Reactome | HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P

HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P

Stable Identifier

R-HSA-70420

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

Synonyms

alpha-D-Glucose + ATP => alpha-D-glucose 6-phosphate + ADP

ReviewStatus

5/5

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HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P

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Cytosolic glucokinase and the three isoforms of hexokinase catalyze the irreversible reaction of glucose and ATP to form glucose 6 phosphate and ADP. In the body glucokinase is found only in hepatocytes and pancreatic beta cells. Glucokinase and the hexokinase enzymes differ in that glucokinase has a higher Km than the hexokinases and is less readily inhibited by the reaction product. As a result, glucokinase should be inactive in the fasting state when glucose concentrations are low but in the fed state should have an activity proportional to glucose concentration. These features are thought to enable efficient glucose uptake and retention in the liver, and to function as a sensor of glucose concentration coupled to insulin release in pancreatic beta cells (Thorens 2001). Glucokinase mutations are associated with MODY2, a heritable early onset form of type II diabetes (Tanizawa et al. 1991; Takeda et al. 1993). Three human hexokinase enzymes, which differ in their expression patterns have been characterized, HK1 (Aleshin et al. 1998), HK2 (Lehto et al. 1995), and HK3 (Rijksen at al. 1982).

An additional gene product, HKDC1, although not classically associated with glycolysis in adult tissues, has hexokinase activity in vitro and may have a role in glucose homeostasis during embryonic development (Guo et al. 2015; Pusik et al. 2019; Zapater et al. 2022). HKDC1 has therefore been annotated here as a candidate member of the set of enzymes that mediates glucose phosphorylation.

Literature References

PubMed ID	Title	Journal	Year
34782236	Hexokinase domain-containing protein-1 in metabolic diseases and beyond Pusec, CM, Khan, MW, Lednovich, KR, Layden, BT, Zapater, JL	Trends Endocrinol Metab	2022
11780755	GLUT2 in pancreatic and extra-pancreatic gluco-detection (review) Thorens, B	Mol Membr Biol	2001
7150652	Compartmentation of hexokinase in human blood cells. Characterization of soluble and particulate enzymes. Akkerman, JW, Beks, PJ, Streefkerk, M, Staal, GE, Rijksen, G	Biochim Biophys Acta	1982
25648650	Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1 Guo, C, Ludvik, AE, Lowe, WL, Brown, CD, Hayes, MG, Armstrong, LL, Arlotto, ME, Newgard, CB, Reddy, TE, Becker, TC, Layden, BT, Scholtens, DM	Nat Commun	2015
30517626	Hepatic HKDC1 Expression Contributes to Liver Metabolism Cordoba-Chacon, J, Terry, AR, Hay, N, Pusec, CM, Khan, MW, Ding, X, Pervaiz, H, Becker, TC, Daviau Smith, E, Layden, BT, Ludvik, AE, Xu, K, Ardehali, H, Harrison, S, De Jesus, A, Giancola, N, Chandel, NS	Endocrinology	2019
9493266	The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate Aleshin, AE, Bourenkov, GP, Bartunik, HD, Fromm, HJ, Zeng, C, Honzatko, RB	Structure	1998
8325892	Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. Gidh-Jain, M, Vionnet, N, Velho, G, Pilkis, SJ, Stoffel, M, Cohen, D, Vaxillaire, M, Harrison, RW, Takeda, J, Bell, GI, Makino, H, Weber, IT, Shimada, F, Xu, LZ, St. Charles, R, Nishi, S, Froguel, P	J Biol Chem	1993
1871135	Human liver glucokinase gene: cloning and sequence determination of two alternatively spliced cDNAs Welling, CM, Tanizawa, Y, Koranyi, LI, Permutt, MA	Proc Natl Acad Sci U S A	1991
8786021	Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity Le Beau, MM, Lehto, M, Laurila, E, Eriksson, KF, Bell, GI, Huang, X, Davis, EM, Groop, LC	Diabetologia	1995