HK3

Last updated
HK3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HK3 , HKIII, HXK3, hexokinase 3
External IDs OMIM: 142570 MGI: 2670962 HomoloGene: 55633 GeneCards: HK3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_002115

NM_001033245
NM_001206390
NM_001206391
NM_001206392

Contents

RefSeq (protein)

NP_002106

NP_001028417
NP_001193319
NP_001193320
NP_001193321

Location (UCSC) Chr 5: 176.88 – 176.9 Mb Chr 13: 55.15 – 55.17 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Hexokinase 3 also known as HK3 is an enzyme which in humans is encoded by the HK3 gene on chromosome 5. [5] [6] 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] [7]

Structure

HK3 is one of four highly homologous hexokinase isoforms in mammalian cells. [8] [9] [10] [11] This protein has a molecular weight of 100 kDa and is composed of two highly similar 50-kDa domains at its N- and C-terminals. [9] [10] [11] [12] [13] This high similarity, along with the[ clarification needed ] and 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] [13] Like with HK1, only the C-terminal domain possesses catalytic ability, whereas the N-terminal domain is predicted to contain glucose and G6P binding sites, as well as a 32-residue region essential for proper protein folding. [9] [10] Moreover, the catalytic activity depends on the interaction between the two terminal domains. [10] Unlike HK1 and HK2, HK3 lacks a mitochondrial binding sequence at its N-terminal. [10] [14] [15]

Function

As a cytoplasmic isoform of hexokinase and a member of the sugar kinase family, HK3 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P. [10] [11] [16] Physiological levels of G6P can regulate this process by inhibiting HK3 as negative feedback, though inorganic phosphate can relieve G6P inhibition. [9] [13] Inorganic phosphate can also directly regulate HK3, and the double regulation may better suit its anabolic functions. [9] By phosphorylating glucose, HK3 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism. [9] [10] [12] [13] Compared to HK1 and HK2, HK3 possesses a higher affinity for glucose and will bind the substrate even at physiological levels, though this binding may be attenuated by intracellular ATP. [9] Uniquely, HK3 can be inhibited by glucose at high concentrations. [14] [17] HK3 is also less sensitive to G6P inhibition. [9] [14]

Despite its lack of mitochondrial association, HK3 also functions to protect the cell against apoptosis. [10] [16] Overexpression of HK3 has resulted in increased ATP levels, decreased reactive oxygen species (ROS) production, attenuated reduction in the mitochondrial membrane potential, and enhanced mitochondrial biogenesis. Overall, HK3 may promote cell survival by controlling ROS levels and boosting energy production. Currently, only hypoxia is known to induce HK3 expression through a HIF-dependent pathway. The inducible expression of HK3 indicates its adaptive role in metabolic responses to changes in the cellular environment. [10]

In particular, HK3 is ubiquitously expressed in tissues, albeit at relatively low abundance. [9] [10] [13] [17] Higher abundance levels have been cited in lung, kidney, and liver tissue. [9] [10] [14] Within cells, HK3 localizes to the cytoplasm and putatively binds the perinuclear envelope. [10] [14] [15] HK3 is the predominant hexokinase in myeloid cells, particularly granulocytes. [18]

Clinical significance

HK3 is found to be overexpressed in malignant follicular thyroid nodules. In conjunction with cyclin A and galectin-3, HK3 could be used as diagnostic biomarker to screen for malignancy in patients. [16] [19] Meanwhile, HK3 was found to be repressed in acute myeloid leukemia (AML) blast cells and acute promyelocytic leukemia (APL) patients. The transcription factor PU.1 is known to directly activate transcription of the antiapoptotic BCL2A1 gene or inhibit transcription of the p53 tumor suppressor to promote cell survival, and is proposed to also directly activate HK3 transcription during neutrophil differentiation to support short-term cell survival of mature neutrophils. [15] Regulators repressing HK3 expression in AML include PML-RARA and CEBPA. [15] [18] Regarding acute lymphoblastic leukemia (ALL), functional enrichment analysis revealed HK3 as a key gene and suggests that HK3 shares antiapoptotic function with HK1 and HK2. [16]

Interactions

The HK3 promoter is known to interact with PU.1, [15] PML-RARA, [15] and CEBPA. [18]

Interactive pathway map

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

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WP534.png go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to Entrezgo to article
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Glycolysis and Gluconeogenesis edit
  1. The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

See also

Related Research Articles

<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.

<span class="mw-page-title-main">Phosphorylation</span> Chemical process of introducing a phosphate

In biochemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology. Protein phosphorylation often activates many enzymes.

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

A hexokinase is an enzyme that irreversibly 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.

<span class="mw-page-title-main">Glucose 6-phosphate</span> Chemical compound

Glucose 6-phosphate is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

The glucokinase regulatory protein (GKRP) also known as glucokinase regulator (GCKR) is a protein produced in hepatocytes. GKRP binds and moves glucokinase (GK), thereby controlling both activity and intracellular location of this key enzyme of glucose metabolism.

<span class="mw-page-title-main">Glucose-6-phosphate isomerase</span> Mammalian protein found in Homo sapiens

Glucose-6-phosphate isomerase (GPI), alternatively known as phosphoglucose isomerase/phosphoglucoisomerase (PGI) or phosphohexose isomerase (PHI), is an enzyme that in humans is encoded by the GPI gene on chromosome 19. This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme that interconverts glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P). Extracellularly, the encoded protein functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor (AMF) based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia, and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

<span class="mw-page-title-main">Tumor metabolome</span>

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.

<span class="mw-page-title-main">Serine hydroxymethyltransferase</span> InterPro Family

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<span class="mw-page-title-main">Enzyme activator</span> Molecules which increase enzyme activity

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

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<span class="mw-page-title-main">HK1</span> Mammalian protein found in Homo sapiens

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]

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

CCAAT/enhancer-binding protein alpha is a protein encoded by the CEBPA gene in humans. CCAAT/enhancer-binding protein alpha is a transcription factor involved in the differentiation of certain blood cells. For details on the CCAAT structural motif in gene enhancers and on CCAAT/Enhancer Binding Proteins see the specific page.

In enzymology, a polyphosphate-glucose phosphotransferase is an enzyme that catalyzes the chemical reaction.

<span class="mw-page-title-main">AKR1B1</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1, member B1 (AKR1B1), also known as aldose reductase, is an enzyme that is encoded by the AKR1B1 gene in humans. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. The involvement of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.

<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.

<span class="mw-page-title-main">ELF4</span> Protein-coding gene in humans

ETS-related transcription factor Elf-4 is a protein that in humans is encoded by the ELF4 gene.

<span class="mw-page-title-main">HK2</span>

Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2. 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]

<span class="mw-page-title-main">TP53-inducible glycolysis and apoptosis regulator</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">HKDC1</span> Protein-coding gene in the species Homo sapiens

Hexokinase domain containing 1 (HKDC1) is an enzyme which in humans is encoded by the HKDC1 gene on chromosome 10. It is a recently discovered hexokinase isoform that likely phosphorylates glucose in maternal metabolism during pregnancy.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025877 - 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.
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Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.