Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101756


Historical Background

The mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) catalyzes the cataplerotic reaction utilizing mitochondrial GTP (mtGTP) to convert oxaloacetate to phosphoenolpyruvate (PEP), GDP, and CO2 in the mitochondrial matrix. Because of its dependence on mtGTP and since mitochondria lack a GTP transporter, mitochondrial PEP synthesis is enzymatically coupled to the GTP-specific isoform of succinyl-CoA synthetase reaction as a source of GTP. In pancreatic beta-cells, this reaction generates a second messenger coupled to insulin secretion (Stark et al. 2009). In the liver and possibly kidney, the mitochondrial PEP is used for gluconeogenesis and glyceroneogenesis (Stark et al. 2014). This chapter will focus on the mammalian mitochondrial isoform and its relationship to maintaining metabolic homeostasis through the secretion of insulin, the production of glucose, and maintenance of mitochondrial pool size. Where appropriate, PEPCK-M will be contrasted with the more widely characterized PEPCK-C.

Phosphoenolpyruvate is the highest energy phosphorylated metabolite in cell. The hydrolysis of phosphoenolpyruvate by pyruvate kinase to generate pyruvate releases the standard free energy equivalent to approximately two ATPs. This highly exergonic reaction strongly drives glycolysis toward pyruvate. This is the energetic barrier that cells or tissue must overcome in order to regenerate PEP from pyruvate in instances where gluconeogenesis and glyceroneogenesis are important. Two separate reactions are required to regenerate PEP from pyruvate. The first is an ATP consuming pyruvate carboxylase (PC) reaction that converts pyruvate into oxaloacetic acid. The second is the phosphoenolpyruvate carboxykinase (PEPCK) reaction that consumes GTP to convert oxaloacetate into PEP.

While the PC reaction is restricted to the mitochondrial matrix, the PEPCK reaction is catalyzed by a mitochondrial- or a cytosol-specific isoform of PEPCK referred to as PEPCK-M and PEPCK-C, respectively. Because of the high degree of transcriptional responsivity of PEPCK-C to insulin and glucagon, it garnered much of the initial attention. Consequently, the term PEPCK has improperly been used to refer to only the PEPCK-C isoform with a high frequency. The discovery the role of the mitochondrial isoform as an important component of the glucose sensing mechanism in pancreatic beta-cells has opened the door increasingly to the recognition of PEPCK-M’s important role in maintaining metabolic homeostasis (Stark et al. 2009).

The PEPCK-M Gene

The Evolution of the PEPCK Gene

PEPCK as an enzyme is shared across archea, bacteria, and eukaryotes. There are GTP- and ATP-specific isoforms which may have developed separately from a less nucleotide discriminating ancestor as suggested by the presence of both forms in different eukaryotic branches not sharing a clear phylogenetic relationship with each other (Aich and Delbaere 2007). Primarily, the ATP-specific isoforms can be found in bacteria and simpler eukaryotes such as fungi and plants, while the GTP-utilizing isoform was adopted and maintained in higher eukaryotes (Watt et al. 2013). Both human genes have a prokaryotic origin suggesting a primordial mitochondria-like existence prior to duplicating into an isoform that “escapes” to the cytosolic compartment. Divergence into subcellular compartment-specific isoforms can ancestrally be traced back as far as fish. It is fitting, then, that the first evidence for the carboxylation activity hinting at the presence of PEPCK was first described in chicken liver where only the mitochondrial isoform is expressed (Hebda and Nowak 1982). The reaction was originally discovered and described as the Wood-Werkman pathway in fermentive bacteria (Wood and Werkman 1938). Here, radioactive carbon dioxide that was incorporated into glycerol was then detected by the isotopic incorporation into succinate in what is now considered as the reverse reaction. The first published description of the decarboxylation reaction of OAA to PEP was in 1953 by Utter and Kurahashi, though ATP and ITP (and not GTP) were used as the energetic substrate (Utter and Kurahashi 1954). The oxaloacetate carboxylase activity was later renamed as phosphoenolpyruvate carboxykinase or PEPCK as it is commonly referred to today.

Organization of PCK2, the PEPCK-M Gene

There are two separate genes found on different nuclear chromosomes that encode for the two PEPCK isoforms. PEPCK-M is encoded by the PCK2 gene and is found on human chromosome 14q11.2 (PCK1 is on chromosome 20) (Beale et al. 2007). Both PCK1 and PCK2 in humans have a similar organization with ten exons and nine introns. The first exon of PCK2 contains a mitochondrial targeting sequence that is removed once the protein enters the matrix. In contrast to the conserved coding sequence, the intronic size for PCK2 is much larger than that of PCK1 and also contains multiple Alu sequences unlike PCK1 (Beale et al. 1985; Modaressi et al. 1998). The gene spans about 10 kb with the largest intron about 2.5 kb. The promoter contains multiple glucocorticoid-binding elements as well as sites for SREBP, CREB, AP-1, AP-2, SRY C/EBPbeta, HNF1alpha, ATF/CRE elements, and others (Suzuki et al. 2004). The two genes encode proteins of similar molecular weight (70 kDa) with PEPCK-M having 640 amino acids and PEPCK-C having 622 (Hanson and Patel 1994). Given that they share a common ancestor, it is not surprising that the DNA sequences share high identity (68%) and homology (82%). Human PEPCK-M also shares ∼90% similarity with the mouse ortholog.

PEPCK-M mRNA Transcription

The striking difference in the transcriptional regulation of the PEPCK isoforms is in part responsible for much of the early attention focused on the cytosolic form at the expense of the other. This is because PEPCK-M message does not share the prominent and dramatic acute stimulation by glucagon and suppression by insulin (Modaressi et al. 1998; Hanson and Patel 1994). Given that the half-life of PEPCK-M mRNA (∼50 h) is much longer than for PEPCK-C (∼30 min), to the extent that activity is driven by mRNA transcription, the two genes are likely respond to different types of stimuli. Both isoforms had been known to be transcriptionally responsive in the mammary gland during the transition to lactation – a period where a greater supply of carbohydrate is needed to support milk production. In this setting, PEPCK-M is much more responsive than PEPCK-C as may be fitting given the prolonged duration of lactation (Jones et al. 1989; Agca et al. 2002). The first evidence of a potential pathophysiological role of excessive PEPCK-M expression was first observed in the chronically glucose-infused rat (Jamison et al. 2011). In this model of type-2 diabetes, progression to hyperglycemia was a consequence of increased endogenous glucose production (EGP). In contrast to PEPCK-C that was suppressed at both the mRNA and protein level, PEPCK-M expression increased and correlated with rates of EGP during the development and resolution of the diabetes. In other studies of obese humans, excessive EGP did not correlate with hepatic mRNA, protein, and activities of either PEPCK isoform making the interpretation of the role of PEPCK much less clear (Samuel et al. 2009).

ID Tissue- and Species-Specific Expression

There is a great deal of diversity of PEPCK isoform expression across different tissues in many species. This has been examined mostly in gluconeogenic tissues such as the liver and kidney. Humans express PEPCK-M in most tissues (those containing mitochondria) but especially in the liver and kidney (Modaressi et al. 1998). Chicken liver has only PEPCK-M and notably guinea pig liver and kidney favor PEPCK-M as the primary activity. Despite the fact that there are equal amounts of the mitochondrial and cytosolic isoforms in human liver, the field has been biased against PEPCK-M because popular rodent models apparently have lower PEPCK-M expression. This discrepancy has been chronicled elsewhere recently and may be explained in part as a consequence of the experimental conditions that favor PEPCK-C over PEPCK-M (Stark et al. 2009, 2014; Stark and Kibbey 2014). Initially there was a controversy whether PEPCK-M was expressed in pancreatic islets with initial reports documenting its presence while subsequent reports disputing it (Hedeskov and Capito 1980; Hedeskov et al. 1984; MacDonald and Chang 1985; MacDonald et al. 1992). The conflict was resolved when it was noted that islets do not contain PEPCK-C and only the cytosol fraction had been assessed (Stark et al. 2009).

The PEPCK-M Protein

Structure and Domain Organization

Most enzymes in central carbon metabolism are homo- or heteroligomers. The PEPCK protein is an exception to this rule and is only known to be formed of a single monomeric subunit consisting of a single functional domain. The 70 kDa protein has a highly conserved complex alpha-beta fold with N- and C-terminal lobes and a P-loop (Chen et al. 1991; Dunten et al. 2002). The two half reactions (decarboxylation and phosphoryl transfer) occur in an active site that has been reasonably conserved even when compared to the ATP-dependent bacteria, yeast, and plant isoforms (Carlson and Holyoak 2009). The active site is built around a critical reactive cysteine and utilizes Mn++ whose coordination state changes throughout the catalytic process and is sensitive to pH, oxidation state, and metal binding. Mg-GTP-binding coordinates a second divalent metal required for catalysis. The reaction requires first a retro-aldol-like mechanism to decarboxylate oxaloacetate and stabilize the enolate tautomer of pyruvate, followed by phosphate transfer from the GTP:
$$ \begin{array}{lll}& 1 \mathrm{st}\ \mathrm{half}\ \mathrm{reaction}:\mathrm{Oxaloacetate}\to \mathrm{Pyruvate}\left(\mathrm{enol}\right)\ \mathrm{ion}+{\mathrm{CO}}_2\hfill \\ & {}2\mathrm{nd}\ \mathrm{half}\ \mathrm{reaction}:\mathrm{Net}\ \mathrm{reaction}:\frac{\mathrm{Pyruvate}\left(\mathrm{enol}\right)\ \mathrm{ion}+\mathrm{GTP}\to \mathrm{PEP}+\mathrm{GDP}}{\mathrm{Oxaloacetate}+\mathrm{GTP}\to \mathrm{PEP}+\mathrm{GDP}+{\mathrm{CO}}_2}\hfill \end{array}$$

Both PEPCK isoforms share similar kinetic properties that favor the reaction toward PEP formation catalyzed by GTP. ITP can also donate a phosphate but has a Km for PEPCK an order of magnitude higher than for GTP. (Hanson and Patel 1994; Dunten et al. 2002). Substrate binding is not ordered, but once GTP is bound, the reaction proceeds to PEP formation.

Regulation of PEPCK-M Activity

PEPCK-C is often described as the classic example of a transcriptionally regulated enzyme, while PEPCK-M is often considered constitutively expressed. The lack of correlation between expression of the gene product and its contribution to gluconeogenesis in vivo suggests that the regulation of both isoforms is too complicated to be described by transcriptional explanations alone (Samuel et al. 2009; Burgess et al. 2007). Regulatory posttranslational modifications have only been described for PEPCK-C where acetylation targets the enzyme for ubiquitin-mediated proteasomal degradation (Lin et al. 2009; Jiang et al. 2011; Xiong et al. 2011). To date, no functional posttranslational modifications of PEPCK-M have been identified. The concentration of GTP and OAA in the mitochondrial matrix are not clearly identified, so it is unclear whether either or both are rate limiting under physiologic situations (Ishihara and Kikuchi 1968). Nevertheless, lacking (1) strong transcriptional regulation, (2) posttranslational modifications, or (3) even evidence of cooperative, allosteric, or orthosteric regulation suggests that PEPCK-M may be solely responsive to the concentration of substrate, product, and cofactors. Consequently, PEPCK-M may be at the mercy of substrate supply and thus only secondarily subject to insulin, glucagon, catecholamines, and cortisol-mediated effects.

Functional Roles of PEPCK-M

Equilibrioceptive Relationship with Mitochondrial GTP

Given the central metabolic importance of this reaction, PEPCK-M is surprisingly devoid of clear evidence of canonical regulation with a susceptibility to substrate concentration. Therefore, in addition to its synthetic role, PEPCK-M has been proposed to have an additional nutrient “sensing” role. This becomes more apparent when considered in terms of its relationship with mtGTP. GTP has a well-established signaling role in the cytosol as a molecular switch controlling a wide variety of cytosolic signaling events. mtGTP is similarly well poised to signal in the mitochondrial matrix (Stark et al. 2009, 2014; Stark and Kibbey 2014; Kibbey et al. 2007) with several parallels to heterotrimeric G-protein signals (Figs. 1 and 2). The mtGTP cycle is coupled to the synthesis and hydrolysis of GTP requiring the involvement of three different enzymes (Fig. 2). The cycle begins with mtGTP synthesis via succinyl-CoA synthetase (SCS-GTP) at a rate proportional to the speed of the TCA cycle. Human mitochondria lack a GTP transporter so mtGTP is trapped within the mitochondrial compartment (McKee et al. 1999, 2000; Vozza et al. 2004). Since there are two isoforms of SCS in mitochondria (one ADP-specific and one GDP-specific), their relative ratio determines the “gain” on the signal. PEPCK-M consumes mtGTP to complete the cycle to make PEP and regenerate GDP. Since “stealing” OAA from citrate synthase (CS) would shut down the TCA cycle, an additional (termed “anaplerotic”) source of OAA is required for PEP synthesis. Balance is achieved at least in part by pyruvate carboxylase (PC), an enzyme with high flux in both the liver and beta-cells that refills the TCA cycle with this anaplerotic OAA. Once made by PEPCK-M, there are no known enzymes to degrade PEP in the mitochondria, but it is rapidly transported to the cytosol (unlike GTP).
PEPCK-M, Fig. 1

The cataplerotic role of PEPCK-M. The dependence of PEPCK-M on mitochondrial GTP (mtGTP) production constrains PEP synthesis to the TCA cycle rate via the enzyme SCS-GTP. Here it integrates the anaplerotic entry of carbon by pyruvate carboxylase (PC) or glutamate dehydrogenase (GDH) through feedforward and feedback mechanisms

PEPCK-M, Fig. 2

Anaplerotic triad formation by pyruvate carboxylase, SCS-GTP, and PEPCK-M. These three mitochondrial proteins are functionally coupled by the sequential sharing of metabolites and products that links the synthesis of PEP to mtGTP levels

Sensing and Balancing Mitochondrial Metabolites

If the TCA cycle turns in the presence of ample AcCoA, it can run indefinitely as long as there are no gains or losses of TCA intermediates. Oxidative tissues (e.g., neurons or muscle) burn AcCoA to generate ATP requiring only limited OAA replenishment. This is because with each addition of AcCoA to OAA to form citrate, a new OAA is generated to accept the next round of AcCoA. But what about tissues with “leaky” mitochondria that consume other substrates (e.g., amino acids, propionate) or export TCA intermediates (e.g., malate, alphaketoglutarate (aKG), 5-aminolevulinate, etc.) for processes such as glucose, glycerol, amino acid, or heme synthesis? If export and import are out of balance, then either a metabolic traffic jam develops (clogged by allosteric or product inhibition) or, if OAA is fully depleted, the CS reaction shuts down altogether. There is, however, an intrinsic mechanism to balance the scales of anaplerosis with cataplerosis (Fig. 3). mtGTP is a metabolic switch that allosterically inhibits GDH to prevent excessive glutamate deamination (Allen et al. 2004). Increased synthesis of mtGTP by the TCA cycle enzyme SCS-GTP will proportionately increase mtGTP that feedback restricts GDH activity. Such a metabolic feedback loop prevents inappropriate amino acid catabolism when SCS flux is sufficient (Stark and Kibbey 2014). In contrast, mtGTP accumulation signals that there are too many TCA intermediates and converts OAA into PEP via PEPCK-M to drain the excess. Or simply, if mtGTP is low, GDH is activated in order to anaplerotically fill the TCA cycle. As aKG accumulates and generates more succinate, then mtGTP levels also rise and inhibit GDH. High mtGTP levels, in contrast, identify a “full” TCA cycle pool. Diverting OAA into PEP synthesis by PEPCK-M drains the pool while lowering mtGTP. Thus, PEPCK-M acts as a mtGTP-dependent sieve that catapleroses oxaloacetate out of the mitochondria to shrink the mitochondrial metabolic pool size.
PEPCK-M, Fig. 3

Equilibrioceptive PEPCK-M metabolism. PEPCK-M balances the mitochondrial pool size of OAA by exporting it in a GTP-dependent manner. In this way, anaplerosis is balanced by PEPCK-M mediated cataplerosis to prevent depletion or accumulation of TCA cycle intermediates

PEPCK-M and Insulin Secretion

The first physiologic role of PEPCK-M was identified as a metabolic coupling factor important for glucose-stimulated insulin secretion (Stark et al. 2009). ATP synthesis had been the classical explanation to link glucose metabolism and insulin secretion in pancreatic beta-cells. However, many arguments against mitochondrial ATP synthesis as the only signal have been raised, such as that observation that islets lacking KATP channels still exhibit glucose-stimulated insulin secretion coupled to cytosolic calcium oscillations. The search for other metabolic coupling factors identified a correlation between anaplerosis and insulin secretion without a clear mechanism. In parallel an important relationship between mtGTP production and insulin secretion was identified (Kibbey et al. 2007) but again without a clear mechanism. Stark et al. examined whether the intersection of anaplerosis with mtGTP synthesis might be mediated through PEPCK-M to generate PEP (Stark et al. 2009). PEPCK-M message, protein, and activity were confirmed in islets, and loss of PEPCK-M impaired insulin secretion. Interestingly, as much of 30 to 40% of glycolytic flux was channeled into mitochondrial PEP synthesis at the expense of ATP production. PEP has a high-energy phosphate with a favorable free energy of hydrolysis (ΔG°′ = −14.8 kcal.mol−1) more than twice that of ATP (ΔG°′ = −7.3 kcal.mol−1). In principle, such a transient, but high-energy, metabolite is ideally suited as an energy-reporting second messenger. Notably, PEP is generated by both glycolysis (by enolase) and cataplerosis (by PEPCK-M) raising the question if such mitochondrial PEP synthesis is used to maintain the cytosolic PEP levels that are coupled to insulin secretion.

PEPCK-M and Gluconeogenesis

The PEPCK reaction is required for any mitochondrial metabolite to reenter the glycolytic/gluconeogenic pathway including the substrates lactate, pyruvate, glutamine, propionate, and alanine. Until recently, the PEPCK-C has been studied to the exclusion of PEPCK-M though 40% of the cellular PEP is mitochondrial (Siess et al. 1977). More modern analytical techniques have been applied to assess the mitochondrial metabolites; here matrix PEP was clearly demonstrated as a large and highly metabolic responsive pool (Chen et al. 2016). Even though normal glucose production in adult mice with complete absence of hepatic PEPCK-C was remarkably present in vivo, it was not appreciated until hepatic PEPCK-M was silenced in adult rats that the mitochondrial enzyme contributed to gluconeogenesis (Stark et al. 2014). Here silencing PEPCK-M reduced fasting and fed glucose and lowered insulin but increased plasma lactate. Turnover measurements indicated that glycerol (which doesn’t require hepatic PEPCK-M) was replacing lactate as the gluconeogenic substrate equivalent to about a third of basal glucose production. Because PEP synthesis from lactate is less energetically demanding via PEPCK-M compared to PEPCK-C, it is the most efficient pathway to complete the Cori cycle (Fig. 4). PEPCK-M just requires two enzymes (SCS-GTP and PEPCK-M) and one transporter (CIC) to generate cytosolic PEP from mitochondrial OAA, while PEPCK-C requires four enzymes, electron transport, oxidative phosphorylation, and four transporters at a 40% higher energetic cost. Nonetheless, given PEPCK-M activity is tethered to mtGTP production rate that limits its throughput, PEPCK-C may function to expand cataplerotic capacity especially during exercise and fasting. Thus, PEPCK-M should be considered in studies of gluconeogenesis, especially in humans where its contribution may be even more important.
PEPCK-M, Fig. 4

PEPCK-M vs. PEPCK-C gluconeogenesis energetics. The energetic requirements at each step are energetically represented in terms of the proton motive force required. For instance, ATP synthesis consumes 3 protons by oxidative phosphorylation and ATP transport to the cytosol costs an additional 1 proton

PEPCK-M and Cancer

Cancer cells, like any dividing cell, must generate the raw materials such as amino acids, lipids, and nucleic acids to turn over. Intuitively, the cataplerotic activity of PEPCK-M could provide a rich source of precursor metabolites from metabolites transiting through the mitochondria. PEPCK-M was first correlated to malignant potential in diffuse large B-cell lymphomas where a reevaluation of the mitochondrial contribution to cancer was considered (Caro et al. 2012). Later, PEPCK-M was linked to lung cancer (Leithner et al. 2014) and other tumor cell lines (Mendez-Lucas et al. 2014). With an increasing appreciation for mitochondrial cataplerosis for cancer metabolism, it may be anticipated that both isoforms of PEPCK may play undiscovered but important roles in tumorigenesis and malignant transformation.

PEPCK-M Deficiency

Aside from tissue-specific deletions, there are no published whole-body knockouts of the gene. Initial cases of PEPCK-M deficiency were later identified as being secondary to mitochondrial DNA depletion, and there is no published evidence of a human PEPCK-M deficiency (Leonard et al. 1991). It is unclear whether the absence of defects is related to congenital lethality or rather to compensation by other metabolic pathways (e.g., PEPCK-C).

Summary and Future Considerations

As one of the primordial metabolic genes, the mitochondrial isoform of PEPCK is an important contributor to the synthetic capacity and function of a cell. It is closely related to whole-body glucose homeostasis both by sensing glucose metabolism in the beta-cell through the mitochondrial GTP cycle and through efficient endogenous glucose production in the liver. An essential role, unique to PEPCK-M, is the ability to balance the mitochondrial metabolite pool size by coordinating the consumption of mtGTP with the production of PEP to be exported from the mitochondria. This equilibrioceptive role prevents a potentially disruptive overaccumulation of metabolites within the matrix. Future studies will be required to better delineate the distinct contributions of the mitochondrial vs. cytosolic isoforms as well as the contribution of this mitochondrial pathway to human diseases such as diabetes and cancer.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Departments of Medicine (Endocrinology) and Cellular and Molecular PhysiologyYale School of MedicineNew HavenUSA