Hexokinase-1 (HK1)
The protein contains 917 amino acids for an estimated molecular weight of 102486 Da.
Catalyzes the phosphorylation of various hexoses, such as D-glucose, D-glucosamine, D-fructose, D-mannose and 2-deoxy-D-glucose, to hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, D-fructose 6-phosphate, D-mannose 6-phosphate and 2-deoxy-D-glucose 6-phosphate, respectively) (PubMed:1637300, PubMed:25316723, PubMed:27374331). Does not phosphorylate N-acetyl-D-glucosamine (PubMed:27374331). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (By similarity). Involved in innate immunity and inflammation by acting as a pattern recognition receptor for bacterial peptidoglycan (PubMed:27374331). When released in the cytosol, N-acetyl-D-glucosamine component of bacterial peptidoglycan inhibits the hexokinase activity of HK1 and causes its dissociation from mitochondrial outer membrane, thereby activating the NLRP3 inflammasome (PubMed:27374331). (updated: July 31, 2019)
Protein identification was indicated in the following studies:
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| HK deficiency | |
| HK deficiency | |
| dbSNP:rs1054203 | |
| RP79 | |
| NEDVIBA | |
| NEDVIBA | |
| NEDVIBA | |
| NEDVIBA |
Biological Process
Canonical glycolysis
Carbohydrate phosphorylation
Cellular glucose homeostasis
Establishment of protein localization to mitochondrion
Fructose 6-phosphate metabolic process
Glucose 6-phosphate metabolic process
Glycolytic process
Inflammatory response
Innate immune response
Maintenance of protein location in mitochondrion
Mannose metabolic process
Positive regulation of cytokine production involved in immune response
Positive regulation of cytokine secretion involved in immune response
Positive regulation of interleukin-1 beta production
Positive regulation of interleukin-1 beta secretion
The reference OMIM entry for this protein is 142600
Hexokinase 1; hk1
DESCRIPTION
Hexokinase (EC 2.7.1.1) catalyzes the first step in glucose metabolism, using ATP for the phosphorylation of glucose to glucose-6-phosphate. Four different forms of hexokinase, designated type HK1, HK2 (601125), HK3 (142570), and HK4 (138079), encoded by different genes, are present in mammalian tissues. Among these, HK1 is the predominant glucose phosphorylating activity in those tissues that share a strict dependence on glucose utilization for their physiologic functions, such as brain, erythrocytes, platelets, lymphocytes, and fibroblasts (summary by Bianchi et al., 1997). Different isoforms of HK1 are either cytoplasmic or associated with the outer mitochondrial membrane (OMM) through a 5-prime porin (VDAC1; 604492)-binding domain (Murakami and Piomelli, 1997).CLONING
Nishi et al. (1988) analyzed cDNA clones encoding human hexokinase isolated from an adult kidney library. Analysis of this 917-amino acid protein showed that the sequences of the N- and C-terminal halves, corresponding to the regulatory and catalytic domains, respectively, are homologous. Eukaryotic hexokinases evolved from duplication of a gene encoding a protein of about 450 amino acids. Griffin et al. (1991) thought that comparisons of sequences in many species supported the theory of Ureta (1982) that the mammalian hexokinases arose from the duplication and fusion of an ancestral protoenzyme and that the yeast and mammalian glucokinases arose twice in evolution. Sequence analysis demonstrated that a 15-amino acid porin-binding domain in the N terminus of HK1 is absolutely conserved and mediates the binding of HK1 to the mitochondria. In the course of their work, Griffin et al. (1991) developed a method for cloning the cDNA for a low abundance protein using knowledge of the evolutionary conservation of amino acid and nucleotide sequence. By liquid chromatography, Murakami et al. (1990) identified 2 distinct major isozymes of human red blood cell (RBC) hexokinase. One had a molecular mass similar to that of HK1 identified in liver, and the other, designated HKR, was larger than HK1 by several kilodaltons. RBC from normal blood contained HK1 and HKR at an equal activity, but in reticulocyte-rich RBC, HKR dominated. Murakami and Piomelli (1997) isolated a cDNA clone for the red cell-specific HK isozyme HKR. Its nucleotide sequence was identical to HK1 cDNA except for the 5-prime end. It lacks the first 62 nucleotides of the HK1 coding region; instead, it contains a unique sequence of 60 nucleotides at the beginning of the coding sequence as well as another unique sequence upstream of the putative translation initiation site. It lacks the porin-binding domain that facilitates binding to mitochondria, thus explaining the exclusive cytoplasmic localization of red blood cell HK. Northern blot analysis showed that it was expressed in reticulocytes and in an erythroleukemic cell line, but not in a lymphocytic cell line. Mori et al. (1996) reported the cloning of cDNAs representing 3 unique human type 1 hexokinase mRNAs expressed in testis, which were not detected by Northern blot analysis in other human tissues. These mRNAs contained unique sequences in the 5-prime terminus and lacked the porin-binding domain (PBD), a conserved sequence that mediates the binding of hexokinase to the mitochondria. The sequences were similar to those identified by Mori et al. (1993) in mouse testis.GENE STRUCTURE
Ruzzo et al. (1998) determined tha ... More on the omim web site
Aug. 20, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Oct. 20, 2018: Protein entry updated
Automatic update: OMIM entry 142600 was added.
Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).