Biochemistry of the Elements – serie

There can be few elements with a biochemistry as coherent as that of sulfur. This important element is crucial to myriad aspects of metabo­ lism, catalysis, and structure. The plurality of functions in which sulfur is involved derives squarely from the numerous oxidation states in which it may exist, some having great stability, some being capable of ready redox interconversions, and yet others having great instability. As a result, the flux of sulfur from the geosphere through the various kingdoms of life leaves few biochemical processes unaffected. Although there are large gaps in the fabric of our basic knowledge of sulfur biochemistry, it is sufficiently framed to allow a unified and organized story, a story which many of the best-known names in bio­ chemistry have helped to write. It has been both a task and a privilege to try and summarize this story, one that is enormous, complex, fast­ moving, still developing and, above all, exciting. I suppose that no mo­ nographer of such a vast subject could be satisfied with his efforts. It is unfortunately probable that in attempting this task I have made as many errors as a Stilton cheese has blue streaks, and as many omissions as a Swiss cheese has holes. Perfection is not to be achieved in a monograph. Inasmuch as I have succeeded, the credit belongs to those whose efforts gave us the knowledge we have. Where I have failed, the fault is only mine.

Copper has long been known as essential to living systems, in part through its fundamental role in electron transport and respiration. Over the years into the present, its involvement in an ever increasing number of processes in all kinds of organisms has become apparent, and new and exciting vistas of its roles in such areas as the central nervous system, and in humoral functions, are appearing on the horizon. Although the biochemistry of this element has not been studied nearly as much as that of many others, a for­ midable amount of work has been carried out. It has thus been a challenge to produce a summary of what has been found that provides both breadth and depth. My goal has been to try to be as comprehensive as possible, within some limitations. I have tried to provide basic information and basic data that should continue to be useful for a long time. The goal has also been to interpret where we currently stand in our knowledge of the structure, function, regulation, and metabolism of Cu-dependent processes and sub­ stances, especially proteins. Thus, I have tried to make this a source book for historic as well as current information on all aspects of copper bio­ chemistry, and a summary of our current knowledge of copper-dependent proteins and processes. Most of the research on copper has been carried out on vertebrates, especially mammals. This has played a role in the organization of the book.

In response to the worldwide health problems caused by nutritional zinc deficiency, coupled with the remarkable advances in our knowledge of zinc metabolism, the author has written this monograph on the clinical effects of this important mineral. Dr. Prasad focuses on biochemical aspects, but also includes chapters on toxicity and assessment techniques in order to provide clinicians who encounter zinc related problems in their practice with a practical reference source.

In this timely monograph, the author summarizes the rapidly growing body of knowledge regarding nickel by providing a balanced discussion of its harmful and beneficial effects. Coverage includes a history of nickel; the chemistry of nickel, descriptions of the four known enzymes which contain nickel; and nickel metabolism in microbes, plants, and animals. Taken as a whole, Dr. Hausinger's work will highlight key features of this important element and help define future research.

Biochemistry of Scandium and Yttrium gathers together existing knowledge about scandium and yttrium from a wide variety of disciplines. Part 1 will present a comparative study of the physical and chemical properties of scandium and yttrium, looking at both their similarities and their differences. (Part 2 will address the biochemical aspects of these two elements, and the various medical and environmental applications.) While these elements are relatively rare in nature, these books will show that they have unusual physical and chemical properties, and a disproportionate number of important applications. Improved analytical techniques have revealed that scandium and yttrium are present throughout living matter, even though only a relatively limited number of species have been analyzed so far. This fact of course has far-ranging implications for biological and environmental concerns. Part 1 also contains a discussion of the interactions of scandium and yttrium with molecules of biological interest, such as organic acids, carbohydrates, proteins, nucleotides, and other biologically active molecules. The major impacts of scandium and yttrium in science, technology, and medicine will be of interest to a wide variety of researchers, including geochemists, inorganic and organic chemists, clinical biochemists, and those specializing in environmental protection. Biochemistry of Scandium and Yttrium, Part 1 and Part 2 will be especially welcome because the last book published on the biochemistry of scandium appeared over 20 years ago, and the only book mentioning the biochemistry of yttrium came out in 1990.

Biochemistry of Scandium and Yttrium gathers together existing knowledge about scandium and yttrium from a wide variety of disciplines. Part 2 addresses the biochemical aspects of these two elements, and the various medical and environmental applications. (Part 1 presents a comparative study of the physical and chemical properties of scandium and yttrium, looking at both their similarities and their differences.) While these elements are relatively rare in nature, these books will show that they have unusual physical and chemical properties, and a disproportionate number of important applications. Improved analytical techniques have revealed that scandium and yttrium are present throughout living matter, even though only a relatively limited number of species have been analyzed so far. This fact of course has far-ranging implications for biological and environmental concerns. The major impacts of scandium and yttrium in science, technology, and medicine will be of interest to a wide variety of researchers, including geochemists, inorganic and organic chemists, clinical biochemists, and those specializing in environmental protection.

This book is written for the research biochemist who needs to know more about the particular field of dioxygen metabolism, whether this be for designing lectures for a graduate level course or for his or her own research needs. We hope researchers in a given area of dioxygen metabolism will gain knowledge of related fields of dioxygen metabolism. We have decided to use the term dioxygen to distinguish molecular oxygen from divalent oxygen in water and organic compounds, dioxygen being a simpler term than molecular oxygen. We do not intend to review the metabolism of all compounds that contain oxygen, since this would include all of biochemistry. An understanding of dioxygen chemistry is essential to the discussion of the biochemistry of dioxygen. While this statement could be made about any biochemical constituent, the chemistry of dioxygen is so unusual that interpre­ tations without detailed chemical background are futile. Prediction of dioxygen reaction products by analogy with other oxidants is impossible. The partial reduction products of dioxygen, superoxide ion and peroxides, develop naturally in the chemistry of dioxygen. It would be difficult to discuss dioxygen biochemistry without first discussing these partial reduction products.

Biochemistry of Scandium and Yttrium gathers together existing knowledge about scandium and yttrium from a wide variety of disciplines. Part 2 addresses the biochemical aspects of these two elements, and the various medical and environmental applications. (Part 1 presents a comparative study of the physical and chemical properties of scandium and yttrium, looking at both their similarities and their differences.) While these elements are relatively rare in nature, these books will show that they have unusual physical and chemical properties, and a disproportionate number of important applications. Improved analytical techniques have revealed that scandium and yttrium are present throughout living matter, even though only a relatively limited number of species have been analyzed so far. This fact of course has far-ranging implications for biological and environmental concerns. The major impacts of scandium and yttrium in science, technology, and medicine will be of interest to a wide variety of researchers, including geochemists, inorganic and organic chemists, clinical biochemists, and those specializing in environmental protection.

Biochemistry of Scandium and Yttrium gathers together existing knowledge about scandium and yttrium from a wide variety of disciplines. Part 1 will present a comparative study of the physical and chemical properties of scandium and yttrium, looking at both their similarities and their differences. (Part 2 will address the biochemical aspects of these two elements, and the various medical and environmental applications.) While these elements are relatively rare in nature, these books will show that they have unusual physical and chemical properties, and a disproportionate number of important applications. Improved analytical techniques have revealed that scandium and yttrium are present throughout living matter, even though only a relatively limited number of species have been analyzed so far. This fact of course has far-ranging implications for biological and environmental concerns. Part 1 also contains a discussion of the interactions of scandium and yttrium with molecules of biological interest, such as organic acids, carbohydrates, proteins, nucleotides, and other biologically active molecules. The major impacts of scandium and yttrium in science, technology, and medicine will be of interest to a wide variety of researchers, including geochemists, inorganic and organic chemists, clinical biochemists, and those specializing in environmental protection. Biochemistry of Scandium and Yttrium, Part 1 and Part 2 will be especially welcome because the last book published on the biochemistry of scandium appeared over 20 years ago, and the only book mentioning the biochemistry of yttrium came out in 1990.

Atomic biology has come of age. Interest in the role of chemical elements in life processes has captured the imagination of a wide spectrum of research scientists-ranging from the nutritionist to the biochemist, the inorganic chemist, and even to some biophysicists. This series, Biochemistry of the Elements, is a recognition of this increasing interest. When complete, the books will assemble the hard facts concerning the biochemistry of each element-singly or in a logical grouping. The series will provide a permanent reference for this active and growing field. Each volume shall represent an integrated effort by one or several authors to describe the current knowledge of an element(s) or the methods by which it is studied. Iron is the only element to which we have devoted two volumes, because its biological and chemical role is so versatile and complex. These two volumes will treat the two main structural categories of iron: heme and nonheme iron. In this volume on nonheme iron, the first in the series, Anatoly Bezkorovainy provides what we believe is the most comprehensive treatment of this important topic.

In recent years many exciting research results have indicated that selen- ium, depending on its concentration, can influence mammalian metabo- lism. It has been estimated that in selenium-deficient areas, selenium or selenium-vitamin E combinations added to animal feed can prevent an- nuallosses to beef and dairy cattle and sheep valued at 545 million dollars and poultry and swine losses valued at 82 million dollars. Some animal diseases that can be prevented by a selenium-supple- mented diet include liver necrosis, nutritional muscular dystrophy, exu- dative diathesis, pancreatic degeneration, mulberry heart disease, infer- tility, growth impairment, periodontal disease, and encephalomalacia. Selenium intake levels are dependent on the plant or animal feed con- centrations, which, in turn, are dependent on the pH of the soil and the types of rocks from which the soils are derived. At normal metabolic levels selenium possesses an antioxidant affect manifested through glutathione peroxidase, and selenium also has an ef- fect on cytochrome P-450 and heme metabolism. Comparisons are made between metabolism of selenium and sulfur in plants, animals, and hu- mans.At greater selenium intake levels acute poisoning occurs when high-selenium-content (10,000 ppm Se) plants are consumed in large quan- tities. The toxic reactions were first manifested in cavalry horses near Fort Randall, Nebraska, in the 1860s.

The remarkable development of molecular biology has had its counterpart in an impressive growth of a segment of biology that might be described as atomic biology. The past several decades have witnessed an explosive growth in our knowledge of the many elements that are essential for life and maintenance of plants and animals. These essential elements include the bulk elements (hydro­ gen, carbon, nitrogen, oxygen, and sulfur), the macrominerals (sodium, potas­ sium, calcium, magnesium, chloride, and phosphorus), and the trace elements. This last group includes the ultra trace elements and iron, zinc, and copper. Only the ultratrace elements are featured in this book. Iron has attracted so much research that two volumes are devoted to this metal-The Biochemistry of Non-Heme Iron by A. Bezkoravainy, Plenum Press, 1980, and The Biochemistry of Heme Iron (in preparation). Copper and zinc are also represented by a separate volume in this series. The present volume begins with a discussion of essentiality as applied to the elements and a survey of the entire spectrum of possible required elements.

This volume is intended for students and professionals in diverse areas of the biological and biochemical sciences. It is oriented to those who are unfamiliar with the use of physical methods in studies of the biological elements. We hope the reader will find the material a helpful reference for other volumes of this series as well as the general literature, and some may see ways to adopt these techniques in their own pursuits. Every effort has been made to avoid an abstruse presentation. It should be clear that one individual cannot be expert in all the disciplines considered here (and the authors recognize that fact with sin­ cere humility). As may be expected of an introductory reference, most of our attention was focused on the commonly used methods. To balance this, we have included a few examples of approaches which are promising but relatively undeveloped at this time. Also, an emphasis has been placed on element selectivity. It is impossible to envision the course of future events, and a volume which deals with instrumentation is especially prone to become outdated. Nevertheless, any valid approach to a scientific question should be applicable indefinitely.

The present book might be regarded as a sequel to my previous work, Bioinorganic Chemistry: An Introduction (Allyn and Bacon, 1977). The latter is essentially a collection of chemical and physical data pertinent to an understanding of the biological functions of the various elements and the proteins dependent on them. The ten years since its publication have seen an enormous increase in research activity in this area, hence of research papers. A number of monographs and review series on specific topics have also appeared, including the volumes in the series of which the present volume is a part. Nevertheless, a gap has developed between the flood of information available at a detailed level (papers and reviews) and a general description of the underlying principles of biofunctions of the elements as presently conceived. It is hoped that this book will help bridge this gap and at the same time provide an overview of the entire Biochemistry of the Elements series. Specifically, the work attempts to focus on "why" questions, especially, "Why has an element been chosen by organisms for a specific biofunction?" and "Why does an element behave the way it does in biological systems?" It therefore complements my 1977 book and, together with Laboratory Introduction to Bio-Inorganic Chemistry (E. -I. Ochiai and D. R. Williams, Macmillan, 1979), completes a trilogy on the topic of bioinorganic chemistry. This book consists of five parts. Two chapters constitute Part I.

The elements in group 17 (VIlA) of the periodic table of elements-fluorine (F), chlorine (CI), bromine (Br), and iodine (I)-were designated by Berzelius as "halogens" (Greek hals, sea salt; gennao, I beget) because of their propensity to form salts. In this first of the two volumes of Bio­ chemistry of the Halogens, the biochemistry of the elemental halogens and inorganic halides is reviewed. Discovery, properties, and biochemistry of the elemental halogens are reviewed first (Chapter 1). This is followed by a review of the developments in the various areas of inorganic halide biochemistry (Chapters 2 through 5). The biochemistry of thyroid hor­ mones is considered in Chapter 6, while biohalogenation, an important link between inorganic and organic halogen biochemistry, is reviewed in Chapter 7. Chapter 8 covers the biochemistry of products produced by human-inspired halogenation, in particular, poly halogenated compounds that present environmental problems. In Chapter 9, the process is reversed and biodehalogenation is reviewed. In each subject, the attempt has been made to find an appropriate balance between depth and breadth of treatment, since a thorough, in­ depth review of this field would not be possible in a single volume. To provide readers not familiar with subjects with the necessary background to place subsequent discussions in perspective, brief historical develop­ ments of many of the topics are given.

By a happy coincidence, the completion of this text coincided with the 200th anniversary of the discovery of gadolinite, the mineral with which the lanthanide story begins. For a group of elements which occur in only trace amounts biologically, and which have no known metabolic role, the lanthanides have spawned a surprisingly large biochemicalliterature. Se­ rious interest in the biochemical properties ofthese elements can be traced to concerns about the safety of radioactive lanthanides toward the end of World War 11. As recent events at Chernobyl indicate, this concern re­ mains topical. However, the literature on lanthanide biochemistry pre­ dates the atomic era, beginning with sporadic, medically motivated studies in the latter part of the 19th century. Much of the present biochemical activity involving the lanthanides centers around their ability to provide 2 important information on the interactions of Ca + with macromolecules and with eukafyotic cells. With the increasing industrial use of the lan­ thanides, their toxicological properties will need to be examined more closely. Rare earth pneumonoconiosis has already been identified as a disease produced by industrial exposure to lanthanides. Several of the biochemical properties of the lanthanides are of relevance to modern medicine. Already cerium-based ointments are used to treat burn wounds, while paramagnetic lanthanides find application in nuclear magnetic res­ onance imaging. This book is an attempt to collate and to present in reasonable detail existing knowledge of lanthanide biochemistry before the literature be­ comes unmanageable.

Biochemistry of Halogenated Organic Compounds has been written as a general reference source for researchers in several related areas, including organic chemists, medicinal chemists, pharmacologists, toxicologists, and medical researchers. The development of halogenated compounds as medicinal agents and pharmacological tools and the fascinating biochemi­ cal processes that have been discovered and studied using these analogues have generated extremely active areas of research and an enormous volume of literature. Thus, halogenated organic compounds pervade every aspect of biochemistry, a fact made apparent by the numerous reviews and monographs available on individual topics-halogenated nucleosides, halogenated carbohydrates, and so forth. Given the quantity of material already written on these topics, some of which material is quite current, it might be asked whether a one-volume review of these subjects is useful, or possible. Having now completed this work, I feel the answer to both questions is an emphatic yes. There are fascinating stories to be related in each area, and, where appropriate, I have attempted to develop these topics . from a historical perspective. For example, the discovery of the anticancer activity of fluorouracil, the unraveling of the several mechanisms of its action, and the development of a host of later generations of anticancer and antiviral agents based on the parent fluoro-, iodo-, bromo-, and trifluoromethylpyrimidines were, and are, contributions of major magnitude to medical science.

Copper has long been known as essential to living systems, in part through its fundamental role in electron transport and respiration. Over the years into the present, its involvement in an ever increasing number of processes in all kinds of organisms has become apparent, and new and exciting vistas of its roles in such areas as the central nervous system, and in humoral functions, are appearing on the horizon. Although the biochemistry of this element has not been studied nearly as much as that of many others, a for­ midable amount of work has been carried out. It has thus been a challenge to produce a summary of what has been found that provides both breadth and depth. My goal has been to try to be as comprehensive as possible, within some limitations. I have tried to provide basic information and basic data that should continue to be useful for a long time. The goal has also been to interpret where we currently stand in our knowledge of the structure, function, regulation, and metabolism of Cu-dependent processes and sub­ stances, especially proteins. Thus, I have tried to make this a source book for historic as well as current information on all aspects of copper bio­ chemistry, and a summary of our current knowledge of copper-dependent proteins and processes. Most of the research on copper has been carried out on vertebrates, especially mammals. This has played a role in the organization of the book.

In this timely monograph, the author summarizes the rapidly growing body of knowledge regarding nickel by providing a balanced discussion of its harmful and beneficial effects. Coverage includes a history of nickel; the chemistry of nickel, descriptions of the four known enzymes which contain nickel; and nickel metabolism in microbes, plants, and animals. Taken as a whole, Dr. Hausinger's work will highlight key features of this important element and help define future research.

There can be few elements with a biochemistry as coherent as that of sulfur. This important element is crucial to myriad aspects of metabo­ lism, catalysis, and structure. The plurality of functions in which sulfur is involved derives squarely from the numerous oxidation states in which it may exist, some having great stability, some being capable of ready redox interconversions, and yet others having great instability. As a result, the flux of sulfur from the geosphere through the various kingdoms of life leaves few biochemical processes unaffected. Although there are large gaps in the fabric of our basic knowledge of sulfur biochemistry, it is sufficiently framed to allow a unified and organized story, a story which many of the best-known names in bio­ chemistry have helped to write. It has been both a task and a privilege to try and summarize this story, one that is enormous, complex, fast­ moving, still developing and, above all, exciting. I suppose that no mo­ nographer of such a vast subject could be satisfied with his efforts. It is unfortunately probable that in attempting this task I have made as many errors as a Stilton cheese has blue streaks, and as many omissions as a Swiss cheese has holes. Perfection is not to be achieved in a monograph. Inasmuch as I have succeeded, the credit belongs to those whose efforts gave us the knowledge we have. Where I have failed, the fault is only mine.