Ageing, carcinogenesis and radiation biology, the role of nucleic acid addition reactions

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294 mones. We are told in Chapter 3 that we need not define too closely the term peptide hormone : ‘it is used in this contribution to mean a polypeptide of known constitution, with a molecular weight of less than 10,000 daltons which has, or may be presumed to have hormonal activity.’ However, four other chapters concern the growth hormone family and the two subunit glycoprotein hormones which have molecular weights in excess of 20,000. ‘Polypeptide hormones’ may have been a more appropriate title. The text, which derives from a meeting sponsored by the Biological Council in 1974, is divided into three sections. The first of these concerns general aspects of the hormones. It begins with a concise summary of the chemistry by J. Rudinger, one of the most outstanding peptide chemists working in this area, whose death sadly occurred last year. However, the discussion in the subsequent chapter of the conformation of hormones represents the most unsatisfactory part of the book. We are treated to diagrams of the cc-helix and /?-sheet - hardly an imaginative contribution - followed by several pages of discussion and methods of conformation prediction which can only be noted for their unreliability. However, there is no mention of the precise determination of the structure of insulin nor of the nuclear magnetic resonance studies of small peptides like oxytocin which must surely be more useful in defining conformations important for receptor binding. Other introductory sections concern the evolution of polypeptide hormones, both in terms of sequence homologies (H.D. Niall) and (A. G. relationships developmental Pearse). A review by D. F. Steiner of hormone precursors contains an interesting discussion of some possible functions of precursors. This is a complicated area; precursors may play many roles including regulation of the secretory product, and precise adjustment of the hormone in terms of not only receptor binding properties but also metabolism, degradation and vascular permeability. Alternatively, the larger sequences may be related to the constraints of transcriptional or translational unit size or to their evolution reflecting their origin from pre-existing gene products. In another chaper J.T. Potts discusses preproparathyroid hormone ; the more recent of other pre-prohormones discovery makes this a general phenomenon which may be related to sequestration of the hormone by the endoplasmic reticulum, immediately after or during synthesis. Endocrine pharmacology is also dealt with in a very useful and well written contribution by J. A. Parsons. The assumption

that hormones do not cause side effects is challenged and the discussion shows that overall patterns of response in vivo vary qualitatively not only with dose but also with the rate and site at which the hormone enters the circulation. This is clearly important in the clinical use of these hormone preparations. The second section comprises reviews of individual hormones. Almost all are contributed by distinguished innovators in their fields of research, G. F. Cahill, M. I. Grossman, R. E. Canfield, R. Guillemin, G. E. Bisset, to name a few. They are concisely written and in general cover the whole range of biochemical and physiological aspects of the hormone, at the same time emphasising recent some important results. In particular, W. S. Peart’s discussion of the renin-angiotensin system is very well presented and its interest is even further heightened by the results, in the last year, on the relation of the enkaphalins to fl-lipotropin which probably involves an enzyme system similar to renin. The final section reviews the biochemical mechanisms of hormone action. Although there are interesting contributions on ACTH-receptor interactions by Schwyzer and Schulster’s groups, the book fails to reflect the great excitement and interest in this area during the last seven years which has qualitatively changed our understanding of hormone action. There is, however, a very useful discussion by P. Cohen which highlights the problems of finding the intracellular sites of action of those hormones like insulin where the nature, and even the existence, of a second messenger is the subject of continued debate. This is a very useful text which is probably the best starting point for students interested in learning about polypeptide hormones in general. It is also one to which I will often make reference. It should be an important part of the library of any research group working with polypeptide hormones. TOM BLUNDELL

T. Blurtdeli is Professor of Crystallography of Molecular Biology and Director of a research group concerned with the structure andbiology ofpolypeptide hormones, at Birkbeck College, University of London, London, U.K.

Helpful

to specialists

Ageing, Carcinogenesis and Radiation Biology, the Role of Nucleic Acid Addition Reactions edited by K. C. Smith, published by Plenum Press, New York and London, 1976. $47.40 (approx &25.-) (xi+561 pages)

The association between, or a unifying theme to link, the three subjects in the title of this book will by no means be immediately obvious to the majority of potential readers. It is therefore very much to the credit of K. C. Smith and the many contributors to this volume that they have kept this objective to the fore in their presentations and have made a strong case for considering that research activities in these three fields have much in common. More specifically the intention has been to delineate a role for nucleic acid addition reactions, and particularly those involving nucleic acids and proteins, in these various areas of research. I shall not attempt to comment on individual chapters or contributions, which would probably only reflect personal interests and prejudices, but rather I shall attempt to give an indication of the broad areas covered by the twenty-four separate articles. Thus there are articles on four main areas of research which relate to the topic of nucleic acid adducts. The first is concerned with such aspects as the contentious role of protein linkers in DNA in determining the architecture of the eukaryotic chromosomal DNA, and how DNA is attached to membranes, and the involvement of membranes in DNA replication and chromosomal segration. The basis for the specificity of such reactions as the interaction of a repressor with its operator DNA, of DNA polymerase with DNA, of ribosomal protein .with RNA, of aminoacyl transfer RNA synthetase with transfer RNAs are important current questions which involve DNA-protein interactions. The selective control of localised DNA strand separation to permit RNA synthesis during transcription and the onset of DNA synthesis during gene replication are no doubt mediated by a variety of associated chromatin molecules, and these processes are presumably vitally involved in the mechanisms of both ageing and carcinogenesis. The inclusion of some recent concepts on the structure of chromatin and its role in these processes would therefore have added to the completeness of the volume. It is relevant that cross-linking techniques evolved in radiation biology have now been used to investigate packing arrangement of the DNA in phage, the association of sites between specific ami-

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noacyl tRNA synthetases and their specific tRNAs and the active sites of enzymes. It can be reasonably argued that the above general background knowledge is essential for an understanding of a second area of research which concerns the cellkilling and mutagenic effects of radiation and chemicals. It is now axiomatic that reactions with DNA play a central role in the production of these effects and, therefore, that a knowledge of DNA repair processes is a prerequisite for a fuller understanding of the mechanisms involved. Many chapters are therefore devoted to a detailed description of the chemical structures formed following ultraviolet or ionising irradiation of nucleic acid bases and model macromolecules in vitro. The topic is developed naturally into a detailed discussion of the effects of these various DNA reactions in more complex biological systems. However, apart from nucleic acid reactions, other reactions involving both protein and DNA also occur in cells as a consequence of radiation. The recognition by some authors of limitations in our knowledge of the exact role of some of these reactions in eliciting diverse biological effects, the nature of the adducts formed between DNA and protein and whether or not they are recognised by cellular repair processes which protect cells from both the lethal and mutagenic effects of radiation, served to focus attention on important and to some extent neglected areas of study. The now generally-accepted view that almost all known chemical carcinogens will react with DNA, either directly or following metabolic activation, provides the link between the radiation biologist and the cancer research worker. A third major area covered by this volume is therefore concerned with the details of these chemical reactions with DNA, the mechanisms by which the DNA damage is repaired and much original and imaginative discussion on how modifications to DNA could eventually lead to the production of the transformed cell. It emerges that while mutagenic events may be well understood in bacteria we are only on the threshold of the subject as far as mammalian cells are concerned. The possibility that mutations arise by faulty DNA repair was discussed in detail with particular reference to genetic, environmental and developmental factors such as differentiation and ageing. This last factor in carcinogenesis is a suitable introduction to the fourth fundamental field of research to which this volume is devoted, namely the relevance of DNA and protein adducts to the cross-linking theory of ageing. The parallel between radiation and age-induced changes in chromatin, sug-

gesting that there may be an agedependent accumulation of DNA adducts, therefore provides the link between research into ageing and radiation biology. With ageing there may be a decrease in the efficiency of the repair processes which normally eliminate these cross-links, and lead to the observed age-dependent increase in chromosome damage. It is evident that the contents of this volume go far to justify its title, in the sense that it contans a well-integrated collection of papers on a number of broad but separate topics of research which nevertheless have much in common. The volume will therefore be particularly helpful to the specialist in the field of, say, radiation biology or cancer research for its coverage of fundamental developments in such related fields as the structure of macromolecules which may be modified by radiation or chemicals. The book is well presented and the characteristic print makes for easy reading. The rapid publication of the proceedings of the meeting on which the book is based should serve as an example to other publishers and meeting organisers. It is clear that much recent material is included as evidenced by the abundance of recent references. It would have been improved by a more comprehensive index, but it is nevertheless to be highly recommended to all who can afford the $47.40. J. J. ROBERTS J. J. Roberts is Senior Lecturer at the Institute of Cancer Research, University of London, Chester Beatty Research Instiiute. Poliards Wood Research Station, Buckinghamshire, U.K.

Taste and smell Structure-Activity Relationships in Chemoreception editedby G. Benz, published by Information Retrieval Ltd, London, Washington D.C. &IO.- ($20.-) (xxi+ 232 pages) Attempts to correlate molecular structure of a stimulus to the magnitude and quality of chemoreceptive response it elicits have been made ever since chemoreceptor systems have been studied. Cohn published a book in 1914 entitled Die Organisthen Geschmacksstoffe in which he related in 936 pages the tastes of various molecules and correlated them to their structures. Today, much more is known concerning both the structure of molecules and the types of chemoreceptive activities they elicit. The book reviewed here is a collection of papers given at a mini-symposium held in Switzerland in 1975. The first section of the book provides a quick insight into membrane structure, drug-receptor interactions, antigen recog-

nition, ligand binding and enzyme-substrate interactions. The second section deals with taste. An a-glucosidase has been isolated from fly legs containing sugar receptor cells. It is hypothesized that this enzyme acts as a receptor protein and its substrate patterns are compared to the specificity pattern of the fly’s sugar receptor. The next article by Kijima is of great importance because it shows that there exists more than one type of sugar receptor site in the fly. A ‘pyranose site’ and a ‘furanose site’ have been proposed and a-glucosidase may be the receptor molecule of the ‘pyranose site’. The sweet taste of a molecule has been related to its ability to bind to the receptor with two hydrogen bonds 2.5-4.0 A apart. Kier presents evidence for a third binding site that involves dispersion interaction with the receptor. Birch gives evidence that only one sugar residue in an oligosaccharide binds to the receptor and that sugar residues are ‘polarized’ so that one end elicits sweetness and other bitterness. The third section of the book is concerned with olfaction. Perhaps the most informative treatment in this book is that by Kaissling, who stresses the complexity of a chemoreceptor cell and the danger in treating the structure-activity problem too simply. Evidence was obtained from his many studies of insect olfaction, particularly those with pheromones. Two other chapters outline properties of the peripheral and central nerve processes of the olfactory system. The olfaction section is concluded with two different approaches to odor-receptor interaction. Laffort suggests that the aflinity of the odor for the receptor depends upon the molecular. volume, proton affinity, local polarizability and proton donor ability and that values for these can be obtained from chromatographic studies. Boelens, on the other hand, emphasizes the partition coefficients, electronic properties and steric properties of the odorant molecules. This book is both interesting and yet disappointing. Perhaps this is due to the lack of depth of a multidisciplinary symposium. Modern and definitive information concerning molecular structure of stimuli is almost absent except in a few brief chapters. In most cases the precise nature of the ‘activity’ is also absent. Rigor in defining the quantity and quality of the response measured must be as good as that used in determining physicochemical properties of the stimulus molecule if reliable correlations are to be expected. One of the most interesting and useful features of this book is the discussion that follows each chapter. The topics chosen,