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Naresuan University Access Provided by: Harper's Illustrated Biochemistry, 32nd Edition Chapter 1: Biochemistry & Medicine Victor W. Rodwell OBJECTIVES OBJECTIVES After studying this chapter, you should be able to: Understand the importance of the ability of cell­free extracts of yeast to ferment sugars, an observation that enabled discovery of the intermediates of fermentation, glycolysis, and other metabolic pathways. Appreciate the scope of biochemistry and its central role in the life sciences, and that biochemistry and medicine are intimately related disciplines. Appreciate that biochemistry integrates knowledge of the chemical processes in living cells with strategies to maintain health, understand disease, identify potential therapies, and enhance our understanding of the origins of life on earth. Describe how genetic approaches have been critical for elucidating many areas of biochemistry, and how the Human Genome Project has furthered advances in numerous aspects of biology and medicine. BIOMEDICAL IMPORTANCE Biochemistry and medicine enjoy a mutually cooperative relationship. Biochemical studies have illuminated many aspects of health and disease, and the study of various aspects of health and disease has opened up new areas of biochemistry. The medical relevance of biochemistry both in normal and abnormal situations is emphasized throughout this book. Biochemistry makes significant contributions to the fields of cell biology, physiology, immunology, microbiology, pharmacology, toxicology, and epidemiology, as well as the fields of inflammation, cell injury, and cancer. These close relationships emphasize that life, as we know it, depends on biochemical reactions and processes. DISCOVERY THAT A CELL­FREE EXTRACT OF YEAST CAN FERMENT SUGAR Although the ability of yeast to “ferment” various sugars to ethyl alcohol has been known for millennia, only comparatively recently did this process initiate the science of biochemistry. The great French microbiologist Louis Pasteur maintained that fermentation could only occur in intact cells. However, in 1899, the brothers Büchner discovered that fermentation could occur in the absence of intact cells when they stored a yeast extract in a crock of concentrated sugar solution, added as a preservative. Overnight, the contents of the crock fermented, spilled over the laboratory bench and floor, and dramatically demonstrated that fermentation can proceed in the absence of an intact cell. This discovery unleashed an avalanche of research that initiated the science of biochemistry. Investigations revealed the vital roles of inorganic phosphate, ADP, ATP, and NAD(H), and ultimately identified the phosphorylated sugars and the chemical reactions and enzymes that convert glucose to pyruvate (glycolysis) or to ethanol and CO2 (fermentation). Research beginning in the 1930s identified the intermediates of the citric acid cycle and of urea biosynthesis, and revealed the essential roles of certain vitamin­derived cofactors or “coenzymes” such as thiamin pyrophosphate, riboflavin, and ultimately coenzyme A, coenzyme Q, and cobamide coenzyme. The 1950s revealed how complex carbohydrates are synthesized from, and broken down into simple sugars, and the pathways for biosynthesis of pentoses, and the catabolism of amino acids and fatty acids. Investigators employed animal models, perfused intact organs, tissue slices, cell homogenates and their subfractions, and subsequently purified Downloaded 2024­8­4 enzymes. Advances were8:40 P YourbyIPthe enhanced is 202.28.21.247 development of analytical ultracentrifugation, paper and other forms of chromatography, and the post­ Chapter 1: Biochemistry & Medicine, Victor W. Rodwell Page 1 / 5 World 14C, 3H, and 32P, as “tracers” to identify the intermediates in complex pathways such as that of ©2024War II availability McGraw Hill. All of radioisotopes, Rights Reserved.principally Terms of Use Privacy Policy Notice Accessibility cholesterol biosynthesis. X­ray crystallography was then used to solve the three­dimensional structures of numerous proteins, polynucleotides, enzymes, and viruses. Genetic advances that followed the realization that DNA was a double helix include the polymerase chain reaction, and (fermentation). Research beginning in the 1930s identified the intermediates of the citric acid cycle and of urea biosynthesis, and revealed the essential Naresuan University roles of certain vitamin­derived cofactors or “coenzymes” such as thiamin pyrophosphate, riboflavin, and ultimately coenzyme A, coenzyme Q, and Access Provided by: cobamide coenzyme. The 1950s revealed how complex carbohydrates are synthesized from, and broken down into simple sugars, and the pathways for biosynthesis of pentoses, and the catabolism of amino acids and fatty acids. Investigators employed animal models, perfused intact organs, tissue slices, cell homogenates and their subfractions, and subsequently purified enzymes. Advances were enhanced by the development of analytical ultracentrifugation, paper and other forms of chromatography, and the post­ World War II availability of radioisotopes, principally 14C, 3H, and 32P, as “tracers” to identify the intermediates in complex pathways such as that of cholesterol biosynthesis. X­ray crystallography was then used to solve the three­dimensional structures of numerous proteins, polynucleotides, enzymes, and viruses. Genetic advances that followed the realization that DNA was a double helix include the polymerase chain reaction, and transgenic animals or those with gene knockouts. The methods used to prepare, analyze, purify, and identify metabolites and the activities of natural and recombinant enzymes and their three­dimensional structures are discussed in the following chapters. BIOCHEMISTRY & MEDICINE HAVE PROVIDED MUTUAL ADVANCES The two major concerns for workers in the health sciences—and particularly physicians—are the understanding and maintenance of health and effective treatment of disease. Biochemistry impacts both of these fundamental concerns, and the interrelationship of biochemistry and medicine is a wide, two­way street. Biochemical studies have illuminated many aspects of health and disease, and conversely, the study of various aspects of health and disease has opened up new areas of biochemistry (Figure 1–1). An early example of how investigation of protein structure and function revealed the single difference in amino acid sequence between normal hemoglobin and sickle cell hemoglobin. Subsequent analysis of numerous variant sickle cell and other hemoglobins has contributed significantly to our understanding of the structure and function both of hemoglobin and of other proteins. During the early 1900s, the English physician Archibald Garrod studied patients with the relatively rare disorders of alkaptonuria, albinism, cystinuria, and pentosuria, and established that these conditions were genetically determined. Garrod designated these conditions as inborn errors of metabolism. His insights provided a foundation for the development of the field of human biochemical genetics. A more recent example was investigation of the genetic and molecular basis of familial hypercholesterolemia, a disease that results in early­onset atherosclerosis. In addition to clarifying different genetic mutations responsible for this disease, this provided a deeper understanding of cell receptors and mechanisms of uptake, not only of cholesterol but also of how other molecules cross cell membranes. Studies of oncogenes and tumor suppressor genes in cancer cells have directed attention to the molecular mechanisms involved in the control of normal cell growth. These examples illustrate how the study of disease can open up areas of basic biochemical research. Science provides physicians and other workers in health care and biology with a foundation that impacts practice, stimulates curiosity, and promotes the adoption of scientific approaches for continued learning. FIGURE 1–1 A two­way street connects biochemistry and medicine. Knowledge of the biochemical topics listed above the green line of the diagram has clarified our understanding of the diseases shown below the green line. Conversely, analyses of the diseases have cast light on many areas of biochemistry. Note that sickle cell anemia is a genetic disease, and that both atherosclerosis and diabetes mellitus have genetic components. BIOCHEMICAL PROCESSES UNDERLIE HUMAN HEALTH Biochemical Research Impacts Nutrition & Preventive Medicine The World Health Organization (WHO) defines health as a state of “complete physical, mental, and social well­being and not merely the absence of disease and infirmity.” From a biochemical viewpoint, health may be considered that situation in which all of the many thousands of intra­ and extracellular reactions that occur in the body are proceeding at rates commensurate with the organism’s survival under pressure from both internal and external challenges. The maintenance of health requires optimal dietary intake of vitamins, certain amino acids and fatty acids, various minerals, and Downloaded water. Understanding 2024­8­4 8:40 P Your IPnutrition depends to a great extent on knowledge of biochemistry, and the sciences of biochemistry and is 202.28.21.247 Chapter nutrition 1: Biochemistry share a focus on& Medicine, Recent these chemicals. Victor W. Rodwellemphasis on systematic attempts to maintain health and forestall disease, or Page 2 / 5 increasing ©2024 preventive medicine, includes nutritional approaches to the McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy of prevention Notice Accessibility diseases such as atherosclerosis and cancer. Most Diseases Have a Biochemical Basis The World Health Organization (WHO) defines health as a state of “complete physical, mental, and social well­being and not merelyNaresuan the absence University of Access Provided by: disease and infirmity.” From a biochemical viewpoint, health may be considered that situation in which all of the many thousands of intra­ and extracellular reactions that occur in the body are proceeding at rates commensurate with the organism’s survival under pressure from both internal and external challenges. The maintenance of health requires optimal dietary intake of vitamins, certain amino acids and fatty acids, various minerals, and water. Understanding nutrition depends to a great extent on knowledge of biochemistry, and the sciences of biochemistry and nutrition share a focus on these chemicals. Recent increasing emphasis on systematic attempts to maintain health and forestall disease, or preventive medicine, includes nutritional approaches to the prevention of diseases such as atherosclerosis and cancer. Most Diseases Have a Biochemical Basis Apart from infectious organisms and environmental pollutants, many diseases are manifestations of abnormalities in genes, proteins, chemical reactions, or biochemical processes, each of which can adversely affect one or more critical biochemical functions. Examples of disturbances in human biochemistry responsible for diseases or other debilitating conditions include electrolyte imbalance, defective nutrient ingestion or absorption, hormonal imbalances, toxic chemicals or biologic agents, and DNA­based genetic disorders. To address these challenges, biochemical research continues to be interwoven with studies in disciplines such as genetics, cell biology, immunology, nutrition, pathology, and pharmacology. In addition, many biochemists are vitally interested in contributing to solutions to key issues such as the ultimate survival of mankind, and educating the public to support use of the scientific method in solving environmental and other major problems that confront our civilization. Impact of the Human Genome Project on Biochemistry, Biology, & Medicine Initially unanticipated rapid progress in the late 1990s in sequencing the human genome led in the mid­2000s to the announcement that over 90% of the genome had been sequenced. This effort was headed by the International Human Genome Sequencing Consortium and by Celera Genomics. Except for a few gaps, the sequence of the entire human genome was completed in 2003, just 50 years after the description of the double­helical nature of DNA by Watson and Crick. The implications for biochemistry, medicine, and indeed for all of biology, are virtually unlimited. For example, the ability to isolate and sequence a gene and to investigate its structure and function by sequencing and “gene knockout” experiments have revealed previously unknown genes and their products, and new insights have been gained concerning human evolution and procedures for identifying disease­related genes. Major advances in biochemistry and understanding human health and disease continue to be made by mutation of the genomes of model organisms such as yeast, the fruit fly Drosophila melanogaster, the roundworm Caenorhabditis elegans, and the zebra fish; all organisms that can be genetically manipulated to provide insight into the functions of individual genes. These advances can potentially provide clues to curing human diseases such as cancer and Alzheimer disease. Figure 1–2 highlights areas that have developed or accelerated as a direct result of progress made in the Human Genome Project (HGP). New “­omics” fields focus on comprehensive study of the structures and functions of the molecules with which each is concerned. The products of genes (RNA molecules and proteins) are being studied using the techniques of transcriptomics and proteomics. A spectacular example of the speed of progress in transcriptomics is the explosion of knowledge about small RNA molecules as regulators of gene activity. Other ­omics fields include glycomics, lipidomics, metabolomics, nutrigenomics, and pharmacogenomics. To keep pace with the information generated, bioinformatics has received much attention. Other related fields to which the impetus from the HGP has carried over are biotechnology, bioengineering, biophysics, and bioethics. Definitions of these ­omics fields and other terms appear in the Glossary of this chapter. Nanotechnology is an active area, which, for example, may provide novel methods of diagnosis and treatment for cancer and other disorders. Stem cell biology is at the center of much current research. Gene therapy has yet to deliver the promise that it appears to offer, but it seems probable that ultimately will occur. Many new molecular diagnostic tests have developed in areas such as genetic, microbiologic, and immunologic testing and diagnosis. Systems biology is also burgeoning. The outcomes of research in the various areas mentioned above will impact tremendously the future of biology, medicine, and the health sciences. Synthetic biology offers the potential for creating living organisms, initially small bacteria, from genetic material in vitro that might carry out specific tasks such as cleansing petroleum spills. All of the above make the 21st century an exhilarating time to be directly involved in biology and medicine. FIGURE 1–2 The Human Genome Project (HGP) has influenced many disciplines and areas of research. Biochemistry is not listed since it predates commencement of the HGP, but disciplines such as bioinformatics, genomics, glycomics, lipidomics, metabolomics, molecular diagnostics, proteomics, and transcriptomics are nevertheless active areas of biochemical research. Downloaded 2024­8­4 8:40 P Your IP is 202.28.21.247 Chapter 1: Biochemistry & Medicine, Victor W. Rodwell Page 3 / 5 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility FIGURE 1–2 Naresuan University The Human Genome Project (HGP) has influenced many disciplines and areas of research. Biochemistry is not listed since it predates Access Provided by: commencement of the HGP, but disciplines such as bioinformatics, genomics, glycomics, lipidomics, metabolomics, molecular diagnostics, proteomics, and transcriptomics are nevertheless active areas of biochemical research. SUMMARY Biochemistry is the science concerned with the molecules present in living organisms, individual chemical reactions and their enzyme catalysts, and the expression and regulation of each metabolic process. Biochemistry has become the basic language of all biologic sciences. Despite the focus on human biochemistry in this text, biochemistry concerns the entire spectrum of life forms, from viruses, bacteria, and plants to complex eukaryotes such as human beings. Biochemistry, medicine, and other health care disciplines are intimately related. Health in all species depends on a harmonious balance of the biochemical reactions occurring in the body, while disease reflects abnormalities in biomolecules, biochemical reactions, or biochemical processes. Advances in biochemical knowledge have illuminated many areas of medicine, and the study of diseases has often revealed previously unsuspected aspects of biochemistry. Biochemical approaches are often fundamental in illuminating the causes of diseases and in designing appropriate therapy. Biochemical laboratory tests also represent an integral component of diagnosis and monitoring of treatment. A sound knowledge of biochemistry and of other related basic disciplines is essential for the rational practice of medicine and related health sciences. Results of the HGP and of research in related areas will have a profound influence on the future of biology, medicine, and other health sciences. Genomic research on model organisms such as yeast, the fruit fly D. melanogaster, the roundworm C. elegans, and the zebra fish provides insight into understanding human diseases. GLOSSARY Bioengineering: The application of engineering to biology and medicine. Bioethics: The area of ethics that is concerned with the application of moral and ethical principles to biology and medicine. Bioinformatics: The discipline concerned with the collection, storage, and analysis of biologic data, for example, DNA, RNA, and protein sequences. Biophysics: The application of physics and its techniques to biology and medicine. Biotechnology: The field in which biochemical, engineering, and other approaches are combined to develop biologic products of use in medicine and industry. Downloaded Gene Therapy:2024­8­4 Applies8:40 P use to the Your ofIP is 202.28.21.247 genetically engineered genes to treat various diseases. Chapter 1: Biochemistry & Medicine, Victor W. Rodwell Page 4 / 5 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Genomics: The genome is the complete set of genes of an organism, and genomics is the in­depth study of the structures and functions of genomes. Glycomics: The glycome is the total complement of simple and complex carbohydrates in an organism. Glycomics is the systematic study of the Bioinformatics: The discipline concerned with the collection, storage, and analysis of biologic data, for example, DNA, RNA, and protein sequences. Naresuan University Biophysics: The application of physics and its techniques to biology and medicine. Access Provided by: Biotechnology: The field in which biochemical, engineering, and other approaches are combined to develop biologic products of use in medicine and industry. Gene Therapy: Applies to the use of genetically engineered genes to treat various diseases. Genomics: The genome is the complete set of genes of an organism, and genomics is the in­depth study of the structures and functions of genomes. Glycomics: The glycome is the total complement of simple and complex carbohydrates in an organism. Glycomics is the systematic study of the structures and functions of glycomes such as the human glycome. Lipidomics: The lipidome is the complete complement of lipids found in an organism. Lipidomics is the in­depth study of the structures and functions of all members of the lipidome and their interactions, in both health and disease. Metabolomics: The metabolome is the complete complement of metabolites (small molecules involved in metabolism) present in an organism. Metabolomics is the in­depth study of their structures, functions, and changes in various metabolic states. Molecular Diagnostics: Refers to the use of molecular approaches such as DNA probes to assist in the diagnosis of various biochemical, genetic, immunologic, microbiologic, and other medical conditions. Nanotechnology: The development and application to medicine and to other areas of devices such as nanoshells, which are only a few nanometers in size (10–9 m = 1 nm). Nutrigenomics: The systematic study of the effects of nutrients on genetic expression and of the effects of genetic variations on the metabolism of nutrients. Pharmacogenomics: The use of genomic information and technologies to optimize the discovery and development of new drugs and drug targets. Proteomics: The proteome is the complete complement of proteins of an organism. Proteomics is the systematic study of the structures and functions of proteomes and their variations in health and disease. Stem Cell Biology: Stem cells are undifferentiated cells that have the potential to self­renew and to differentiate into any of the adult cells of an organism. Stem cell biology concerns the biology of stem cells and their potential for treating various diseases. Synthetic Biology: The field that combines biomolecular techniques with engineering approaches to build new biologic functions and systems. Systems Biology: The field concerns complex biologic systems studied as integrated entities. Transcriptomics: The comprehensive study of the transcriptome, the complete set of RNA transcripts produced by the genome during a fixed period of time. APPENDIX Shown are selected examples of databases that assemble, annotate, and analyze data of biomedical importance. ENCODE: ENCyclopedia Of DNA Elements. A collaborative effort that combines laboratory and computational approaches to identify every functional element in the human genome. GenBank: Protein sequence database of the National Institutes of Health (NIH) stores all known biologic nucleotide sequences and their translations in a searchable form. HapMap: Haplotype M a p, an international effort to identify single nucleotide polymorphisms (SNPs) associated with common human diseases and differential responses to pharmaceuticals. ISDB: International Sequence DataBase that incorporates DNA databases of Japan and of the European Molecular Biology Laboratory (EMBL). PDB: Protein DataBase. Three­dimensional structures of proteins, polynucleotides, and other macromolecules, including proteins bound to substrates, inhibitors, or other proteins. Downloaded 2024­8­4 8:40 P Your IP is 202.28.21.247 Chapter 1: Biochemistry & Medicine, Victor W. Rodwell Page 5 / 5 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility