueness from the others by providing selective advantage in tumor growth. PKM2 activity supports the
survival of cancer cells under oxidative stress conditions. PKM2 comes out to be a critical player in
reprogramming the cellular metabolism facilitating the cancer cell growth. Understanding the role of this
enzymic isoform can pave the way for an early-stage cancer diagnosis and therapy, lighting a ray of hope to
ailing humanity.

Key words: Cancer, Pyruvate Kinase, PKM gene, PKM2 isoform.

1. INTRODUCTION
An unregulated quickened pace of growth and division of cancer cells is attributed to the altered metabolism
as compared to normal cells (Zhou et al., 2012). The cellular proliferation needs adequate metabolic
intermediates that can ensure the synthesis of cell building components along with sufficient energy (Mazurek,
2011). To carry out anabolic processes, the cancer cells use glucose excessively (Hsu and Sabatini, 2008); and
the consistent switch over to energy production pathways ie. from oxidative to glycolysis, an important
characteristic of cancerous cell metabolism (Kondoh et al., 2007). Hence, aerobic glycolysis appeared as a
hallmark of cancer cell growth (Toschi et al., 2010). Glycolysis generates energy for rapid tumor growth
promoting cancer metastasis (Gao and Chen, 2015). Along with infrequent mitochondrial defects studied in
the cancer cells (Koppenol et al., 2011; Ward & Thompson, 2012), A key glycolytic enzyme pyruvate kinase
isoform M2 (PKM2) that regulate the glycolysis pathway appeared as a component necessary for tumor
growth (Christofk et al., 2008a).

2. GLYCOLYSIS
Glycolysis is a metabolic pathway through which glucose is catabolized to pyruvate producing four
ATPs (Li et al., 2015). Normally, in cells the glycolysis is prioritized only in the limited supply of oxygen.
In the presence of oxygen, pyruvate undergoes the tricarboxylic acid cycle (TCA cycle) in mitochondria
for fully oxidation to CO2 and H2O (oxidative pathway) resulting production of 36 ATP molecules approx.
(Annibaldi and Widmann, 2010). after complete oxidation one glucose molecule produces 38 ATPs. In
tumor cells, the pyruvate oxidation is replaced by lactate production yielding no ATP, rection being
catalyzed by lactate dehydrogenase (LDH); thereby, only two ATPs per glucose are generated (Li et al.,
2015).

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3. PYRUVATE KINASE
Pyruvate kinase (PK) dephosphorylates the phosphoenolpyruvate to pyruvate as a rate-limiting step in
glycolysis (Lyssiotis et al., 2012; Lu, 2012a), releases a significant amount of energy for generation of one
ATP (Mazurek et al., 2002; Dombrauckas et al., 2005). Divalent cations (Mg2+ or Mn2+) are required for PK
activity. An essentially irreversible reaction under normal cellular conditions, is critical to control the central
metabolic flux, as both the substrate Phosphoenolpyruvate and its product pyruvate are involved in various
other metabolic pathways also (Valentini et al., 2000).

Pyruvate kinase
Phosphoenolpyruvate + ADP -------------------→ Pyruvate + ATP

4. PYRUVATE KINASE ISOFORMS

Four PK isoforms of (R, L, M1 and M2) exist in the mammals (Zhou et al., 2012a). Two isoforms Pyruvate
kinase R (PKR) and Pyruvate kinase L (PKL) are products of the common PKL gene but transcribed involving
different promoters (Wu & Le, 2013). PKR is found in erythrocytes whereas PKL is present in organs
performing gluconeogenesis like liver (Chen et al., 2010). Pyruvate kinase M1 (PKM1) is located found in
brain and adult skeletal muscles; while Pyruvate kinase M2 (PKM2) predominates in proliferating cells both
being the alternative splicing products of same PKM gene (Figure 1). Existence of PK isoforms helps
glycolysis to cope with variable metabolic situations in different cells/tissues (Iqbal et al., 2014).

Gene PKL PKM

Isoform PKL PKR PKM1 PKM

Figure 1. Genes and isoforms of pyruvate kinase

5. ISOFORM PKM2
Various factors ie. splicing repressors, polypyrimidine tract binding protein (hnRNPI) as well as
heterogeneous nuclear ribonucleoprotein A1& A2 (hnRNP A1/A2) control the PKM gene splicing and the
expression of repressors is upregulated by oncoprotein (Clower et al., 2010; David et al., 2010). These proteins
repress PKM1 mRNA splicing and contributes towards the increased expression of PKM2 isoform (Chen et
al., 2012). The isoform PKM2 exists in two states 1) a low-active dimeric state or 2) highly active tetrameric
state (Dang, 2009). During tumorigenesis, other isoforms of pyruvate kinase are replaced by PKM2, playing
an essential role in aerobic glycolysis (Oremek et al., 1999). PKM2 also acts like an on/off switch and its
expression in the cancer cells paves way to cellular proliferation. The shift of isoform PKM2 from the dimer
state to tetramer state changes its activity that regulates the speed of celllar proliferation (Wu and Le, 2013).
Cancer cells predominantly express the dimer with low-activity (Hitosugi et al., 2009) but the normal
proliferating cells express the tetramer with high-activity (Mazurek et al., 2005). Slow active dimer drives
glycolysis while the more active tetramer drives the tricarboxylic acid cycle (TCA) (Christofk et al., 2008b;
Vander Heiden et al., 2009). Each subunit in the homotetramer of four identical subunits is composed of 4
domains (Gupta and Bamezai, 2010).

6. PKM2 ACTIVITY
Low activity of PKM2 allowing the smooth operation of glycolysis customarily promotes the cellular
proliferation and help the cancer cells to stockpile metabolites upstream of PEP, thereby, supply sufficient
amounts of metabolites for the synthesis of precursors (Mazurek, 2011). The glycolytic intermediates
produced due to the low activity of PKM2, enters the glycerol biosynthesis and pentose phosphate pathway
(glycolysis branch pathways) generating reducing power NADPH for nucleotide biosynthesis and to suppress
ROS production also (Jiang et al., 2010; Hamanaka and Chandel, 2012).

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7. DIMER/TETRAMER SWITCHING
Homotetrameric isoform PKM2 can form nexus with additional enzymes too and upon convertion of
phosphoenolpyruvate to pyruvate, the lactic acid is formed quickly fulfilling the cellular energy needs
(Mazurek et al., 2001). The shifting of PKM2 from the dimer to tetramer state changes its activity that alters
the ratio of the generated energy to metabolic precursor and thereby, regulate the cellular proliferation pace
(Wu and Le, 2013). A number of factors effect the dimeric/tetrameric switching (Mazurek et al., 2007; Wu et
al., 2008) and fructose-1,6-bisphosphate, serine, tyrosine kinase, oncoproteins, reactive oxygen species (ROS)
are the major ones (Tamada et al., 2012). When PKM2 is in the inactive dimeric state, glucose carbon skeleton
is streamed into biosynthetic processes and hence, are no longer available for energy generation under
glycolysis. That necessitates the demand for an alternative source of energy production (Mazurek et al., 2005).
Consequently, cancer cells utilise glutamine excessively and thereby, proliferate even at diminished glucose
concentrations (Wu and Le, 2013).

8. DOMAIN STRUCTURE
Characterized from a large number of prokaryotic as well as eukaryotic sources, Pyruvate kinase is
considered as an evolutionary conserved enzyme. has been and in most of the cases, it has been found that the
composed of 4 identical subunits, the enzyme usually exist as a homotetramer. With each subunit composed
of 500 - 600 amino acids (approx.) depending upon the enzyme source. PKs from different species show high
degree of structural homology (Wang et al., 2001). As crystal structures of PKs from variable reports show
similar architecture. Each subunit shows 3 domains: A domain - (α/β)8 barrel, B domain - β-stranded
(irregular β-barrel folds) and C domain - (α/β) open-sheet (α+β organization) (Valentini et al., 2000). An
auxillary N-terminal fourth domain in eukaryotic PK, is however, not present in the prokaryotic ones (Jurica
et al., 1998).

9. LIGAND BINDING SITES

PK tetramers comprise three distinct ligand binding sites- (i) active site, (ii) effector site along with (iii)
amino acid binding site and exhibit cooperative binding for the substrate Phosphoenolpyruvate that may
enhance the glycolytic flux in response to Phosphoenolpyruvate concentration (Morgan et al., 2014). Location
wise active site is situated on the C-terminal end of A-domain (α/β)8 barrel, whereas, Fructose-1,6-
bisphosphate binding site is on C-domain (Jurica et al., 1998). Assembling of all four subunits result in a
tetrameric enzyme (Valentini et al., 2000).

10. PK ACTIVITY REGULATION

Two different mechanisms regulating PK activity in mammals are allosteric control and expression control.
In spite of the comparatively small size of catalytic site, the allosteric control is extended over a wide range
of regulatory molecules that involves reciprocal rotations of A- and C-domains within each subunit of tetramer
(Takenaka et al., 1991). The amino acid residues at domain and subunit interfaces function critically in
imparting the allosteric communicative signal from and to the catalytic as well as regulatory sites (Gupta and
Bamezai, 2010). However, the transmission of the allosteric communicative signal between the
Phosphoenolpyruvate and Fructose-1,6-bisphosphate binding sites may be through intra-subunit interface
between both A- and C-domains. (Valentini et al., 2000). Owing to the involvement of a variety of effector
molecules in allosteric response, the enzyme adopts two different conformations: R-state (active form) and T-
state (inactive from) (Wang et al., 2001). R and T forms propose two-state model showing differential
affinities for the ligands (Wooll et al., 2001). Binding of effector molecules trigger the transition between both
R and T-states (ie. Phosphoenolpyruvate homotropically). The multidomain architecture of pyruvate kinase is
instrumental in its regulation and activation that involves both domain and subunit rotations along with active
site geometry alterations. Amino acid residues on domain and subunit interfaces crucially communicate
between activator-binding site and catalytic centre (Valentini et al., 2002). During T-state to R-state transition,
domains of the functional tetramer modify their respective orientation which is coupled to the conformational
swap in the active centre; and that upon transition from R-state to the T-state there occurs a distortion in the
Phosphoenolpyruvate binding site (Valentini et al., 2000). The Phosphoenolpyruvate affinity as well as

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activity of the PKM2 isoform depends upon its quaternary shape and both metabolic intermediates as well as
the oncogenes work in its regulation (Mazurek, 2011).

11. PKM GENE SPLICING

Human PKM gene organisation contains 12 exons as well as 11 introns (Hasan, 2012). Mutually exclusive
alternative splicing of the PKM pre-mRNA results in two isoforms viz. PKM1 and PKM2, reflecting the
insertion of either exon-9 or exon-10 resp. (Yang and Lu, 2013). ie. PKM1 splice variant holds exon-9, while
PKM2 holds exon-10 (Hasan, 2012). Out of 531 amino acids, both PKM1 and PKM2 proteins vary only in 23
amino acids (Noguchi et al., 1986). Both mRNAs are composed of 1593 base pairs and differ from one another
by only 160 nucleotides from site 1143-1303 base pairs that corresponds to a variation of 23 amino acid
residues (Hasan, 2012). These 23 amino acids are concentrated in a stretch of 56 amino acid ranging from
378-434 amino acid residues at the carboxyl end of the PKM2 protein. out of the 56 amino acid long stretch
the 44 residues, that belong to the C-domain of the PKM2 protein participate in the association of the two
dimers to yield a tetrameric state (Dombrauckas et al., 2005).

12. PKM GENE EXPRESSION

Numerous conditions regulate PKM gene expression (Yamada and Noguchi, 1999b) as follows.
a) PKM1 is expressed in tissues/organs demanding high energy ie. brain and skeletal muscles. It possesses the
highest affinity towards substrate phosphoenolpyruvate and is not prone to allosteric regulation or
phosphorylation (Mazurek, 2011).
b) PKM2 is expressed in tissues that involves excessive nucleic acid biosynthesis ie. fetal tissues. Initially,
identified in the hepatoma cell line, its raised levels are recorded in the cancerous cells (Kato et al., 1989;
Obata et al., 1989; Dombrauckas et al., 2005). The promoter sequence of the PKM gene consists of the three
cis-acting regions: region A (-279 to -265), region B (-256 to -242) and region C (-235 to -216), downstream
at -279 to -216 residues (Wang et al., 1994). Additionally, there are 3 GC boxes: Box 1 (-48 to -39), Box 2 (-
86 to -77) and Box 3 (-133 to -124), which reside -133 bp residue from the transcription initiation site (Netzker
et al., 1997). Mutation in either box 1 or 3 results in a 50% reduction in the promoter activity (Yamada and
Noguchi, 1999a).

13. PKM2 EXPRESSION REGULATION

The isoform PKM2 expression is achieved by a multiplex of signalling pathways that operate at different
levels. PKM2 expression is induced by the insulin in adipocytes, by activating PI3K and the MAPK signalling
pathways (Mazurek, 2011). Insulin promotes the PKM2 expression independently of the glucose and the
glucosamine (Asai et al., 2003). In contrary to the PKM2 expression upregulation, the insulin decreases its
activity and thereby, encourage cancer metabolism (Iqbal et al., 2013). As the insulin signalling is implicated
in the cancer (Gallagher and LeRoith, 2011), therefore insulin is an important contributes in cancer metabolism
(Iqbal et al., 2013). Glucose also favours the PKM2 expression in rat hepatoma cells as well as isolated
adipocytes (Schafer et al., 1997). Additionally, hormones viz. Triiodothyronine and Glucocorticoids are also
known to regulate the PKM gene expression (Iqbal et al., 2014). PKM2 expression is also investigated to get
increased in the proliferating thymocytes by interleukin-2 stimulation (Netzker et al., 1992).

14. CONCLUSION
1. PKM2 a critical enzyme which control the speed restricting step of glycolysis and plays a major role not
only in the metabolic reprogramming during cancer but also in the direct synchronization of the gene
expression.
2. Improved expression of the PKM2 results in more glucose uptake and thereby, building up of glycolytic
intermediates helping the cancer cell survival.
3. Receiving the impact of proliferative signals, the PKM2 can split glycolytic products in two lineages-
(i) for energy requirements, (ii) for transformation into precursor for biosynthesis.
4. PKM2 can switch between an active tetrameric state and an inactive dimeric state, serving as a critical
regulator of the Warburg effect and metabolic budget in the tumor cells. In this way, PKM2 plays a dual
role ie. as an on/off switch as well as a pace controller in the cancer metabolism.
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5. PKM2 also serves as a key diagnostic biomarker in the cancer diagnosis. Quantification of the tumor
PKM2 in plasma allows an early tumor detection.
6. PKM2 can be a potential therapeutic target to inhibit the cancer cell proliferation.
7. PKM2 play multiple roles in the cancer and therefore, is a more important in comparison to other
isozymes of pyruvate kinase.

15. FUTURE PROPECTUS

Further studies on cancer metabolism are required to translate Glycolytic Pyruvate Kinase Isoform PKM2
effective therapy.
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