生物化學(xué)：Chapter 1-2 Foundations_of_Biochemistry

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1、The textbook we use:The textbook we use:A classic in A classic in Biochemistry since 1970Biochemistry since 19703rd edition (2000)5th edition (2008)4th edition (2004)2nd edition (1993)1st edition (1982)Albert L. LehningerHe has been studying bioenergeticsMember of US Academy of Sciences (elected in

2、1956)lAnother classic written by Lubert StryerlSince 1975l7th edition, 2010(Born March 2, 1938, in Tianjin, China) He has been studying the interplay of light and life (vision signaling)Member of the National Academy of Sciences, USA (elected 1984) History books onHistory books onBiochemistry.Bioche

3、mistry.Prof. Zengyi ChangProf. Zengyi Chang have translated these have translated these two bookstwo booksinto Chinese!into Chinese!Dr. Michel Morange in Shanghai (2009)attending the Education & HistorySession of the 21st IUBMB CongressTopic 1 the prebioticprebiotic Origin of LifeStanley L. Miller.(

4、1953) “A Production of Amino Acids Under Possible Primitive Earth Conditions”, Science, 117:528-9.Topic 2 Protein structure determinationM.F.PERUTZ, et.al. (1960) “Structure of Haemoglobin-A Three-Dimensional Fourier Synthesis at 5.5A Resolution, Obtained By X-Ray Analysis”, Nature, 185:416-22.Topic

5、 3 Enzyme catalysisScoTr J. POLLACK, JEFFREY W. JACOBS, PETER G. SCHULTZ (1986), “Selective Chemical Catalysis by an Antibody”, Science, 234:1570-3.Topic 4 Nucleic acid structureWatson, J and Crick F. (1953) “Molecular Structure of Nucleic Acids-A Structure for Deoxyribose Nucleic Acid”, Nature, 171

6、:737-8.The eight classic papers (to be read by all students)Topic 5 Bioenergetics and catabolismPAUL D. BOYER, RICHARD L. CROSS, AND WILLIAM MOMSEN (1973) “A New Concept for Energy Coupling in Oxidative Phosphorylation Based on a Molecular Explanation of the Oxygen Exchange Reactions”, Proc. Nat. Ac

7、ad. Sci. USA, 70: 2837-2839.Topic 6 AnabolismKONRAD BLOCH AND D. RITTENBERG (1942) “ON THE UTILIZATION OF ACETIC ACID FOR CHOLESTEROL FORMATION” ,J. Biol. Chem., 145:625-636.Topic 7 Regulation of metabolismH. KACSER and J. A. BURNS (1995) “The Control of Flux”, Biochem. Soc. Trans. 23, 341366 (1995)

8、 (republished from a paper published in 1973.)Topic 8 Molecular evolutionP. J. McLaughlin and M. O. Dayhoff, (1973) “Eukaryote Evolution A View Based on Cytochrome c Sequence Data”, J. Mol. Evol., 2: 99-116.lWhole-class lecturing: 50%lSmall-class discussion: 50%lAbsence of class: -2 Points for each

9、missing class (deduced from the final score)lWhole-class lecturing:lTests (one at each whole-class lecture): 10%lMid-term exam: 30%.lFinal Exam: 60%lSmall-class discussion:lOral presentation (in English): 30%lParticipation of discussion: 70%Requirements for the small-class discussion -Critical think

10、ing -Active participation-Effective communicate skillsProfessor Zengyi Chang (昌增益昌增益 教授）教授） Room 204, New Life Science BuildingTel. 6275-8822Sept. 11, 2012 lLiving organisms contain some non-physical element (e.g., “spirit”) and are governed by different principles than are inanimate things. lThere

11、is a vital force present only in organic, but not in inorganic materials, the former can not be synthesized form the latter.lLife can not be simply considered as machines, interaction (“force”) between components is essential for life organization (Ernst Mayr, 2002).Pasteur(1822-1895)Galen(AD 129c.

12、200) Mayr(1904-2005)Berzelius (17791848) lSynthesis of urea from inorganic components (Friedrich Wohler, 1828) . l(“If not the compounds, at least the reactions of living matter could occur only in living cells”)lCell-free fermentation (Edward Buchner, 1898). (“But the nature of biological catalysts

13、 are far too complex to be described in chemical terms”)lEnzymes, “catalysts of life”, crystallized and found to be proteins (J. Sumner, 1926 ).lDNA found to be the carrier of genetic information (Oswald Avery, 1943).F. Wohler（1800-1882）E. Buchner(1860-1917)J. Sumner(1887-1955)O. Avery(1877-1955)lPo

14、ssessing the following basic features: Homeostasis;Organization;Metabolism;Growth;Adaptation;Response to stimuli;Reproduction.Everyone knows what life is but there is no simple definition.Scientists in the 17th century had the same problem trying to define water! An open or continuous systems able t

15、o decrease their internal entropy at the expense of substances or free energy taken in from the environment (i.e., function on negative entropy) , “avoids the decay into equilibrium”, and subsequently rejected in a degraded form. Erwin Schrodinger(1887-1961) lProgram: an organized plan (implemented

16、by the DNA) for the ingredients (proteins, nucleic acids, etc) and the kinetics of their interactions.lImprovisation: mutation plus selection for the program to be optimized for the new environmental challenges.lCompartmentalization: maintain concentration and arrangement (ensure the proper reaction

17、 kinetics; to provide protection from the outside).lEnergy: To compensate for the entropy gain and movements occurring.lRegeneration: compensation for the losses of chemicals; diffusion and active transport of chemicals into living organisms; constant re-synthesis of constituents (e.g., heart protei

18、ns); aging and starting over of cells and individuals after death.lAdaptability: feedback and feedforward reajustments; the behavioral responses being part of the Program.lSeclusion: To avoid undesired contacts and interference of biochemical processes; via the specificity of enzymes and specific nu

19、cleic acid interactions. The goddess of Life: PICERASD. Koshland(1920-2007)lSeeks to describe the structure, function, interaction and chemical transformation of life molecules, as well as the energetics involved in living organisms. lChemical foundations: Life is made around carbon (Structure and r

20、eaction).lPhysical foundations: Energy transformation, as explored using the terms of thermodynamics, occurs in life process.lMathematical foundations: The quantitative description of life processes.lComputational foundations: Simulation of the biomolecules and bioprocesses; Analysis and storage of

21、the huge amount of biochemical data.Many chemists, physicists, mathematician and computer scientistsare joining the community of studying the life phenomena at the molecular level!lOrganic chemistry: Properties of biomolecules.lBiophysics: Applies techniques and theories of physics to study the life

22、 processes.lMedical research: Disease states in molecular terms.lNutrition: Dietary requirements for maintenance of health,lMicrobiology: Single-celled organisms and viruses have been used to understand life at the molecular level.lPhysiology: Tissue and organ functions at the molecular level.lCell

23、biology: Biochemical division of labor within a celllGenetics: Nature of heredity at the molecular level.Biochemistry nourishes them in return and is actually penetrating all disciplines of life sciences and fuel their growth! l1. The structural chemistry of the components of living matter and the r

24、elationship of biological function to chemical structure.l2. Metabolism - the totality of chemical reactions and energy transformation that occur in living matter.l3. The chemistry of processes and substances that store, transmit and express biological information.Biochemistry, cell biology, and gen

25、etics became inextricably interwoven! LeukemiaAIDSHeart block異丙基去甲腎上腺素、異丙基去甲腎上腺素、或或 喘息定喘息定 疊氮胸苷疊氮胸苷,齊多夫定齊多夫定 (Zidovudine)立妥威立妥威 （Retrovir) 6-巰基嘌呤，樂疾疾寧巰基嘌呤，樂疾疾寧 AZTl1. Purification and analysisl2. Structure and propertyl3. Function and mechanisml4. Chemical transformationl5. Catalysisl6. Regulationl7

26、. Informationl8. Interactionl9. Transport and translocationl10. Energyl11. Evolutionl lComponents have to be isolated and purified before physical and chemical analysis and characterization can be performed.l1926, The Svedberg: ultracentrifugation.l1948, Arne Tiselius: electrophoresis (of serum prot

27、eins).l1952, Archer J. P. Martin, Richard L. M. Synge: partition chromatography.M. Tsvet(1872-1919) Tiselius(1902-1971) Martin(1910-2002) Synge(1914-1994) Svedberg(1884-1971)lCovalent and non-covalent structures, and properties of biomolecules.l Methods for analyzing the structure and property of mo

28、lecules: Spectroscopy, electrophoresis, chromatography, X-ray diffraction, NMR, Mass spectrometry, atomic force and cryo- electronmicroscopy, etc.l1902, Emil Fischer: chemical syntheses of sugar and purine.l1910, Albrecht Kossel: cell chemistry made through work on proteins, including the nucleic su

29、bstances.l1915, Richard Willstatter: plant pigments.l1923, Frederick G. Banting and John Macleod: insulin.l1927, Heirich Wieland: bile acids. E. Fischer(1852-1919) Willsttter(1872-1942) Wieland1877-1857) l1928, Adolf Windaus: sterols.l1930, Hans Fischer: haemin and chlorophyll.l1937, Norman Haworth:

30、 carbohydrates and vitamin C; Paul Karrer: carotenoids, flavins and vitamins A and B2.Windaus(1876-1959)H. Fischer(1881-1945) Haworth(1883-1950) Karrer1889-1971) l1939. Adolf Butenandt: sex hormones; Leopold Ruzicka: terpenes.l1943, Henric Dam, Edward A. Doisy: vitamin K.l1950, Edward C. Kendall, Ta

31、deus Reichstein, Philip S. Hench: hormones of the adrenal cortex.l1954, Linus Pauling: structure of complex substances (i.e., proteins).Butenandt1903-1995) Doisy1893-1986) Dam(1895-1976) Hench(1896-1965)Kendall(1886-1972) Reichstein(1897-1996) Paulingl1957, Lord Todd: nucleotides and nucleotide co-e

32、nzymes.l1958, Frederick Sanger: structure of proteins (insulin sequence).l1962, Max F. Perutz and John C. Kendrew: structures of globular proteins.l1962, Francis Crick, James Watson, Maurice Wilkins: molecular structure of nucleic acids.l1964, Dorothy Crowfoot Hodgkin: structures of important bioche

33、mical substances (penicillin).l1970, Luis Leloir: sugar nucleotides.ToddPerutz(1914-2002)KendrewHodgkin(1910-1994)Leloir(1906-1987)SangerWatson & Crickl1972, Gerald M. Edelman, Rodney R. Porter: chemical structure of antibodies.l1977, Roger Guillemin, Andrew V. Schally, Rosalyn Yalow: peptide hormon

34、es.l1978, Werner Arber, Daniel Nahans, Hamilton O. Smith: restriction enzymes.l1982, Sune K. Bergstrom, Bengt, I. Samuelsson, John R. Vane: prostaglandins.Porter(1917-1985)Porter(1929-)Bergstrm Guilleminl1989, Sidney Altman, Thomas E. Cech: catalytic properties of RNA.l1998, Robert F. Furchgott, Lou

35、is J. Ignarro, Ferid Murad: nitric oxide.l2006，Roger D. Kornberg: molecular basis of eukaryotic transcription (RNA Polymerase II).l2009, Venkatraman Ramakrishnan, Thomas A. Steitz, Ada E. Yonath: structure and function of the ribosome.FurchgottRamakrishnanKornberglIt accounts for more than half of t

36、he dry weight of all cells.lIt is able to link into linear or branched chains and cyclic structures, to which all kinds of functional groups (e.g., alcohol, amino, carboxyl) can be attached.lIt makes the skeleton for proteins, nucleic acids, carbohydrates, lipids and other important biomolecules.Dia

37、mond (the hardest)Graphite (one of the softest)10 million carbon compounds are found! The four single bonds around a carbon have a characteristic tetrahedral arrangement (1875):Life is three-dimensional.Carbon-carbon single bonds: Free to rotate.Carbon-carbon double bonds:The two carbons and atoms a

38、ttached to them all lie in the same rigid (non-rotatable) plane.J. H. van t Hoff(1852-1911)J. A. Le Bel(18471930) lConfiguration (構(gòu)型構(gòu)型) defines the different spatial arrangements in covalent bond linkages to carbons that are chiral or form double bonds (unable to be interconverted without breaking c

39、ovalent bonds). lConformation （構(gòu)象）（構(gòu)象）defines the different spatial arrangements of atoms due to the rotational C-C bonds (all having the same covalent linkages; countless for small molecules but usually unique for large ones). George Wald(1967 Nobel Prize) Photoisomerization The two are enantiomers

40、The two are the same The presence of an asymmetric carbon also generates two configurational isomers designated as enantiomers (對映體對映體) one tothe other.Asymmetric carbon(chiral center)Jns Jacob Berzelius (1779-1848)Introduced the conceptof isomerismEnantionmers may exhibit dramatically different phy

41、siological effects: to be sweet or bitter! Non-saccharide sweetenerPhenylketonuria (PKU) patient should avoid it. AminoSweet 200 times sweeter than sucrose lWater is a polar molecule, forming H-bonds between themselves (thus highly cohesivehighly cohesive and commonly exist as liquidliquid ) or with

42、 other molecules.lWater greatly weakens electrostatic forces and hydrogen bonding between polar molecules, thus being an excellent solventexcellent solvent for polar molecules.lLife undoubted could not have arisen in the absence of water!北大水科學(xué)復(fù)合型拔尖人才培養(yǎng)計劃北大水科學(xué)復(fù)合型拔尖人才培養(yǎng)計劃Thermal properties of waterThe

43、rmal properties of water: high boiling : high boiling point, high melting point, high heat of point, high melting point, high heat of vaporization and vaporization and high heat capacityhigh heat capacity ( (good good thermal bufferthermal buffer). ). A liquid at room temperature. A liquid at room t

44、emperature. .Each water canEach water canForm H-bondForm H-bondwith 4 otherwith 4 otherwater moleculeswater moleculesHydrogen bonding between water molecules generates hydrophobic interaction between hydrophobic molecules, which in turndrive the formation ofbiomembranes.Water forces amphipathic mole

45、cules to spontaneously rearrange themselves to form uniquestructures.lNearly all biomolecules assume their shapes (and Nearly all biomolecules assume their shapes (and therefore their functions) in response to the physical therefore their functions) in response to the physical and chemical propertie

46、s of the surrounding water, and chemical properties of the surrounding water, thus proteins fold into their native conformations thus proteins fold into their native conformations and lipid bilayers are formed and maintained).and lipid bilayers are formed and maintained).lWater is the medium for the

47、 majority of biochemical Water is the medium for the majority of biochemical reactions.reactions.lWater actively participate in many chemical Water actively participate in many chemical reactions supporting life.reactions supporting life.lOxidation of water (producing OOxidation of water (producing

48、O2 2) is fundamental to ) is fundamental to photosynthesis.photosynthesis.lThe role (function) of a biomolecule in a living organism, as well as its action mechanism have to be explored.l1923, Frederick G. Bantiing and John Macleod: insulin.l1931, Otto Warburg: nature and mode of action of the respi

49、ratory enzyme.l1947, Bernardo Houssay: hormone of the anterior pituitary lobe in the metabolism of sugar.l1955, Hugo Theorell: nature and mode of action of oxidation enzymes.l1962, Max F. Perutz and John C. Kendrew: structures of globular proteins.l1972, Christian Anfinsen: amino acid sequence and t

50、he biologically active conformation; Stanford Moore and William H. Stein: catalytic activity of the active centre of the ribonuclease.l1975, John Corforth: stereochemistry of enzyme-catalyzed reactions.l1977, Roger Guillemin, Andrew V. Schally, Rosalyn Yalow: peptide hormones.l1978, Werner Arber, Da

51、niel Nahans, Hamilton O. Smith: restriction enzymes.l1986, Stanley Cohn, Rita Levi-Montalcini: growth factors.l1989, Sidney Altman, Thomas E. Cech: catalytic properties of RNA.l1991, Erwin Neher, Bert Sakmann: single ion channels.l1994, Alfred G. Gilman, Martin Rodbell: G-proteins.l1997, Stanley B.

52、Prusiner: Prions.l1997,Jens C. Skou: ion-transporting enzyme.l1988, Johann Deisenhofer, Robert Huber, Hartmut Michel: photosynthetic reaction center.l1997, Paul D. Boyer, John E .Walker: synthesis of ATP.l2001, Leland H. Hartwell, Tim Hunt, Sir Paul Nurse: regulators of the cell cycle.l2002, Sydney

53、Brenner, H. Robert Horvitz, John E. Sulston: regulation of organ development and programmed cell death.l2006, Andrew Z. Fire, Craig C. Mello: RNA interference.l2007, Mario R. Capecchi, Sir Martin J. Evans, Oliver Smithies: gene targeting in mice.lBiodegradation and biosynthesis, and energy transduct

54、ion (metabolism) occur via a large number of chemical transformations.lStepwise reactions, catalytic enzymes, structure of metabolites, thermodynamic parameters, spacial localization, rate regulation, are some of the aspects that have to be addressed.l1907, Eduard Buchner: cell-free fermentation.l19

55、22, Otto Meyerhof: fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle.l1929, Arthur Harden, Hand von Euler-Chelpin: fermentation of sugar and fermentative enzymes.l1937, Albert Szent-Gyorgyi: biological combustion, vitamin C and the catalysis of fuma

56、ric acid.l1947, Carl Cori and Gerty Cori: catalytic conversion of glycogen; Bernardo Houssay: hormone of the anterior pituitary lobe in the metabolism of sugar.l1953, Hans Krebs: citric acid cycle; Fritz Lipmann: role of co-enzyme A in metabolism.l1961, Melvin Calvin: carbon dioxide assimilation in

57、plants.l1964, Konrad Bloch, Feodor Lynen: cholesterol and fatty acid metabolism.l1988, Sir James W. Black, Gertrude B. Elion, George H. Hitchings: principles for drug treatment.l2004, Aaron Ciechanover, Avram Hershko, Irwin Rose: ubiquitin-mediated protein degradation.Condensation Condensation Group

58、 transfer Group transfer IsomerizationIsomerizationNucleophilic substitutionNucleophilic substitutionOxidation-Oxidation-reductionreductionA change in oxidation state. lEarly studies on food digestions by animals (1870s, Kuhne);lFermentation of sugar to alcohol by yeast (Pasteur, 1860s; Buchner, 189

59、0s).lThe concept of biocatalyst in sugar conversion (Emil Fischer, 1890).lDiscoveries of intracellular enzymes (oxidases, synthetases, zymases).lEnzyme theory replaces the protoplasm theory (Hofmeister, 1901): Almost all the chemical reactions occurring in a living organism are catalyzed by enzymes;

60、 life can not exist without enzyme catalysis.lEnzymes found to be proteins (Sumner, 1926).W. Kuhne(1837-1900)Buchner(1860-1917)Fischer(1852-1919) Pasteur(1822-1895)Sumner(1887-1955)lMany processes in the living organism are efficiently regulated to achieve the best economy and the homeostatic state.

61、l1939. Adolf Butenandt: sex hormones;l1947,Bernardo Houssay: hormone of the anterior pituitary lobe in the metabolism of sugar.l 1950, Edward C. Kendall, Tadeus Reichstein, Philip S. Hench: hormones of the adrenal cortex.l1971, Earl W. Sutherland, Jr.: mechanisms of the action of hormones.l1977, Rog

62、er Guillemin, Andrew V. Schally, Rosalyn Yalow: peptide hormones.l1982, Sune K. Bergstrom, Bengt, I. Samuelsson, John R. Vane: prostaglandins.l1985. Michael S. Brown, Joseph L. Goldstein: regulation of cholesterol metabolism.l1986, Stanley Cohn, Rita Levi-Montalcini: growth factors.l1992, Edmond H.

63、Fischer, Edwin G. Krebs: reversible protein phosphorylation.l1994, Alfred G. Gilman, Martin Rodbell: G-proteins.l1998, Robert F. Furchgott, Louis J. Ignarro, Ferid Murad: nitric oxide.lProper storage, duplication and expression of genetic information and proper transduction of environmental informat

64、ion is essential for the organisms to be alive.l1958, George Beadle, Edward Tatum: genes act by regulating definite chemical events; Joshua Lederberg: genetic recombination and the organization of the genetic material of bacteria.l1959, Severo Ochoa, Arthur Kornberg: biological synthesis of ribonucl

65、eic acid and deoxyribonucleic acid.l1962, Francis Crick, James Watson, Maurice Wilkins: molecular structure of nucleic acids. l1965, Francois Jacob, Andre Lwoff, Jacques Monod: genetic control of enzyme and virus synthesis.l1968, Robert W. Holley, H. Gobind Khorana, Marshall W. Nirenberg: interpreta

66、tion of the genetic code and its function in protein synthesis.l1969, Max Delbruck, Alfred D. Hershey, Salvador E. Luria: replication mechanism and the genetic structure of viruses. 1975, David Baltimore, Renato Dulbecco, Howard M. Temin: interaction between tumour viruses and the genetic material of the cell.l1983, Barbara McClintock: mobile genetic elements.l1987, Susumu Tonegawa: generation of antibody diversity.l1993, Richard J. Roberts, Philip A. Sharp: split genes.l1995, Edward B. Lewis, C