Biochemistry: The chemical reactions of living cells


Metzler, David E.; Metzler; Harcourt/Academic Press, San Diego, 2nd ed., 2001, 1900 pp., ISBN 0-12-492543-X, two-volume set, $170.00.

David Metzler published the first edition of his book (with the same title) in 1977, with 1129 pages and no color or use of tone. The second edition, now in two volumes, has been a long time coming and now runs to 1900 pages, with the use of a second color (green). It hardly needs to be said that Biochemistry has changed a lot since 1977, and indeed the exponential growth of the subject is not reflected in the increased size of the book (fortunately!). The first edition has been on my shelves and has been referred to frequently over the years, whereas other standard texts have found much less regular use. The title of the book is important. It is about chemical reactions, and probably the subtitle is a very good description of what biochemistry is about. The emphasis of the 1977 edition was very much chemical in its approach, reflected in the subtitle. I thought that this chemical approach was all to the good, but I have a feeling that this view was not shared by students, at least by most British students, who find chemistry “hard” (and therefore to be avoided), and who prefer a more descriptive and literally colorful approach. This chemical emphasis continues: in the new book, chapter 12 is entitled “Transforming Groups By Displacement Reactions.” It is interesting to speculate what the average biochemistry student would make of this. In fact, it is about transmethylations, glycosylations, the mechanism of lysozyme, glycogen phosphorylase, all of the proteases, protease inhibitors, blood clotting, and many other enzymes.

We should also remember that in 1977 molecular biology had hardly been invented and that it was a good 10 years after this that biochemical societies and the International Union changed their names to “Biochemistry and Molecular Biology.” As the author says, “during the 24 years between editions biochemistry and the related disciplines of biochemical genetics and molecular biology have blossomed.” What, then, has the new edition to offer? The Preface says that it is aimed at graduate students and undergraduates with an adequate training in chemistry. (These students must also be strong enough to carry a pair of volumes weighing about 7 kg). I would agree with this: I think most undergraduates would be overwhelmed, although this book is a tremendous reference work for both students and professors.

Much of the book, on leafing through, has the same feel or style as the first edition, such as an abundance of detailed chemical structures and reaction mechanisms, as well as boxes dealing with special issues. What is new is the presence of many more photographs (e.g. micrographs, although not all that many) as well as macromolecular structures, very few of which, of course, were available in 1977. Many of the molecular structures are stereo views, some of better quality than others. There are several general themes, such as biomolecular structure, metabolism, enzyme catalysis, and the genetic code, for example, and a wide variety of techniques are dealt with in some detail. The abundant boxes (usually one or two pages long) deal with a range of issues such as Nobel prizes, human diseases, metals such as magnesium and calcium, electron paramagnetic resonance spectroscopy, and many others, and each box has its own reference list, separate from the references at the end of the chapters. The book contains over 17,000 literature references, and some chapters have 1,000 of them! There is also a warning box: “Not everything in this book is true. Despite all efforts to get it right, there are unintentional errors and misinterpretations of experimental results.” A somewhat strange feature is that most of the spectra are shown with a linear scale in wave numbers, making them somewhat unfamiliar (ie. backwards) to those of us accustomed to linear wavelength scales. At the chapter ends there are some study questions. These may be little problems or data-handling exercises, as well as more descriptive questions that start with the words “describe,” “compare,” or “outline.” Two examples will suffice: “List some of the mechanisms that cells can use to combat the toxicity of metal ions?” and “Why can't acetyl CoA be converted to glucose in animals?” These seem to be a bit of an afterthought, perhaps requested by the publisher, and no answers are given. It is not too easy to see how the student might use these.

Early chapters deal with amino acids and proteins, sugars, polysaccharides and glycoproteins, and nucleic acids (very detailed on structure but very little on function at this point, including the PCR and sequencing). The topic of chapter 6 is thermodynamics (Table VI-4 is a huge table of Gibbs' energies of formation and of oxidation for compounds of biochemical interest), and then chapter 7 deals with associations of macromolecules—a vast range—including hemoglobin and HbS. Chapter 8 is about lipids, and chapter 9 is enzymes, comprehensive and detailed. We are then ready to start on the subject of metabolism, which is attacked in chapter 10 as a brief but comprehensive overview in preparation for the succeeding chapters in this first volume. This metabolism chapter deals with digestion, sources of energy, CoA, sugar phosphates, all the pathways of catabolism in outline, the electron transport chain, the biosynthesis and photosynthesis, turnover of macromolecules, transport of proteins, Golgi, post-translational modifications, indeed almost a whole book by itself on metabolism!

The general approach is to deal with all of metabolism, in animals, plants, and bacteria, and this achieves a glorious synthesis, showing how all metabolism is related in different organisms. In some ways it is like looking at the typical metabolic pathways charts. Philosophically this is very satisfying but may not appeal to those students who want their metabolism organized into chunks relating to individual types of organisms. Volume 2 (chapters 17–32) starts with metabolism, now in much greater detail, but Volume 1 continues after this rather breathless outline, with the regulation of enzyme activity, extensive detail about enzymes in chapters 12 (mentioned above) and 13, followed by co-enzymes and redox coenzymes (chapters 14 and 15), and finally chapter 16, the roles of transition metals.

It is worth considering the structure of some of the metabolism chapters (17–25) that form the major part of volume 2, in order to see how subjects are dealt with and what the author is trying to achieve. One major approach is to try to tease out the chemical logic of why certain reactions seem to have been “chosen” by evolution. The following quotation in the section about acetoacetate shows how this works:

“Step a of this sequence is a Claisen condensation, catalyzed by HMG-CoA synthase and followed by hydrolysis of one thioester linkage. It is therefore similar to the citrate synthase reaction [reference to chapter 13]. Step c is a simple aldol cleavage. The overall reaction has the stoichiometry of a direct hydrolysis of acetoacetyl-CoA.”

Chapter 17 starts with the oxidation of fatty acids in animals, plants, and microorganisms, with references to fibrates, and the oxidation of hydrocarbons, as well as to Refsum and Zellweger diseases. Many of the boxes in the book, in fact, deal with metabolic and inherited diseases, and in general these presentations are very well done. They are probably not sufficiently detailed as to make the book all that attractive to medical students, however. Following the fatty acids is the tricarboxylic acid cycle (also in chapter 13, and the history of Krebs' discovery can be found on p. 517), but here again there is an attempt to explain in detail the chemical logic of regenerating substrates. There is a large box on the use of 13C by Harland Wood and C. Werkman referring to a study of the Krebs cycle in 1941, with the inclusion of later NMR studies. One wonders what students will make of this. It is interesting, I suppose, but not something you would remember for an exam or indeed for any purpose. Did the book need this exegesis or would references to the literature have been sufficient for those who wanted to look it up? This illustrates the “fullness” of the text, really the attempt to cover and explain the whole of biochemistry, for whatever reason. No one is going to learn even a small part of this text, so is it a satisfying exercise for the author, with the product being a reference text for others, ie. more than a textbook? It raises the question of what textbooks are for.

After this we have the glyoxylate cycle, the catabolism of sugars (glycolysis, the pentose phosphate pathway), the fermentations and all the bacterial pathways such as mixed acid fermentations. Then we start on biosynthesis, again explaining the chemical logic of “activated” groups and appropriate reducing agents (ie. NADPH), the Calvin-Benson cycle, gluconeogenesis, fatty acid synthesis, substrate cycles, and so on—all of this in chapter 17. Chapter 18 deals with mitochondria in great detail, their structure, mitochondrial DNA, mitochondrial diseases, why mitochondrial DNA exists, the problems of importing proteins into mitochondria, structures of the carriers, thermodynamics, the mechanism of oxidative phosphorylation, and ATPase structure and mechanism; then anaerobic respiration, oxygenases, cytochrome P450s (here a box on the toxicity of acetaminophen), respiratory bursts, etc. The chapter has 614 references at the end. As with all the chapters, there are a couple of pages of questions at the end for self-study. I do not really know how a student might answer the question on p. 1085: “Describe the operation of the F1F0ATP synthase of mitochondrial membranes” but I have to remember that this book is aimed at the postgraduate level and would therefore assume that such a question might come up in graduate courses. Or perhaps those postgraduate students carrying out research in this area would find this section of the book very helpful as a first stop. Chapter 24 starts with the metabolism of nucleic and amino acids. The richness of the text can be illustrated by some of the issues discussed here: skunk odor, Jamaican vomiting sickness (due to eating unripe ackee fruit), onions and garlic, porphyrins, etc. Again, this metabolism is all mixed up, in the sense that prokaryotes and eukaryotes (animals and plants) are dealt with. Chapter 25 is on purine and pyrimidine metabolism.

This takes us to approximately half way through volume 2 when we start on biochemical genetics. Chapter 26 gives a very good overview of the history and the tools and then describes the cell cycle, meiosis, chromosomes, the Human Genome Project (the author gives the number of genes as 50–150,000), and, briefly, bioinformatics. (Curiously Fig 26–8 is a mirror image, one of the few typos in an almost error-free text.) The text continues with quite a lot on our understanding of human disease from this standpoint, including genetic engineering. Pages 1529–1739, a sizable chunk, cover the majority of molecular biology, and subsequently chapter 30 is on cell-cell communication, including the brain, pain, and memory. The last two chapters are on defense, antibodies and complement, etc., and on growth and development. The impression might be that these are rather short sections compared with the extensive sections of, for example, enzymes and those covering metabolism, but one must remember what a vast book this is (the author refers to it as a book, although it is in two volumes, and this is fair enough, the two are not separate texts), and also that the earlier chapters have set a lot of the scene for this later action.

Overall, what to make of this huge compendium of biochemistry (and it is more biochemistry than biochemistry and molecular biology)? As mentioned, it is a tremendous reference work, a gathering together of an enormous amount of information, and not just a gathering together, but importantly, the text attempts to digest and explain the chemical logic of life in all its forms. It obviously represents almost a life's work of scholarship, and I guess it will be an important book for teachers and postgraduates in biochemistry for many years to come.