Specificity and properties of
liver hexokinase ("glucokinase")
All of the pages in this series are in urgent need of updating.
The biochemical principles have not changed, of course, but textbooks have: some of
those that were current when I first prepared these pages in 2000 have appeared in new editions, and
others have ceased to be widely used. New books have appeared that are not discussed. Unfortunately
I do not have easy access to any of the commonly used textbooks, as I work in a research (not teaching)
environment in a country where English is not the everyday working language. I could buy them, of course,
but that would represent rather a large investment for the sake of a few web pages.
Accordingly
I should be grateful if someone would collaborate with me in the revision. If you have access to
all of the textbooks published in English in the past ten years (say 1996 or later)
that are commonly used for teaching biochemistry, and if you would like to
help, please contact me at acornish@ibsm.cnrs-mrs.fr.
Examples of the problem
The basic error is to be misled into thinking that the misnomer glucokinase gives a correct
impression of the specificity of liver hexokinase, as in the following statement from p. 298 of
Campbell:
In some organisms there is a glucokinase, an enzyme that specifically phosphorylates glucose
However, some authors add to the confusion with a whole series of incorrect statements,
as on p. 576 of Garrett and Grisham:
Liver contains an enzyme called glucokinase, which also carries out the [hexokinase] reaction,
but is highly specific for D-glucose, has a much higher Km for
glucose (approximately 10.0 mM), and is not product-inhibited... (Patients with diabetes mellitus
produce insufficient insulin. They have low levels of glucokinase, cannot tolerate high levels of blood
glucose, and produce little liver glycogen.)
We are mainly concerned here with the first sentence, though the parenthesis quoted after it also
contains some less frequently encountered confusion that is mentioned below. The first sentence makes
three points, all of them wrong:
- Liver hexokinase is not more specific for glucose than the other three hexokinase
isoenzymes commonly found in mammals: by the most appropriate definition of specificity one uses it falls within the range
of the other three when glucose and fructose (the usual criterion of hexokinase specificity) are compared; on the basis
of V values (admittedly not the best criterion) it is actually the least specific for glucose.
- It does not follow Michaelis–Menten kinetics with respect to glucose, and thus has no Km for
glucose. It is true, however, that it is half-saturated at much higher glucose concentrations than the other isoenzymes.
- It is weakly inhibited by glucose 6-phosphate (with an inhibition constant around 50 mM). This is admittedly much
too weak to have any physiological significance, but from the mechanistic point of view it is misleading to state that the
enzyme is not product-inhibited, because the ratio of sensitivities to glucose and to glucose 6-phosphate is very similar
to the ratios found with other hexokinase isoenzymes.
The sentence about diabetes mellitus confuses different types of this disease: the type in which liver
hexokinase has been implicated is maturity-onset diabetes of the young (often called MODY), which in adulthood leads to
symptoms of non-insulin-dependent diabetes mellitus (NIDDM;
, type II diabetes mellitus),
whereas the type normally treated by administration of insulin is insulin-dependent diabetes mellitus (IDDM;
, type I diabetes mellitus).
The following passage from Stryer (p. 495) is not a lot better:
Liver possesses glucokinase, a specialized isoform of hexokinase that is not inhibited by glucose 6-phosphate. Glucokinase phosphorylates glucose only when it is abundant because it has a much higher KM
for glucose than does hexokinase (5 mM, compared with 0.1 mM). the role of glucokinase is to provide
glucose 6-phosphate for the synthesis of glycogen, a storage form of glucose (p. 586). The high KM
of glucokinase in the liver gives brain and muscle first call on glucose when its supply is limited.
The following passage from Zubay (p. 326) is less objectionable, but repeats the error relating
to Km, and although it doesn't explicitly state
that the name glucokinase refers to different specificity from hexokinase it
certainly leaves that impression. Moreover, the remarks about the physiological function are so vague that one is left wondering why the
enzyme is mentioned at all:
The liver contains another enzyme, named glucokinase, that catalyzes the same reaction as hexokinase. Its Michaelis constant (about 10 mM)
is 1,000 times as large as that of hexokinase; thus glucokinase can function only when the concentration of glucose is relatively high. Probably
this enzyme is active only when blood glucose is high and the liver is taking up glucose for conversion to glycogen.
The following passage from McKee and McKee (p. 181) illustrates that it is quite possible for
authors to be scientifically correct if they try. Although the statement that hexokinase D is not inhibited by glucose 6-phosphate might be
objectionable in a mechanistic context, the reference here is clearly to the physiological role. Although the account does
not specifically mention that hexokinase D does not follow Michaelis–Menten kinetics, the use of the term half-saturated
avoids giving the
wrong impression that it does:
Hexokinase D, an isoenzyme found only in liver, has specific properties. The other hexokinases have high affinities for glucose
relative to its concentration in blood (i.e., they are half-saturated at concentrations of less than 0.1 mM).
(Blood glucose levels are
approximately 4–5 mM.) In addition, hexokinase D requires much higher glucose concentrations for optimal activity
(about 10 mM). Because
hexokinase D activity is not inhibited by glucose 6-phosphate, this enzyme contributes significantly to the liver’s capacity to regulate
blood glucose.
Likewise the following statement from Mathews, van Holde and Ahern
(p. 452) is largely correct apart from the misleading mention of a very high KM:
Vertebrate liver contains a distinctive form of hexokinase, characterized by a very high KM
for glucose (about 10 mM), a sigmoidal concentration dependence on glucose, and an insensitivity to inhibition
by glucose-6-phosphate. This special hexokinase allows the liver to adjust its rate of glucose utilization in response
to variations in blood glucose levels. In fact, as discussed in Chapters 16 and 23, a major role of liver is to
regulate blood glucose levels, and this enzyme represents one of the principal
mechanisms by which it does so. This form of hexokinase is often called glucokinase, although its substrate
specificity is identical to that of hexokinase.
Why does it matter?
This error is perhaps less fundamental than most of the others here, but it is common in modern textbooks and
raises the question of whether textbook authors ever read the primary literature or just content themselves with
paraphrasing one another. This particular one happens to be close to my past interests, but there are probably others
just as common that I don't notice.
The main reason why it matters is that it clearly confuses authors of reviews and research articles about the evolution of
enzyme properties and structures, who speculate about meaningless questions of why hexokinase specificity evolved independently
in the vertebrate and other lines. Note that the name glucokinase and the EC number 2.7.1.2
are quite properly applied to the
genuinely specific enzymes that occur in bacteria and some other organisms. The
IUBMB compilation
Enzyme Nomenclature allows
(misguidedly, in my view) the
name but not the number to be applied to liver hexokinase.
Further reading
M. L. Cárdenas (1995)
Glucokinase
: its regulation and role in liver metabolism
R. G. Landes, Austin, Texas
M. L. Cárdenas, A. Cornish-Bowden and T. Ureta (1998)
Evolution and Regulatory Role of the Hexokinases
,
Biochim. Biophys. Acta 1401, 242-264
Textbook checklist
Other common errors in textbooks
List of books considered
