Phosphoenolpyruvate carboxykinase

Last updated
Phosphoenolpyruvate carboxykinase
PBB Protein PCK1 image.jpg
PDB rendering based on 1khb.
Identifiers
SymbolPEPCK
Pfam PF00821
InterPro IPR008209
PROSITE PDOC00421
SCOP2 1khf / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 1khb ​, 1khe ​, 1khf ​, 1khg ​, 1m51 ​, 1nhx ​, 2gmv ​
phosphoenolpyruvate carboxykinase 1 (soluble)
1nhx.jpg
Phosphoenolpyruvate carboxykinase (GTP, cytosolic) monomer, Human
Identifiers
Symbol PCK1
Alt. symbolsPEPCK-C
NCBI gene 5105
HGNC 8724
OMIM 261680
RefSeq NM_002591
Other data
EC number 4.1.1.32
Locus Chr. 20 q13.31
phosphoenolpyruvate carboxykinase 2 (mitochondrial)
Identifiers
Symbol PCK2
Alt. symbolsPEPCK-M, PEPCK2
NCBI gene 5106
HGNC 8725
OMIM 261650
RefSeq NM_001018073
Other data
EC number 4.1.1.32
Locus Chr. 14 q12

Phosphoenolpyruvate carboxykinase (EC 4.1.1.32, PEPCK) is an enzyme in the lyase family used in the metabolic pathway of gluconeogenesis. It converts oxaloacetate into phosphoenolpyruvate and carbon dioxide. [1] [2] [3]

Contents

It is found in two forms, cytosolic and mitochondrial.

Structure

In humans there are two isoforms of PEPCK; a cytosolic form (SwissProt P35558) and a mitochondrial isoform (SwissProt Q16822) which have 63.4% sequence identity. The cytosolic form is important in gluconeogenesis. However, there is a known transport mechanism to move PEP from the mitochondria to the cytosol, using specific membrane transport proteins. [4] [5] [6] [7] [8] PEP transport across the inner mitochondrial membrane involves the mitochondrial tricarboxylate transport protein and to a lesser extent the adenine nucleotide carrier. The possibility of a PEP/pyruvate transporter has also been put forward. [9]

X-ray structures of PEPCK provide insight into the structure and the mechanism of PEPCK enzymatic activity. The mitochondrial isoform of chicken liver PEPCK complexed with Mn2+, Mn2+-phosphoenolpyruvate (PEP), and Mn2+-GDP provides information about its structure and how this enzyme catalyzes reactions. [10] Delbaere et al. (2004) resolved PEPCK in E. coli and found the active site sitting between a C-terminal domain and an N-terminal domain. The active site was observed to be closed upon rotation of these domains. [11]

Phosphoryl groups are transferred during PEPCK action, which is likely facilitated by the eclipsed conformation of the phosphoryl groups when ATP is bound to PEPCK. [11]

Since the eclipsed formation is one that is high in energy, phosphoryl group transfer has a decreased energy of activation, meaning that the groups will transfer more readily. This transfer likely happens via a mechanism similar to SN2 displacement. [11]

In different species

PEPCK gene transcription occurs in many species, and the amino acid sequence of PEPCK is distinct for each species.

For example, its structure and its specificity differ in humans, Escherichia coli ( E. coli ), and the parasite Trypanosoma cruzi . [12]

Mechanism

PEPCKase converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.

As PEPCK acts at the junction between glycolysis and the Krebs cycle, it causes decarboxylation of a C4 molecule, creating a C3 molecule. As the first committed step in gluconeogenesis, PEPCK decarboxylates and phosphorylates oxaloacetate (OAA) for its conversion to PEP, when GTP is present. As a phosphate is transferred, the reaction results in a GDP molecule. [10] When pyruvate kinase – the enzyme that normally catalyzes the reaction that converts PEP to pyruvate – is knocked out in mutants of Bacillus subtilis , PEPCK participates in one of the replacement anaplerotic reactions, working in the reverse direction of its normal function, converting PEP to OAA. [13] Although this reaction is possible, the kinetics are so unfavorable that the mutants grow at a very slow pace or do not grow at all. [13]

Function

Gluconeogenesis

PEPCK-C catalyzes an irreversible step of gluconeogenesis, the process whereby glucose is synthesized. The enzyme has therefore been thought to be essential in glucose homeostasis, as evidenced by laboratory mice that contracted diabetes mellitus type 2 as a result of the overexpression of PEPCK-C. [14]

The role that PEPCK-C plays in gluconeogenesis may be mediated by the citric acid cycle, the activity of which was found to be directly related to PEPCK-C abundance. [15]

PEPCK-C levels alone were not highly correlated with gluconeogenesis in the mouse liver, as previous studies have suggested. [15] While the mouse liver almost exclusively expresses PEPCK-C, humans equally present a mitochondrial isozyme (PEPCK-M). PEPCK-M has gluconeogenic potential per se. [2] Therefore, the role of PEPCK-C and PEPCK-M in gluconeogenesis may be more complex and involve more factors than was previously believed.

Animals

In animals, this is a rate-controlling step of gluconeogenesis, the process by which cells synthesize glucose from metabolic precursors. The blood glucose level is maintained within well-defined limits in part due to precise regulation of PEPCK gene expression. To emphasize the importance of PEPCK in glucose homeostasis, over expression of this enzyme in mice results in symptoms of type II diabetes mellitus, by far the most common form of diabetes in humans. Due to the importance of blood glucose homeostasis, a number of hormones regulate a set of genes (including PEPCK) in the liver that modulate the rate of glucose synthesis.

PEPCK-C is controlled by two different hormonal mechanisms. PEPCK-C activity is increased upon the secretion of both cortisol from the adrenal cortex and glucagon from the alpha cells of the pancreas. Glucagon indirectly elevates the expression of PEPCK-C by increasing the levels of cAMP (via activation of adenylyl cyclase) in the liver which consequently leads to the phosphorylation of S133 on a beta sheet in the CREB protein. CREB then binds upstream of the PEPCK-C gene at CRE (cAMP response element) and induces PEPCK-C transcription. Cortisol on the other hand, when released by the adrenal cortex, passes through the lipid membrane of liver cells (due to its hydrophobic nature it can pass directly through cell membranes) and then binds to a Glucocorticoid Receptor (GR). This receptor dimerizes and the cortisol/GR complex passes into the nucleus where it then binds to the Glucocorticoid Response Element (GRE) region in a similar manner to CREB and produces similar results (synthesis of more PEPCK-C).

Together, cortisol and glucagon can have huge synergistic results, activating the PEPCK-C gene to levels that neither cortisol or glucagon could reach on their own. PEPCK-C is most abundant in the liver, kidney, and adipose tissue. [3]

A collaborative study between the U.S. Environmental Protection Agency (EPA) and the University of New Hampshire investigated the effect of DE-71, a commercial PBDE mixture, on PEPCK enzyme kinetics and determined that in vivo treatment of the environmental pollutant compromises liver glucose and lipid metabolism possibly by activation of the pregnane xenobiotic receptor (PXR), and may influence whole-body insulin sensitivity. [16]

Researchers at Case Western Reserve University have discovered that overexpression of cytosolic PEPCK in skeletal muscle of mice causes them to be more active, more aggressive, and have longer lives than normal mice; see metabolic supermice .

Plants

PEPCK (EC 4.1.1.49) is one of three decarboxylation enzymes used in the inorganic carbon concentrating mechanisms of C4 and CAM plants. The others are NADP-malic enzyme and NAD-malic enzyme. [17] [18] In C4 carbon fixation, carbon dioxide is first fixed by combination with phosphoenolpyruvate to form oxaloacetate in the mesophyll. In PEPCK-type C4 plants the oxaloacetate is then converted to aspartate, which travels to the bundle sheath. In the bundle sheath cells, aspartate is converted back to oxaloacetate. PEPCK decarboxylates the bundle sheath oxaloacetate, releasing carbon dioxide, which is then fixed by the enzyme Rubisco. For each molecule of carbon dioxide produced by PEPCK, a molecule of ATP is consumed.

PEPCK acts in plants that undergo C4 carbon fixation, where its action has been localized to the cytosol, in contrast to mammals, where it has been found that PEPCK works in mitochondria. [19]

Although it is found in many different parts of plants, it has been seen only in specific cell types, including the areas of the phloem. [20]

It has also been discovered that, in cucumber (Cucumis sativus L.), PEPCK levels are increased by multiple effects that are known to decrease the cellular pH of plants, although these effects are specific to the part of the plant. [20]

PEPCK levels rose in roots and stems when the plants were watered with ammonium chloride at a low pH (but not at high pH), or with butyric acid. However, PEPCK levels did not increase in leaves under these conditions.

In leaves, 5% CO2 content in the atmosphere leads to higher PEPCK abundance. [20]

Bacteria

In an effort to explore the role of PEPCK, researchers caused the overexpression of PEPCK in E. coli bacteria via recombinant DNA. [21]

PEPCK of Mycobacterium tuberculosis has been shown to trigger the immune system in mice by increasing cytokine activity. [22]

As a result, it has been found that PEPCK may be an appropriate ingredient in the development of an effective subunit vaccination for tuberculosis. [22]

Clinical significance

Activity in cancer

PEPCK has not been considered in cancer research until recently. It has been shown that in human tumor samples and human cancer cell lines (breast, colon and lung cancer cells) PEPCK-M, and not PEPCK-C, was expressed at enough levels to play a relevant metabolic role. [1] [23] Therefore, PEPCK-M could have a role in cancer cells, especially under nutrient limitation or other stress conditions.

Regulation

In humans

PEPCK-C is enhanced, both in terms of its production and activation, by many factors. Transcription of the PEPCK-C gene is stimulated by glucagon, glucocorticoids, retinoic acid, and adenosine 3',5'-monophosphate (cAMP), while it is inhibited by insulin. [24] Of these factors, insulin, a hormone that is deficient in the case of type 1 diabetes mellitus, is considered dominant, as it inhibits the transcription of many of the stimulatory elements. [24] PEPCK activity is also inhibited by hydrazine sulfate, and the inhibition therefore decreases the rate of gluconeogenesis. [25]

In prolonged acidosis, PEPCK-C is upregulated in renal proximal tubule brush border cells, in order to secrete more NH3 and thus to produce more HCO3−. [26]

The GTP-specific activity of PEPCK is highest when Mn2+ and Mg2+ are available. [21] In addition, hyper-reactive cysteine (C307) is involved in the binding of Mn2+ to the active site. [10]

Plants

As discussed previously, PEPCK abundance increased when plants were watered with low-pH ammonium chloride, though high pH did not have this effect. [20]

Classification

It is classified under EC number 4.1.1. There are three main types, distinguished by the source of the energy to drive the reaction:

Related Research Articles

<span class="mw-page-title-main">Citric acid cycle</span> Interconnected biochemical reactions releasing energy

The citric acid cycle—also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The chemical energy released is available under the form of ATP. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Fructose bisphosphatase deficiency</span> Medical condition

In fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis will still work, as it does not use this enzyme.

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Oxaloacetic acid</span> Organic compound

Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes that occur in animals. It takes part in gluconeogenesis, the urea cycle, the glyoxylate cycle, amino acid synthesis, fatty acid synthesis and the citric acid cycle.

<span class="mw-page-title-main">Mixed inhibition</span>

Mixed inhibition is a type of enzyme inhibition in which the inhibitor may bind to the enzyme whether or not the enzyme has already bound the substrate but has a greater affinity for one state or the other. It is called "mixed" because it can be seen as a conceptual "mixture" of competitive inhibition, in which the inhibitor can only bind the enzyme if the substrate has not already bound, and uncompetitive inhibition, in which the inhibitor can only bind the enzyme if the substrate has already bound. If the ability of the inhibitor to bind the enzyme is exactly the same whether or not the enzyme has already bound the substrate, it is known as a non-competitive inhibitor. Non-competitive inhibition is sometimes thought of as a special case of mixed inhibition.

<span class="mw-page-title-main">Malate dehydrogenase</span> Class of enzymes

Malate dehydrogenase (EC 1.1.1.37) (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate dehydrogenases, which have other EC numbers and catalyze other reactions oxidizing malate, have qualified names like malate dehydrogenase (NADP+).

Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processes that generate energy and (2) anabolic processes where they serve as building blocks for other compounds.

<span class="mw-page-title-main">Pyruvate carboxylase</span> Enzyme

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

<span class="mw-page-title-main">Phosphoenolpyruvic acid</span> Chemical compound

Phosphoenolpyruvate is the carboxylic acid derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found in organisms, and is involved in glycolysis and gluconeogenesis. In plants, it is also involved in the biosynthesis of various aromatic compounds, and in carbon fixation; in bacteria, it is also used as the source of energy for the phosphotransferase system.

<span class="mw-page-title-main">Glyoxylate cycle</span> Series of interconnected biochemical reactions

The glyoxylate cycle, a variation of the tricarboxylic acid cycle, is an anabolic pathway occurring in plants, bacteria, protists, and fungi. The glyoxylate cycle centers on the conversion of acetyl-CoA to succinate for the synthesis of carbohydrates. In microorganisms, the glyoxylate cycle allows cells to use two carbons, such as acetate, to satisfy cellular carbon requirements when simple sugars such as glucose or fructose are not available. The cycle is generally assumed to be absent in animals, with the exception of nematodes at the early stages of embryogenesis. In recent years, however, the detection of malate synthase (MS) and isocitrate lyase (ICL), key enzymes involved in the glyoxylate cycle, in some animal tissue has raised questions regarding the evolutionary relationship of enzymes in bacteria and animals and suggests that animals encode alternative enzymes of the cycle that differ in function from known MS and ICL in non-metazoan species.

<span class="mw-page-title-main">Phosphoenolpyruvate carboxylase</span> Class of enzymes

Phosphoenolpyruvate carboxylase (also known as PEP carboxylase, PEPCase, or PEPC; EC 4.1.1.31, PDB ID: 3ZGE) is an enzyme in the family of carboxy-lyases found in plants and some bacteria that catalyzes the addition of bicarbonate (HCO3−) to phosphoenolpyruvate (PEP) to form the four-carbon compound oxaloacetate and inorganic phosphate:

<span class="mw-page-title-main">Oxaloacetate decarboxylase</span> Enzyme

Oxaloacetate decarboxylase is a carboxy-lyase involved in the conversion of oxaloacetate into pyruvate.

Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP<sup>+</sup>) Enzyme

Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) (EC 1.1.1.40) or NADP-malic enzyme (NADP-ME) is an enzyme that catalyzes the chemical reaction in the presence of a bivalent metal ion:

<span class="mw-page-title-main">PCK1</span> Protein-coding gene in the species Homo sapiens

Phosphoenolpyruvate carboxykinase 1 (soluble), also known as PCK1, is an enzyme which in humans is encoded by the PCK1 gene.

<span class="mw-page-title-main">GOT2</span> Mitochondrial enzyme involved in amino acid metabolism

Aspartate aminotransferase, mitochondrial is an enzyme that in humans is encoded by the GOT2 gene. Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and Kreb's cycle. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the cytosol to the mitochondria. The two enzymes are homodimeric and show close homology. GOT2 has been seen to have a role in cell proliferation, especially in terms of tumor growth.

Pyruvate cycling commonly refers to an intracellular loop of spatial movements and chemical transformations involving pyruvate. Spatial movements occur between mitochondria and cytosol and chemical transformations create various Krebs cycle intermediates. In all variants, pyruvate is imported into the mitochondrion for processing through part of the Krebs cycle. In addition to pyruvate, alpha-ketoglutarate may also be imported. At various points, the intermediate product is exported to the cytosol for additional transformations and then re-imported. Three specific pyruvate cycles are generally considered, each named for the principal molecule exported from the mitochondrion: malate, citrate, and isocitrate. Other variants may exist, such as dissipative or "futile" pyruvate cycles.

Glyceroneogenesis is a metabolic pathway which synthesizes glycerol 3-phosphate from precursors other than glucose. Usually, glycerol 3-phosphate is generated from glucose by glycolysis, in the liquid of the cell's cytoplasm. Glyceroneogenesis is used when the concentrations of glucose in the cytosol are low, and typically uses pyruvate as the precursor, but can also use alanine, glutamine, or any substances from the TCA cycle. The main regulator enzyme for this pathway is an enzyme called phosphoenolpyruvate carboxykinase (PEPC-K), which catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. Glyceroneogenesis is observed mainly in adipose tissue, and in the liver. A significant biochemical pathway regulates cytosolic lipid levels. Intense suppression of glyceroneogenesis may lead to metabolic disorders such as type 2 diabetes.

<span class="mw-page-title-main">PCK2</span> Protein-coding gene in the species Homo sapiens

Phosphoenolpyruvate carboxykinase 2, mitochondrial, is an isozyme of phosphoenolpyruvate carboxykinase that in humans is encoded by the PCK2 gene on chromosome 14. This gene encodes a mitochondrial enzyme that catalyzes the conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) in the presence of guanosine triphosphate (GTP). A cytosolic form of this protein is encoded by a different gene and is the key enzyme of gluconeogenesis in the liver. Alternatively spliced transcript variants have been described.[provided by RefSeq, Apr 2014]

References

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  2. 1 2 Méndez-Lucas A, Duarte JA, Sunny NE, Satapati S, He T, Fu X, et al. (July 2013). "PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis". Journal of Hepatology. 59 (1): 105–13. doi:10.1016/j.jhep.2013.02.020. PMC   3910155 . PMID   23466304.
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  4. ↑ Robinson BH (May 1971). "Transport of phosphoenolpyruvate by the tricarboxylate transporting system in mammalian mitochondria". FEBS Letters. 14 (5): 309–312. doi: 10.1016/0014-5793(71)80287-9 . PMID   11945784. S2CID   9617975.
  5. ↑ Söling HD, Walter U, Sauer H, Kleineke J (December 1971). "Effects of synthetic analogues of phosphoenolpyruvate on muscle and liver pyruvate kinase, muscle enolase, liver phosphoenolpyruvate carboxykinase and on the intra-/extra-mitochondrial tricarboxylic acid carrier transport system". FEBS Letters. 19 (2): 139–143. doi:10.1016/0014-5793(71)80498-2. PMID   11946196. S2CID   40637963.
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  12. ↑ Trapani S, Linss J, Goldenberg S, Fischer H, Craievich AF, Oliva G (November 2001). "Crystal structure of the dimeric phosphoenolpyruvate carboxykinase (PEPCK) from Trypanosoma cruzi at 2 A resolution". Journal of Molecular Biology. 313 (5): 1059–72. doi:10.1006/jmbi.2001.5093. PMID   11700062.
  13. 1 2 Zamboni N, Maaheimo H, Szyperski T, Hohmann HP, Sauer U (October 2004). "The phosphoenolpyruvate carboxykinase also catalyzes C3 carboxylation at the interface of glycolysis and the TCA cycle of Bacillus subtilis". Metabolic Engineering. 6 (4): 277–84. doi:10.1016/j.ymben.2004.03.001. PMID   15491857.
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  16. ↑ Nash JT, Szabo DT, Carey GB (2012). "Polybrominated diphenyl ethers alter hepatic phosphoenolpyruvate carboxykinase enzyme kinetics in male Wistar rats: implications for lipid and glucose metabolism". Journal of Toxicology and Environmental Health. Part A. 76 (2): 142–56. doi:10.1080/15287394.2012.738457. PMID   23294302. S2CID   24458236.
  17. ↑ Kanai R, Edwards, GE (1998). "The Biochemistry of C4 Photosynthesis". In Sage RF, Monson RK (eds.). C4 Plant Biology. Elsevier. pp. 49–87. ISBN   978-0-08-052839-7.{{cite book}}: CS1 maint: multiple names: authors list (link)
  18. ↑ Christopher JT, Holtum J (September 1996). "Patterns of Carbon Partitioning in Leaves of Crassulacean Acid Metabolism Species during Deacidification". Plant Physiology. 112 (1): 393–399. doi:10.1104/pp.112.1.393. PMC   157961 . PMID   12226397.
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  20. 1 2 3 4 Chen ZH, Walker RP, Técsi LI, Lea PJ, Leegood RC (May 2004). "Phosphoenolpyruvate carboxykinase in cucumber plants is increased both by ammonium and by acidification, and is present in the phloem". Planta. 219 (1): 48–58. Bibcode:2004Plant.219...48C. doi:10.1007/s00425-004-1220-y. PMID   14991407. S2CID   23800457.
  21. 1 2 Aich S, Imabayashi F, Delbaere LT (October 2003). "Expression, purification, and characterization of a bacterial GTP-dependent PEP carboxykinase". Protein Expression and Purification. 31 (2): 298–304. doi:10.1016/S1046-5928(03)00189-X. PMID   14550651.
  22. 1 2 Liu K, Ba X, Yu J, Li J, Wei Q, Han G, et al. (August 2006). "The phosphoenolpyruvate carboxykinase of Mycobacterium tuberculosis induces strong cell-mediated immune responses in mice". Molecular and Cellular Biochemistry. 288 (1–2): 65–71. doi:10.1007/s11010-006-9119-5. PMID   16691317. S2CID   36284611.
  23. ↑ Leithner K, Hrzenjak A, Trötzmüller M, Moustafa T, Köfeler HC, Wohlkoenig C, et al. (February 2015). "PCK2 activation mediates an adaptive response to glucose depletion in lung cancer". Oncogene. 34 (8): 1044–50. doi: 10.1038/onc.2014.47 . PMID   24632615. S2CID   11902696.
  24. 1 2 O'Brien RM, Lucas PC, Forest CD, Magnuson MA, Granner DK (August 1990). "Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription". Science. 249 (4968): 533–7. Bibcode:1990Sci...249..533O. doi:10.1126/science.2166335. PMID   2166335.
  25. ↑ Mazzio E, Soliman KF (January 2003). "The role of glycolysis and gluconeogenesis in the cytoprotection of neuroblastoma cells against 1-methyl 4-phenylpyridinium ion toxicity". Neurotoxicology. 24 (1): 137–47. doi:10.1016/S0161-813X(02)00110-9. PMID   12564389.
  26. ↑ Walter F. Boron (2005). Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. p. 858. ISBN   978-1-4160-2328-9.
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