The 3D Structure of The Human Hexokinase II

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Crystal structure of human hexokinase II
Figure 1. The 3D
structure of the human hexokinase II
The HK2 gene on chromosome 2 encodes an enzyme known as hexokinase 2 (HK2).
First, most glucose metabolism routes begin with the phosphorylation of glucose by
hexokinases, yielding glucose-6-phosphate (G6P). Hexokinase 2 is the most common type in
skeletal muscle and this gene codes for it. It's found only on the mitochondria's outer
membrane. Since this gene is insulin-responsive, investigations in rats have shown that it
contributes to cancer cells' accelerated glycolysis rate.
Hexokinase's tertiary structure has an open alpha/beta-sheet. This structure carries a
great deal of variety. Five beta sheets and three alpha-helices make up the ATP-binding
domain. Four of the beta-sheets are parallel and one is antiparallel in an open alpha/beta-sheet.
This open alpha/beta-sheet is made up of alpha helices and beta loops that link beta-sheets.
This glycolytic enzyme's ATP-binding domain may be seen in the crevice. Hexokinases have
molecular weights in the range of 100 kD. Only in hexokinase II do both 50kD halves have
functioning active sites; the others all have two identical 50kD halves. A decade before the
structure of hexokinase was discovered, Daniel Koshland recognized that water must be kept
out of this chemical process to prevent the phosphate from being ripped off of ATP by a water
molecule. As a result, he hypothesized that hexokinase undergoes an induced fit after binding
ATP and glucose. Solving the crystal structures for many yeast hexokinases in the 1970s
showed that this was correct. Hexokinase has a large groove on one side and resembles a
clamp.
At glucose's C-6, the gamma-phosphoryl group of an ATP molecule transfers to oxygen
for the first step of glycolysis. ATP's reactive state is a compound with magnesium (II) ion, which
necessitates the presence of magnesium ion. ATP's terminal phosphoryl group is attacked by
the hydroxyl group, which acts as a direct nucleophile. Thus, glucose-6-phosphate and ADP are
generated (Pollard-Knight & Cornish-Bowden, 1982). A magnesium ion is required as a cofactor
for the enzyme hexokinase. Glucose reacts better with magnesium ions because they protect
ATP's negatively charged groups. The enzyme hexokinase is responsible for catalyzing the
transfer of the phosphoryl group. When hexokinase binds to glucose, it experiences an induced-
fit conformational shift that inhibits ATP hydrolysis. glucose-6-phosphate, a physiological
quantity of its immediate product, allosterically inhibits the enzyme as well. Control of substrate
inflow into the glycolytic pathway is accomplished via this method.
Feature Key Position(s) Description

30 ATP 1
209, 232 Glucose-6-phosphate 1
235, 260, 449 Substrate 1
Binding Site
657, 680, 897 Glucose-6-phosphate 2
680 ATP 2
708 Substrate 2
84-89, 425-426 ATP 1
Nucleotide binding 532-537, 747-748, 784-788, ATP 2
863-867
Table 1. The binding site and nucleotide-binding in the primary structure of human hexokinase II
Source: https://www.uniprot.org/uniprot/P52789
The binding site refers to the portion of the function section that describes the interaction
between a single amino acid and another chemical entity in human hexokinase II. Section of the
function termed "nucleotide-binding" specifies a protein region recognized for binding nucleotide
phosphates. A distinct amino acid binds to each of the nucleotide-binding residues. These
fragments may be found in the deep cleft that separates the two lobes. Glucose and glucose-6-
phosphate may both bind to this active site. When glucose binds to hexokinase, it causes a
conformational change. Glucose-6-phosphate in physiological amounts prevents ATP hydrolysis
by blocking a conformational change. When hexokinase is active, it may reside in one of two
conformational states. The open state occurs before glucose binds to a receptor. The glucose
binding site, on the other hand, is situated away from the large lobe and in a different part of the
active site than where ATP is found. A substantial structural shift takes place when glucose
interacts with hexokinase. As a consequence of this change, the glucose substrate's two lobes
are now closed. This stage of conformation is referred known as the closed state (Kitto, Caras,
& Caras, 2008).
References:
Pollard-Knight D. & Cornish-Bowden A. (1982). Mechanism of liver glucokinase. Mol Cell
Biochem. Apr 30;44(2):71-80. PMID:7048063
Koshland D. (2010). Induced Fit and Hexokinase.Fig.7 Active Site of Glucokinase/Hexokinase.
Kitto B.G, Caras J., Caras P. (2008). Interactive Concepts in Biochemistry. Structural Tutorials.;
Chp: 15.1, 15.5.
HK2 - Hexokinase-2 - Homo sapiens (Human) - HK2 gene & protein. (2021). Retrieved 17
October 2021, from https://www.uniprot.org/uniprot/P52789

The 3D Structure of The Human Hexokinase II

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Crystal structure of human hexokinase II

Feature Key Position(s) Description

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