The glucose-induced structural changes are significant in two respects. First, the environment around the glucose becomes more nonpolar, which favors reaction between the hydrophilic hydroxyl group of glucose and the terminal phosphoryl group of ATP.

I am unable to understand the chemistry behind this. How is a hydrophobic environment helping bond formation between two polar molecules?

Source: Biochemistry 8th edition by Jeremy M. Berg John L. Tymoczko Gregory J. Gatto, Jr. Lubert Stryer

  • $\begingroup$ Basically forcing them to themselves $\endgroup$
    – Alchimista
    Commented Jul 15, 2017 at 15:53
  • $\begingroup$ What is the physical reason for that? $\endgroup$
    – JM97
    Commented Jul 15, 2017 at 15:56
  • $\begingroup$ Whatever polar group will be less solvated in a hydrophobic environment. May I make it too simple, but alike oil forms droplets in water, or viceversa. Molecules find each others, and droplets do finally the same. In hydrophilic environment the reacting polar groups are shielded by the surrounding medium molecules, e.g. water. $\endgroup$
    – Alchimista
    Commented Jul 15, 2017 at 16:11
  • $\begingroup$ But how does that lead to covalent bonding? $\endgroup$
    – JM97
    Commented Jul 15, 2017 at 16:13

1 Answer 1


The major reason of the ‘hydrophobic environment’ is to block the enzyme-complex from accessing the solvent (water), which might otherwise enter the active site and hydrolyse ATP.

The reduction of polarity also helps to speed up the subsequent nucleophilic substitution.

Note: Hexokinase is a soluble, cytosolic protein

The reasoning behind this statement comes from the X-ray structural studies of yeast hexokinase (HK) by Thomas Steitz.

Comparison of the X-ray structures of HK and the glucose–HK complex indicates that glucose induces a large conformational change in HK. The two lobes that form its active site cleft swing together by up to 11.5 Å so as to engulf the glucose in a manner that suggests the closing of jaws.

This movement places the ATP in close proximity to the group of $\ce{-C6H2OH}$ glucose such that water is sequestered from the active site. Water is certainly small enough to fit into the phosphoryl acceptor group’s enzymatic binding site. Moreover, phosphoryl transfer from ATP to water is more exergonic than it is to glucose. If the catalytic and reacting groups were in the proper position for reaction while the enzyme was in the open position, ATP hydrolysis (to yield ADP + Pi) would almost certainly be the dominant reaction.

However, the large conformational change of the enzyme induced by glucose causing the exclusion of water from the active site making the phosphorus atom more accessible for the nucleophilic attack of the C6-OH group of glucose ensures that HK catalyses the phosphoryl transfer to glucose rather than ATP hydrolysis and also reduces the polarity of the active site, which help accelerate the nucleophilic reaction process.

This substrate-induced conformational change in HK is responsible for the enzyme’s specificity.


  • Lehninger Principles of Biochemistry

  • Voet and Voet Biochemistry


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