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Glucokinase: its regulation and role in liver metabolism

This page describes the book Glucokinase: its regulation and role in liver metabolism by María Luz Cárdenas, published by R. G. Landes Company (1995): ISBN 3-540-59285-7. A Czech translation may be found at

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Published by R. G. Landes Company, (now Landes Bioscience), Austin, Texas, 1995 in the Molecular Biology Intelligence Unit series

Hardback: US and Canada ISBN 1-57059-207-1; International ISBN 3-540-59285-7

210 pages, $89.00

Enquiries may be addressed to the Publisher: Landes Bioscience, 810 S Church Street, Georgetown, Texas, USA 78626, or PO Box 4858, Austin, Texas, USA 78765; fax 512 863 0081

International copyright 1995, Springer-Verlag, Heidelberg, Germany

The book appears to be out of print and is no longer listed in the catalogues of either Landes Bioscience or Springer-Verlag.


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This book describes an enzyme that has long interested both physiologically and kinetically minded biochemists, the former because of its importance in liver function, and the latter because of its unusual kinetics for a monomeric enzyme. It provides an example of a single gene that codes for two different proteins, producing a pancreatic enzyme that is slightly different from the one that occurs in the liver, and during the last few years the development of molecular genetics has given a new lease of life to the subject.

Hexokinase D (EC, often called glucokinase) is the characteristic isoenzyme of hexokinase in the liver, and it is responsible for glucose phosphorylation in hepatocytes. Its importance derives from the fact that glucose uptake by the liver is an essential physiological process, crucial for glucose homeostasis. This point will be present throughout the book.

Hexokinase D has attracted attention since its discovery because of the effects of diet and hormones on its level of activity. These effects correspond to changes in the amount of enzyme, i.e. in gene expression, and will be described in Chapter 1 and further developed in Chapter 8, where the molecular bases for gene expression under different conditions will be discussed.

The name glucokinase, together with the earlier classification as EC, contrasts with treatment of the other isoenzymes in higher organisms, which have always been known under the broader denomination of hexokinases (EC The implication that it is an enzyme specific for glucose, like certain bacterial glucokinases, is quite misleading, as vertebrate glucokinase can also phosphorylate other hexoses, such as mannose, 2-deoxyglucose and fructose. In Chapter 2 I shall describe the origin of this misleading name and discuss why it is misleading.

The fact that the name glucokinase is misleading has created a difficult problem of deciding what to call the enzyme in the book. In the title, I have stayed with glucokinase, albeit with quotation marks, because this is the name that most biochemists use, whether rightly or wrongly, and I want potential readers to know what the book is about. Within the book itself, using quotations marks throughout would certainly be so irritating to many readers that it would be self-defeating. Omitting the quotation marks, on the other hand, would perpetuate an error and lead to confusion in the contexts where I need to refer to the genuine glucokinases that are found in bacteria and other lower organisms. I have opted, therefore, for the name that is most satisfactory in the research literature and is the least objectionable, namely hexokinase D. Provided the reader realizes that this name refers to the enzyme that many people call glucokinase (or sometimes hexokinase IV) there should be no misunderstanding. In other publications, where the name glucokinase remains very common, readers should try to read it with quotation marks even if they not written, unless, of course, the article is about an enzyme that is really specific for glucose.

As regulation of an enzyme by changes in its total activity is a long-term form of regulation, one might expect that additional and faster mechanisms should exist to allow fine adjustment of the activity of hexokinase D in response to the physiological conditions of variable input of glucose. As will be described in Chapter 3, the kinetic characteristics of hexokinase D allow this fine adjustment. hexokinase D is half-saturated at a high concentration of glucose that is within the range of physiological concentrations of glucose arriving in the liver; moreover, the effect of this high value is supplemented by kinetic cooperativity with respect to glucose. This kinetic cooperativity is particularly interesting, as discussed in Chapter 6, not only because of its physiological role of increasing the sensitivity of the response to varying glucose concentrations, but also because hexokinase D is a monomeric enzyme with a single binding site for glucose, which means that the traditional binding models to explain cooperativity cannot be applied.

Hexokinase D accounts for more than 85% of the total glucose phosphorylating activity of the liver, although, as described in Chapter 1, it is just one of four hexokinase isoenzymes in the liver. Moreover, as presented in Chapter 4, all four of them are present in the hepatocyte, the only type of liver cell in which the hexokinase D gene is expressed. It follows that hexokinase D gene expression is specific for one cell type and active hexokinase D has been unambiguously detected only in hepatocytes and pancreatic β-cells. Despite this, several authors have described a glucose phosphorylating activity of low affinity in various tissues that they have identified as glucokinase (meaning hexokinase D), but in reality this enzyme is not a hexokinase D but an N-acetylglucosamine kinase. The reasons for the confusion and the precautions needed for avoiding it are described in Chapter 4.

In this book I deal mainly with liver hexokinase D. However, as hexokinase D plays an important role in controlling glucose phosphorylation and metabolism in both the liver and pancreatic islets, and as metabolism controls hexose-induced insulin release, the metabolic role of liver hexokinase D cannot be properly analyzed without reference to the pancreatic enzyme. Pancreatic hexokinase D is the major enzyme that phosphorylates glucose upon entry into islet β-cells. The slight differences in aminoacid sequence from the liver enzyme that result from different processing of the same gene are described in Chapter 5. The important role played by hexokinase D in regulating insulin secretion and the uptake of glucose by the liver has led its gene to be identified as a prime candidate for one whose genetic variation or altered regulation could contribute to the development of type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM). Chapter 5 therefore also describes the connection between hexokinase D and NIDDM, which is responsible for much of the current interest in hexokinase D.

For a long time the control by substrate concentration represented the only known type of fast regulation of hexokinase D. It is now clearly established that there is an additional short-term regulation by the action of a regulatory protein; this will be presented in Chapter 7.

Some readers may feel that I pay too much attention in this book to the history of our knowledge and understanding of hexokinase D, and may feel that there is no reason for the modern experimenter to know why we had particular ideas — many now discarded — at particular times. However, I make no apology for this emphasis, because we can only avoid repeating the mistakes of the past if we understand why they were made in the first place. The possibility of large-scale production of mutant forms of hexokinase D with selected properties has opened the way towards doing many interesting experiments that could not be done in the 1970s; but if these are done without understanding of the behavior that led to confusion between hexokinase D and N-acetylglucosamine kinase, and of the precautions that need to be taken for ensuring that the cooperativity is not an artefact, the same confusion will certainly occur again.

I am grateful to the Faculty of Sciences of the University of Chile for appointing me to the visiting Chair set up in memory of the late Professor Hermann Niemeyer Fernández. Professor Niemeyer was one of the pioneers in the study of hexokinase D, and introduced me to it when I was his student; his spirit is very much present in the book. Later visits to his former laboratory in Santiago have been very stimulating for writing the book, and I thank the members of the laboratory, especially Dr Tito Ureta, for giving me the opportunity to do some of the work on it there. It has also greatly benefitted from the criticisms of my colleague Dr Athel Cornish-Bowden, and his aid in preparing the figures and tables; his invaluable help and encouragement has made the whole project possible. (He is my husband as well as my colleague, and I am grateful to hexokinase D for bringing about our meeting). I would also like to thank my daughter Isadora for her patience and understanding during the many hours she has spend in the laboratory over the past months to allow this book to be completed, and for her constant love and support. Finally I thank Mr J. Victor, the librarian of the CNRS campus in Marseilles, and his colleague Mrs. M. Charpin, for help in tracking down many of the references.

I want to end by quoting some words of Dr S. A. Kauffman from the Preface to his recent book The Origins of Order, which express my own thoughts very accurately: Authors know that books are not easily written. This one has been no exception. Yet writing a scientific book can be like writing a novel. Ideas, like characters, once loose upon a page harbor their own unsuspected paths, and mingle with their own logic. If useful, they have progeny.


1. Diet and carbohydrate utilization: glucokinase, an adaptive enzyme

2. Glucokinase or hexokinase?

3. Kinetic and structural properties of hepatic hexokinase D, a monomeric cooperative enzyme

4. Tissue and cellular distribution of hexokinase D

5. Pancreatic and liver glucokinase: one gene, two proteins

6. Instantaneous regulation

7. Short-term regulation: the regulatory protein

8. Control of gene expression


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