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Structure

Though the structure of hexokinase varies slightly between different types, they are similar enough in structure that they continue to have relaticely the same function. The Primary Structure of hexokinase has been found to be roughly 461 amino acids in most organisms. The Secondary Structure of hexokinase consists of 12 alpha helicies, and 12 beta strands. The Tertiary Structure of hexokinase consists of two domains: a N-Terminal Regulatory Domain, and a C-Terminal Catalytic Domain. The Quaternary Structure of hexokinase consists of two identical monomers of hexokinase forming a homodimer.

Each of the domains within Hexokinase has a molecular weight of ~50 kDa meaning that the overall molecular weight of Hexokinase is ~100 kDa ^[1].

Structural highlights

The N-terminal and C-terminal domains of hexokinase are connected by a single alpha-helix. This creates a cleft region which acts as the active site for the enzyme^[2].

The N-terminal domain of hexokinase has also been shown to bind directly to mitochondria within the cell, allowing it to have direct and constant access to ATP^[3].

Function

Hexokinase serves to initiate the first step of glycolysis in the metabolic pathway. Hexokinase reacts with glucose and ATP to produce glucose-6-phosphate, it does this by taking glucose into it's active site. Once in the active site, the carbon-6 hydroxyl group on hexokinase performs a nucleophilic attack on the terminal phosphate group of ATP, creating the glucose-6-phosphate, and ADP products.

Hexokinase has also been shown to be linked to the cell survival pathway, as signals from metabolic pathways go to cell survival pathways which allows metabolic status to rapidly activate adaptive responses to ensure preservation of homeostasis and cell survivability^[4]

Hexokinase I is found in most mammalian tissues attached to the outer mitochondrial membrane within cells. Hexokinase I is the most prominent isoform of hexokinase.

Hexokinase II is commonly found in muscle and heart tissues. It is also found in higher concentrations in tumor cells^[5] . Hexokinase II functions as a molecular switch between glycolysis and autophagy to maintain energy homeostasis during starvation. ^[6]

Hexokinase III is characterized by its lack of a mitochondria-binding N-terminal sequence, meaning it is usually found floating free in the cell.

Hexokinase IV is also known as glucokinase. It differs from the other isoforms in that it is not found in all body tissues, but in certain tissues like liver, pancreas, and small intestine cells. This isoform is only activated in higher concentrations of substrate.

Hexokinase can be inhibited by glucose-6-phosphate and other mono-/bis- phosphate sugars.^[7] Glucose-6-phosphate prevents the Hexokinase from breaking down the inorganic phosphate within the body so they can be used for other biological functions.

Relevance

As the first step of glycolysis, hexokinase plays an important role in the breakdown of sugars, and the creation of energy and pyruvic acid within the body. Hexokinase I is found in most tissues within the body but, it is primarily found in Red Blood Cells, kidney tissue, and brain tissue. Hexokinase also exists within all phyla and contains multiple isoforms just like mammalian hexokinase. ^[8]

Although rare, mutations in the Hexokinase I gene on chromosome 10 can reduce the amount of Hexokinase found in tissues. this reduction has been found to be directly related to early-onset nonspherocytic Hemolytic anemia^[9] Other mutations have also been observed causing retinitis pigmentosa, Russe type of hereditary motor and sensory neuropathy, and jaundice. ^[10]

References

1. ↑ Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB. 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. Structure. 1998 Jan 15;6(1):39-50. doi: 10.1016/s0969-2126(98)00006-9.
2. ↑ Mulichak, A., Wilson, J., Padmanabhan, K. et al. The structure of mammalian hexokinase-1. Nat Struct Mol Biol 5, 555–560 (1998). https://doi.org/10.1038/811
3. ↑ Richard S, Katherine D, Alice W, Pamila G. A reevaluation of the roles of hexokinase I and II in the heart. Am. J. Physiol 2007 Jan .https://doi.org/10.1152/ajpheart.00664.2006
4. ↑ Roberts DJ, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ. 2015 Feb;22(2):248-57. doi: 10.1038/cdd.2014.173.
5. ↑ Wilson, J. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function J Exp Biol (2003) 206 (12): 2049–2057 DOI:https://doi.org/10.1242/jeb.00241
6. ↑ Valerie P. Tan, Shigeki Miyamoto. HK2/hexokinase-II integrates glycolysis and autophagy to confer cellular protection. https://pubmed.ncbi.nlm.nih.gov/26075878/. (Accessed 10/21/2022).
7. ↑ M. Magnani, M. Bianchi, A. Casabianca, V. Stocchi, A. Daniele, F. Altruda, M. Ferrone, L. Silengo. A recombinant human 'mini'-hexokinase is catalytically active and regulated by hexose 6-phosphates. https://pubmed.ncbi.nlm.nih.gov/1637300/. (Accessed 10/21/2022).
8. ↑ Èric Claeyssen, Jean Rivoal. Isozymes of plant hexokinase: Occurrence, properties and functions. https://www.sciencedirect.com/science/article/abs/pii/S0031942206007606. (Accessed 10/21/2022)
9. ↑ McKusick V. HEMOLYTIC ANEMIA, NONSPHEROCYTIC, DUE TO HEXOKINASE DEFICENCY. (accessed 2022-11-01 from OMIM: Online Mendelian Inheritance of Man)
10. ↑ McKusick V., Hexokinase 1; HK1. (accessed 11/15/2022 from OMIM: Online Mendelian Inheritance of Man).