E.O. DANCHENKO BIOCHEMISTRY Gomel, 2004 УДК 577.1=20 (042.3/.4) ББК 28.902 я 7 Д 19 Reviewers: Chief of the department of chemistry of Vitebsk State University, Doctor of biological sciences, Professor A.A. Chirkin Chief of the department of biochemistry of Gomel State Medical Univer- sity, Doctor of medical sciences, Professor A.I. Grizuk Danchenko E.O. Д 19 Biochemistry: course of lectures. Gomel: VSMU Press, 2004. – 360 р., 119 fig., 9 tab. The course of the lectures is designed for students of higher medical educa- tional establishments. The lectures can be used as an integrated curriculum in which ready access to biochemical information is required. The course of lectures corresponds with typical educational plan and pro- gram proved by Ministry of Health Care of Republic of Belarus. Утверждено Центральным учебным научно-методическим советом Гомельского государственного медицинского университета 10.09.2004., протокол № 7 УДК 577.1=20(042.3/.4) ББК 28.902 я 7 © E.O. Danchenko © УО «Гомельский государственный медицинский университет» 2 LECTURE 1 INTRODUCTION TO BIOCHEMISTRY. STRUCTURE AND FUNCTION OF PROTEINS Biochemistry seeks to describe the structure, organization, and functions of living matter in molecular terms. It can be divided into three principal areas: 1. The structural chemistry of the components of living matter and the rela- tionship of biological function to chemical structure. 2. Metabolism — the totality of chemical reactions that occur in living matter. 3. The chemistry of processes and substances that store and transmit bio- logical information. The medical students who acquire a sound knowledge of biochemistry will be in a position to confront, in practice and research, the 2 central concerns of the health sciences: (1) the understanding and maintenance of health and (2) the un- derstanding and effective treatment of disease. The major objective of biochemistry is the complete understanding at the molecular level of all of the chemical processes associated with living cells. To achieve this objective, biochemists have sought to isolate the numerous molecules found in cells, determine their structures, and analyze how they function. All diseases are manifestations of abnormalities of molecules, chemical re- actions, or processes. The major factors responsible for causing diseases in ani- mals and humans are follows 1. Physical agents: Mechanical trauma, extremes of temperature, sudden changes in atmospheric pressure, radiation, electric shock. 2. Chemical agents and drugs: Certain toxic compounds, therapeutic drugs, etc. 3. Biologic agents: Viruses, rickettsiae, bacteria, fungi, higher forms of parasites. 4. Oxygen lack: Loss of blood supply, depletion of the oxygen-carrying capacity of the blood, poisoning of the oxidative enzymes. 5. Genetic: Congenital, molecular. 6. Immunologic reactions: Anaphylaxis, autoimmune disease. 7. Nutritional imbalances: Nutritional deficiencies, nutritional excesses. 8. Endocrine imbalances: Hormonal deficiencies, hormonal excesses. HISTORY OF BIOCHEMISTRY Biochemistry's roots as a distinct field of study date to the early 19th cen- tury, with the pioneering work of Friedrich Wöhler. Prior to that time, it was believed that the substances in living matter were somehow qualitatively differ- ent from those in nonliving matter and did not behave according to the known laws of physics and chemistry. In 1828 Wöhler showed that urea, a substance of biological origin, could be synthesized in the laboratory from the inorganic compound ammonium cyanate. 3 Chromosomes were discovered in 1875 by Walter Flemming and identi- fied as genetic elements by 1902. The development of the electron microscope, between about 1930 and 1950, provided a whole new level of insight into cellu- lar structure. With it, subcellular organelles like mitochondria and chloroplasts could be studied, and it was realized that specific biochemical processes were localized in these subcellular particles. Nucleic acids had been isolated in 1869 by Friedrich Miescher, but their chemical structures were poorly understood, and in the early 1900s they were thought to be simple substances, fit only for structural roles in the cell. The idea of the gene, a unit of hereditary information, was first proposed in the mid- nineteenth century by Gregor Mendel. By about 1900, cell biologists realized that genes must be found in chromosomes, which are composed of proteins and nucleic acids. Most biochemists believed that only the proteins were structurally complex enough to carry genetic information. That belief was dead wrong. Experiments in the 1940s and early 1950s proved conclusively that deoxyribonucleic acid (DNA) is the bearer of genetic information. One of the most important advances in the history of science oc- curred in 1953, when James Watson and Francis Crick described the double- helical structure of DNA. This concept immediately suggested ways in which in- formation could be encoded in the structure of molecules and transmitted intact from one generation to the next. Biochemistry draws its major themes from 1. Organic chemistry, which describes the properties of biomolecules. 2. Biophysics, which applies the techniques of physics to study the struc- tures of biomolecules. 3. Medical research, which increasingly seeks to understand disease states in molecular terms. 4. Nutrition, which has illuminated metabolism by describing the dietary requirements for maintenance of health. 5. Microbiology, which has shown that single-celled organisms and viruses are ideally suited for the elucidation of many metabolic pathways and regulatory mechanisms. 6. Pharmacology and pharmacy rest on a sound knowledge of biochemistry and physiology; in particular, most drugs are metabolized by enzyme-catalyzed reactions. 7. Physiology which investigates life processes at the tissue and organ- ism levels. 8. Cell biology, which describes the biochemical division of labor within a cell. 9. Genetics, which describes mechanisms that give a particular cell or or- ganism its biochemical identity. 4 USES OF BIOCHEMISTRY 1. The results of biochemical research are used extensively in the world outside the laboratory — in agriculture, medical sciences, nutrition, and many other fields. In clinical chemistry, biochemical measurements on people help diagnose illnesses and monitor responses to treatment. 2. Pharmacology and toxicology are concerned with the effects of external chemical substances on metabolism. Drugs and poisons usually act by interfer- ing with specific metabolic pathways. 3. A particularly exciting prospect in contemporary biochemistry is that of creating so-called designer drugs. If the target site for action of a drug is a pro- tein enzyme or receptor, determining the detailed molecular structure of that tar- get allows us to design inhibitors that bind to it with great selectivity. 4. Herbicides and pesticides, in many instances, act in similar ways — by blocking enzymes or receptors in the target organism. Biochemistry is involved in understanding the actions of herbicides and pesticides, in increasing their se- lectivity, and in understanding and dealing with mechanisms by which target or- ganisms become resistant to them. Thus, biochemistry has become an important component of environmental science. BIOCHEMISTRY AS A CHEMICAL SCIENCE In order to understand the impact of biochemistry on biology, one must un- derstand the chemical elements of living matter and the complete structures of many biological compounds — amino acids, sugars, lipids, nucleotides, vita- mins, and hormones — and their behavior during metabolic reactions. Essen- tial understanding of biochemistry requires knowledge of the stoichiometry and mechanisms of a large number of reactions. In addition, an understanding of the basic thermodynamic principles is essential for learning how plants derive en- ergy from sunlight (photosynthesis) and how animals derive energy from food (catabolism). Living creatures on the earth are composed mainly of a very few elements, principally carbon, hydrogen, oxygen, and nitrogen (C, H, O, N). Life is not built on these four elements alone. Many other elements are necessary for terres- trial organisms. A "second tier" of essential elements includes sulfur and phos- phorus, which form covalent bonds, and the ions Na+, K+, Mg2+, Ca2+, and Cl-. PROTEINS Proteins are the most abundant organic molecules of the living system. They occur in every part of the cell and constitute about 50% of cellular dry weight. Pro- teins form the fundamental basis of structure and function of life. The term “protein” is derived from a Greek word “proteios”, meaning “hold- ing the first place”. Berzelius (Swedish chemist) suggested the name proteins to the group of organic compounds that are utmost important to life. Mudler (Dutch 5 chemist) in 1838 used the term “proteins” for the high molecular weight nitrogen- rich and most abundant substances present in animals and plants. Function of proteins Proteins perform a great variety of specialized and essential functions in the living cells. These functions may be broadly grouped as static (structural) and dy- namic. 1. Structural functions. Certain proteins perform “brick and mortal” roles and are primarily responsible for structure and strength of body. These include col- lagen and elastin found in bone matrix, vascular system and other organ and α- keratin present in epidermal tissues. 2. Dynamic function. The dynamic functions of proteins are more diversi- fied in nature. These include proteins