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

Stable Identifier
Reaction [transition]
Homo sapiens
alpha-D-Glucose + ATP => alpha-D-glucose 6-phosphate + ADP
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

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
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
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
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
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
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
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
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
11780755 GLUT2 in pancreatic and extra-pancreatic gluco-detection (review)

Thorens, B

Mol Membr Biol 2001
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
Catalyst Activity

glucokinase activity of glucokinase and hexokinases [cytosol]

Orthologous Events
Cross References
Cite Us!