HK2

Last updated
HK2
PDB 2nzt EBI.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HK2 , HKII, HXK2, hexokinase 2
External IDs OMIM: 601125 MGI: 1315197 HomoloGene: 37273 GeneCards: HK2
Orthologs
SpeciesHumanMouse
Entrez

3099

15277

Ensembl

ENSG00000159399

ENSMUSG00000000628

UniProt

P52789

O08528

RefSeq (mRNA)

NM_000189
NM_001371525

NM_013820

RefSeq (protein)

NP_000180
NP_001358454

NP_038848

Location (UCSC) Chr 2: 74.83 – 74.89 Mb Chr 6: 82.73 – 82.77 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2. [5] [6] Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. [provided by RefSeq, Apr 2009] [6]

Contents

Structure

HK2 is one of four highly homologous hexokinase isoforms in mammalian cells. [7] [8] [9] [10] [11]

Gene

The HK2 gene spans approximately 50 kb and consists of 18 exons. There is also an HK2 pseudogene integrated into a long interspersed nuclear repetitive DNA element located on the X chromosome. Though its DNA sequence is similar to the cDNA product of the actual HK2 mRNA transcript, it lacks an open reading frame for gene expression. [10]

Protein

This gene encodes a 100-kDa, 917-residue enzyme with highly similar N- and C-terminal domains that each form half of the protein. [10] [12] This high similarity, along with the existence of a 50-kDa hexokinase (HK4), suggests that the 100-kDa hexokinases originated from a 50-kDa precursor via gene duplication and tandem ligation. [10] [11] Both N- and C-terminal domains possess catalytic ability and can be inhibited by G6P, though the C-terminal domain demonstrates lower affinity for ATP and is only inhibited at higher concentrations of G6P. [10] Despite there being two binding sites for glucose, it is proposed that glucose binding at one site induces a conformational change which prevents a second glucose from binding the other site. [13] Meanwhile, the first 12 amino acids of the highly hydrophobic N-terminal serve to bind the enzyme to the mitochondria, while the first 18 amino acids contribute to the enzyme’s stability. [9] [11]

Function

As an isoform of hexokinase and a member of the sugar kinase family, HK2 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P. [11] Physiological levels of G6P can regulate this process by inhibiting HK2 as negative feedback, though inorganic phosphate (Pi) can relieve G6P inhibition. [8] [10] [11] Pi can also directly regulate HK2, and the double regulation may better suit its anabolic functions. [8] By phosphorylating glucose, HK2 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism. [10] [12] Moreover, its localization and attachment to the OMM promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation, which greatly enhances ATP production to meet the cell’s energy demands. [14] [15] Specifically, HK2 binds VDAC to trigger opening of the channel and release mitochondrial ATP to further fuel the glycolytic process. [8] [15]

Another critical function for OMM-bound HK2 is mediation of cell survival. [8] [9] Activation of Akt kinase maintains HK2-VDAC coupling, which subsequently prevents cytochrome c release and apoptosis, though the exact mechanism remains to be confirmed. [8] One model proposes that HK2 competes with the pro-apoptotic proteins BAX to bind VDAC, and in the absence of HK2, BAX induces cytochrome c release. [8] [15] In fact, there is evidence that HK2 restricts BAX and BAK oligomerization and binding to the OMM. In a similar mechanism, the pro-apoptotic creatine kinase binds and opens VDAC in the absence of HK2. [8] An alternative model proposes the opposite, that HK2 regulates binding of the anti-apoptotic protein Bcl-Xl to VDAC. [15]

In particular, HK2 is ubiquitously expressed in tissues, though it is majorly found in muscle and adipose tissue. [8] [10] [15] In cardiac and skeletal muscle, HK2 can be found bound to both the mitochondrial and sarcoplasmic membrane. [16] HK2 gene expression is regulated by a phosphatidylinositol 3-kinaselp70 S6 protein kinase-dependent pathway and can be induced by factors such as insulin, hypoxia, cold temperatures, and exercise. [10] [17] Its inducible expression indicates its adaptive role in metabolic responses to changes in the cellular environment. [17]

Clinical significance

Cancer

HK2 is highly expressed in several cancers, including breast cancer and colon cancer. [9] [15] [18] Its role in coupling ATP from oxidative phosphorylation to the rate-limiting step of glycolysis may help drive the tumor cells’ growth. [15] Notably, inhibition of HK2 has demonstrably improved the effectiveness of anticancer drugs., [18] Thus, HK2 stands as a promising therapeutic target, though considering its ubiquitous expression and crucial role in energy metabolism, a reduction rather than complete inhibition of its activity should be pursued. [15] [18]

Non-insulin-dependent diabetes mellitus

A study on non-insulin-dependent diabetes mellitus (NIDDM) revealed low basal G6P levels in NIDDM patients that failed to increase with the addition of insulin. One possible cause is decreased phosphorylation of glucose due to a defect in HK2, which was confirmed in further experiments. However, the study could not establish any links between NIDDM and mutations in the HK2 gene, indicating that the defect may lie in HK2 regulation. [10]

Interactions

HK2 is known to interact with:

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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|alt=Glycolysis and Gluconeogenesis edit]]
Glycolysis and Gluconeogenesis edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

See also

Related Research Articles

Glycolysis Metabolic pathway

Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvic acid, CH3COCOOH. 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.

Kinase Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. This transesterification produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

Hexokinase Class of enzymes

A hexokinase is an enzyme that phosphorylates hexoses, forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokinase possesses the ability to transfer an inorganic phosphate group from ATP to a substrate.

Tumor hypoxia

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

Pyruvate kinase

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.

AMP-activated protein kinase

5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic beta-cells.

In oncology, the Warburg effect is a form of modified cellular metabolism found in cancer cells, which tend to favor a specialised fermentation over the aerobic respiration pathway that most other cells of the body prefer. This observation was first published by Otto Heinrich Warburg who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme".

Phosphofructokinase 2

Phosphofructokinase-2 (6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation of a significant allosteric regulator, fructose-2,6-bisphosphate (Fru-2,6-P2) from substrate fructose-6-phosphate. Fru-2,6-P2 contributes to the rate-determining step of glycolysis as it activates enzyme phosphofructokinase 1 in the glycolysis pathway, and inhibits fructose-1,6-bisphosphatase 1 in gluconeogenesis. Since Fru-2,6-P2 differentially regulates glycolysis and gluconeogenesis, it can act as a key signal to switch between the opposing pathways. Because PFK-2 produces Fru-2,6-P2 in response to hormonal signaling, metabolism can be more sensitively and efficiently controlled to align with the organism's glycolytic needs. This enzyme participates in fructose and mannose metabolism. The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity. The family described here bears a resemblance to the ATP-driven phospho-fructokinases, however, they share little sequence similarity, although a few residues seem key to their interaction with fructose 6-phosphate.

Tumor metabolome

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine.

Bcl-2-associated X protein

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

Enzyme activator

Enzyme activators are molecules that bind to enzymes and increase their activity. They are the opposite of enzyme inhibitors. These molecules are often involved in the allosteric regulation of enzymes in the control of metabolism. An example of an enzyme activator working in this way is fructose 2,6-bisphosphate, which activates phosphofructokinase 1 and increases the rate of glycolysis in response to the hormone glucagon. In some cases, when a substrate binds to one catalytic subunit of an enzyme, this can trigger an increase in the substrate affinity as well as catalytic activity in the enzyme's other subunits, and thus the substrate acts as an activator.

Voltage-dependent anion channel Class of porin ion channels in the outer mitochondrial membrane

Voltage-dependent anion channels, or mitochondrial porins, are a class of porin ion channel located on the outer mitochondrial membrane. There is debate as to whether or not this channel is expressed in the cell surface membrane.

HK1

Hexokinase-1 (HK1) is an enzyme that in humans is encoded by the HK1 gene on chromosome 10. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in five transcript variants which encode different isoforms, some of which are tissue-specific. Each isoform has a distinct N-terminus; the remainder of the protein is identical among all the isoforms. A sixth transcript variant has been described, but due to the presence of several stop codons, it is not thought to encode a protein. [provided by RefSeq, Apr 2009]

PFKFB3

PFKFB3 is a gene that encodes the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme in humans. It is one of 4 tissue-specific PFKFB isoenzymes identified currently (PFKFB1-4).

GOT2

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 tricarboxylic acid cycles. 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.

VDAC1

Voltage-dependent anion-selective channel 1 (VDAC-1) is a beta barrel protein that in humans is encoded by the VDAC1 gene located on chromosome 5. It forms an ion channel in the outer mitochondrial membrane (OMM) and also the outer cell membrane. In the OMM, it allows ATP to diffuse out of the mitochondria into the cytoplasm. In the cell membrane, it is involved in volume regulation. Within all eukaryotic cells, mitochondria are responsible for synthesis of ATP among other metabolite needed for cell survival. VDAC1 therefore allows for communication between the mitochondrion and the cell mediating the balance between cell metabolism and cell death. Besides metabolic permeation, VDAC1 also acts as a scaffold for proteins such as hexokinase that can in turn regulate metabolism.

PKM2

Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene.

VDAC2

Voltage-dependent anion-selective channel protein 2 is a protein that in humans is encoded by the VDAC2 gene on chromosome 10. This protein is a voltage-dependent anion channel and shares high structural homology with the other VDAC isoforms. VDACs are generally involved in the regulation of cell metabolism, mitochondrial apoptosis, and spermatogenesis. Additionally, VDAC2 participates in cardiac contractions and pulmonary circulation, which implicate it in cardiopulmonary diseases. VDAC2 also mediates immune response to infectious bursal disease (IBD).

HK3

Hexokinase 3 also known as HK3 is an enzyme which in humans is encoded by the HK3 gene on chromosome 5. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes hexokinase 3. Similar to hexokinases 1 and 2, this allosteric enzyme is inhibited by its product glucose-6-phosphate. [provided by RefSeq, Apr 2009]

TP53-inducible glycolysis and apoptosis regulator

The TP53-inducible glycolysis and apoptosis regulator (TIGAR) also known as fructose-2,6-bisphosphatase TIGAR is an enzyme that in humans is encoded by the C12orf5 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000159399 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000628 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Lehto M, Xiang K, Stoffel M, Espinosa R, Groop LC, Le Beau MM, Bell GI (Dec 1993). "Human hexokinase II: localization of the polymorphic gene to chromosome 2". Diabetologia. 36 (12): 1299–302. doi: 10.1007/BF00400809 . PMID   8307259.
  6. 1 2 "Entrez Gene: HK2 hexokinase 2".
  7. ↑ Murakami K, Kanno H, Tancabelic J, Fujii H (2002). "Gene expression and biological significance of hexokinase in erythroid cells". Acta Haematologica. 108 (4): 204–9. doi:10.1159/000065656. PMID   12432216. S2CID   23521290.
  8. 1 2 3 4 5 6 7 8 9 10 Okatsu K, Iemura S, Koyano F, Go E, Kimura M, Natsume T, Tanaka K, Matsuda N (Nov 2012). "Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase". Biochemical and Biophysical Research Communications. 428 (1): 197–202. doi:10.1016/j.bbrc.2012.10.041. PMID   23068103.
  9. 1 2 3 4 Schindler A, Foley E (Dec 2013). "Hexokinase 1 blocks apoptotic signals at the mitochondria". Cellular Signalling. 25 (12): 2685–92. doi:10.1016/j.cellsig.2013.08.035. PMID   24018046.
  10. 1 2 3 4 5 6 7 8 9 10 Printz RL, Osawa H, Ardehali H, Koch S, Granner DK (Feb 1997). "Hexokinase II gene: structure, regulation and promoter organization". Biochemical Society Transactions. 25 (1): 107–12. doi:10.1042/bst0250107. PMID   9056853.
  11. 1 2 3 4 5 Ahn KJ, Kim J, Yun M, Park JH, Lee JD (Jun 2009). "Enzymatic properties of the N- and C-terminal halves of human hexokinase II". BMB Reports. 42 (6): 350–5. doi: 10.5483/bmbrep.2009.42.6.350 . PMID   19558793.
  12. 1 2 Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB (Jan 1998). "The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate". Structure. 6 (1): 39–50. doi: 10.1016/s0969-2126(98)00006-9 . PMID   9493266.
  13. ↑ Cárdenas, ML; Cornish-Bowden, A; Ureta, T (5 March 1998). "Evolution and regulatory role of the hexokinases". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1401 (3): 242–64. doi: 10.1016/s0167-4889(97)00150-x . PMID   9540816.
  14. ↑ Shan D, Mount D, Moore S, Haroutunian V, Meador-Woodruff JH, McCullumsmith RE (Apr 2014). "Abnormal partitioning of hexokinase 1 suggests disruption of a glutamate transport protein complex in schizophrenia". Schizophrenia Research. 154 (1–3): 1–13. doi:10.1016/j.schres.2014.01.028. PMC   4151500 . PMID   24560881.
  15. 1 2 3 4 5 6 7 8 Palmieri D, Fitzgerald D, Shreeve SM, Hua E, Bronder JL, Weil RJ, Davis S, Stark AM, Merino MJ, Kurek R, Mehdorn HM, Davis G, Steinberg SM, Meltzer PS, Aldape K, Steeg PS (Sep 2009). "Analyses of resected human brain metastases of breast cancer reveal the association between up-regulation of hexokinase 2 and poor prognosis". Molecular Cancer Research. 7 (9): 1438–45. doi:10.1158/1541-7786.MCR-09-0234. PMC   2746883 . PMID   19723875.
  16. ↑ Reid, S; Masters, C (1985). "On the developmental properties and tissue interactions of hexokinase". Mechanisms of Ageing and Development. 31 (2): 197–212. doi:10.1016/s0047-6374(85)80030-0. PMID   4058069. S2CID   40877603.
  17. 1 2 Wyatt, E; Wu, R; Rabeh, W; Park, HW; Ghanefar, M; Ardehali, H (3 November 2010). "Regulation and cytoprotective role of hexokinase III". PLOS ONE. 5 (11): e13823. Bibcode:2010PLoSO...513823W. doi: 10.1371/journal.pone.0013823 . PMC   2972215 . PMID   21072205.
  18. 1 2 3 Peng Q, Zhou J, Zhou Q, Pan F, Zhong D, Liang H (2009). "Silencing hexokinase II gene sensitizes human colon cancer cells to 5-fluorouracil". Hepato-Gastroenterology. 56 (90): 355–60. PMID   19579598.

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