《生物化学》课程教学资源（文献资料）Harper’s Illustrated Biochemistry，26th edition，Robert K. Murray Daryl K. Granner Peter A. Mayes Victor W. Rodwell

Biochemistry&MedicineRobert K.Murray,MD,PhDINTRODUCTIONbiochemistry is increasinglybecoming their commonlanguage.Biochemistry can be defined as the science concernedwith the chemical basis of life (Gk bios"life").The cell isthe structural unit of living systems. Thus, biochem-AReciprocalRelationshipBetweenistry can also be described as the science concerned withBiochemistry&MedicineHasStimulatedthe chemical constituents of living cells and with the reac-MutualAdvancestions and processes they undergo.By this definition, bioThe two major concerns for workers in the health sci-chemistry encompasses large areas of cell biology,ofences-—and particularly physicians-are the understand-molecularbiology,and of moleculargenetics.ing and maintenance of health and the understandingand effective treatment of diseases.Biochemistry im-TheAimof BiochemistryIstoDescribe&pacts enormously on both of these fundamental con-Explain,inMolecularTerms,All Chemicalcerns of medicine. In fact, the interrelationship of bio-ProcessesofLivingCellschemistry and medicine is a wide, two-way streetBiochemical studieshaveilluminated manyaspects ofThe major objective of biochemistry is the completehealth and disease,and conversely,the study of variousunderstanding, at the molecular level, of all of theaspects of health and disease has opened up new areaschemical processes associated with living cells.Toof biochemistry.Some examples of this two-way streetachieve this objective, biochemists have sought to iso-are shown in Figure 1-1. For instance, a knowledge oflate the numerous molecules found in cells, determineprotein structure and function was necessary to eluci-their structures, and analyze how they function. Manydate the single biochemical difference between normaltechniques have been used for these purposes, some ofhemoglobin and sickle cell hemoglobin. On the otherthem are summarized in Table I-1.hand, analysis of sickle cell hemoglobin has contributedsignificantly to our understanding of the structure andAKnowledgeofBiochemistryIsEssentialfunctionof bothnormal hemoglobinandotherproto All Life Sciencesteins.Analogous examples ofreciprocalbenefitbetweenThe biochemistry of the nucleic acids lies at the heart ofbiochemistry and medicine could be cited for the othergenetics; in turn, the use of genetic approaches has beenpaired items shown in Figure I-1. Another example iscritical for elucidating many areas of biochemistry.the pioneering work of Archibald Garrod, a physicianPhysiology, the study of body function, overlaps within England during the early1900s.He studied patientsbiochemistry almost completely.Immunology employswith a number of relatively rare disorders (alkap-numerous biochemical techniques,and many immuno-tonuria, albinism, cystinuria, and pentosuria; these arelogic approaches have found wide use by biochemists.described in later chapters) and established that thesePharmacology and pharmacy rest on a sound knowlconditions were genetically determined. Garrod desig-edge of biochemistry and physiology,in particularnated these conditions as inborn errors of metabo-most drugs are metabolized by enzyme-catalyzed reaclism.His insights provided a major foundation for thetions.Poisons act on biochemical reactions or processessdevelopmentofthefieldof human biochemical genet-this is the subject matter of toxicology.Biochemical apics. More recent efforts to understand the basis of theproaches are being used increasingly to study basic as-genetic disease known as familial hypercholesterol-pects of pathology (the study of disease), such as in-emia, which results in severe atherosclerosis at an earlyflammation, cell injury, and cancer.Many workers inage, have led to dramatic progress in understanding ofmicrobiology,zoology,andbotanyemploybiochemicalcell receptors and of mechanisms of uptake of choles-approaches almost exclusively.These relationships areterol into cells. Studies of oncogenes in cancer cellsnot surprising,because life as weknow it depends onhave directed attention to the molecular mechanismsbiochemical reactions and processes.In fact, the oldinvolved in the control of normal cell growth. Thesebarriers among the life sciences are breaking down,andand many other examples emphasize how the study of-

Biochemistry & Medicine 1 1 Robert K. Murray, MD, PhD biochemistry is increasingly becoming their common language. A Reciprocal Relationship Between Biochemistry & Medicine Has Stimulated Mutual Advances The two major concerns for workers in the health sci￾ences—and particularly physicians—are the understand￾ing and maintenance of health and the understanding and effective treatment of diseases. Biochemistry im￾pacts enormously on both of these fundamental con￾cerns of medicine. In fact, the interrelationship of bio￾chemistry and medicine is a wide, two-way 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. Some examples of this two-way street are shown in Figure 1–1. For instance, a knowledge of protein structure and function was necessary to eluci￾date the single biochemical difference between normal hemoglobin and sickle cell hemoglobin. On the other hand, analysis of sickle cell hemoglobin has contributed significantly to our understanding of the structure and function of both normal hemoglobin and other pro￾teins. Analogous examples of reciprocal benefit between biochemistry and medicine could be cited for the other paired items shown in Figure 1–1. Another example is the pioneering work of Archibald Garrod, a physician in England during the early 1900s. He studied patients with a number of relatively rare disorders (alkap￾tonuria, albinism, cystinuria, and pentosuria; these are described in later chapters) and established that these conditions were genetically determined. Garrod desig￾nated these conditions as inborn errors of metabo￾lism. His insights provided a major foundation for the development of the field of human biochemical genet￾ics. More recent efforts to understand the basis of the genetic disease known as familial hypercholesterol￾emia, which results in severe atherosclerosis at an early age, have led to dramatic progress in understanding of cell receptors and of mechanisms of uptake of choles￾terol into cells. Studies of oncogenes in cancer cells have directed attention to the molecular mechanisms involved in the control of normal cell growth. These and many other examples emphasize how the study of INTRODUCTION Biochemistry can be defined as the science concerned with the chemical basis of life (Gk bios “life”). The cell is the structural unit of living systems. Thus, biochem￾istry can also be described as the science concerned with the chemical constituents of living cells and with the reac￾tions and processes they undergo. By this definition, bio￾chemistry encompasses large areas of cell biology, of molecular biology, and of molecular genetics. The Aim of Biochemistry Is to Describe & Explain, in Molecular Terms, All Chemical Processes of Living Cells 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 iso￾late the numerous molecules found in cells, determine their structures, and analyze how they function. Many techniques have been used for these purposes; some of them are summarized in Table 1–1. A Knowledge of Biochemistry Is Essential to All Life Sciences The biochemistry of the nucleic acids lies at the heart of genetics; in turn, the use of genetic approaches has been critical for elucidating many areas of biochemistry. Physiology, the study of body function, overlaps with biochemistry almost completely. Immunology employs numerous biochemical techniques, and many immuno￾logic approaches have found wide use by biochemists. Pharmacology and pharmacy rest on a sound knowl￾edge of biochemistry and physiology; in particular, most drugs are metabolized by enzyme-catalyzed reac￾tions. Poisons act on biochemical reactions or processes; this is the subject matter of toxicology. Biochemical ap￾proaches are being used increasingly to study basic as￾pects of pathology (the study of disease), such as in￾flammation, cell injury, and cancer. Many workers in microbiology, zoology, and botany employ biochemical approaches almost exclusively. These relationships are not surprising, because life as we know it depends on biochemical reactions and processes. In fact, the old barriers among the life sciences are breaking down, and ch01.qxd 2/13/2003 1:20 PM Page 1

21CHAPTER1Table1-1.Theprincipal methods andNORMALBIOCHEMICALPROCESSESAREpreparationsused inbiochemical laboratoriesTHEBASISOFHEALTHThe World Health Organization (WHO) definesMethodsfor Separating and Purifying Biomolecules'healthas a state of"complete physical, mental and so-Saltfractionation (eg,precipitation of proteins with ammo-cial well-being and not merely the absence of diseasenium sulfate)and infirmity."From a strictly biochemical viewpoint,Chromatography: Paper; ion exchange; affinity; thin-layer,health may be considered that situation in which all ofgas-liquid; high-pressure liquid; gel filtrationthe many thousands of intra-and extracellular reactionsElectrophoresis: Paper;high-voltage; agarose; cellulosethat occur in the body are proceeding at rates commen-acetate; starch gel; polyacrylamide gel; SDS-polyacryl-surate with the organism's maximal survival in theamide gelphysiologic state. However, this is an extremely reduc-Ultracentrifugationtionist view, and it should be apparent that caring forMethodsfor Determining Biomolecular Structuresthe health of patients requires not only a wide knowl-Elemental analysisedge of biologic principles but also of psychologic andUV,visible, infrared,and NMR spectroscopyUse of acid or alkaline hydrolysis to degrade the biomole-social principles.cule under study into its basic constituentsUse of a battery of enzymes of known specificity to de-Biochemical ResearchHas Impact ongrade the biomolecule under study (eg,proteases,nucleNutrition&PreventiveMedicineases, glycosidases)Mass spectrometryOne major prerequisite for the maintenanceof health isSpecific sequencing methods (eg, for proteins and nucleicthat there be optimal dietary intake of a number ofacids)chemicals; the chief of these are vitamins, certainX-ray crystallographyamino acids, certain fatty acids, various minerals, andPreparations for Studying Biochemical Processeswater.Because much of the subject matter of both bio-Whole animal (includes transgenic animals and animalschemistry and nutrition is concerned with the study ofwith geneknockouts)various aspects of these chemicals, there is a close rela-Isolated perfused organtionship berween these rwo sciences. Moreover, moreTissue sliceemphasis is being placed on systematic attempts toWhole cellsmaintain health and forestall disease, ie, on preventiveHomogenatemedicine.Thus,nutritional approaches to-for exam-Isolated cell organellespletheprevention of atherosclerosis and cancer areSubfractionation oforganellesreceiving increased emphasis. Understanding nutritionPurified metabolites andenzymesIsolated genes (including polymerase chain reaction anddepends to a great extent on a knowledge of biochem-site-directed mutagenesis)istry.'Most of these methods are suitable for analyzing the compo-nentspresent incellhomogenatesandotherbiochemicalprepa-Most&PerhapsAll DiseaseHasrations.The sequential use of several techniques will generallya BiochemicaiBasispermitpurificationofmostbiomolecules.Thereaderisreferredtotextsonmethodsofbiochemical researchfordetails.Webelieve that most if not all diseases are manifestations ofabnormalities of molecules,chemical reactions,or biochemical processes.The major factors responsibledisease can open up areas of cell function forbasic bio-for causing diseases in animals and humans are listed inchemical research.Table 1-2. All of them affect one or more criticalThe relationship between medicine and biochemchemical reactions or molecules in the body.Numerousistryhas important implications for the former.As longexamples of thebiochemical bases of diseases will be en-as medical treatment is firmly grounded in a knowledgecountered in this text; the majority of them are due toof biochemistry and other basic sciences,the practice ofcauses 5,7,and 8.In most of these conditions, bio-medicine will have a rational basis that can be adaptedchemical studies contribute to both the diagnosis andto accommodate newknowledge.Thiscontrastswithtreatment.Some major uses of biochemical investiga-tions and of laboratory tests in relation to diseases areunorthodox health cults and at least somealternativemedicine"practices, which are often founded on lirtlesummarized in Table 1-3.more than myth and wishful thinking and generallyAdditional examples of many of these uses are pre-lack any intellectual basis.sented in various sections of thistext

2 / CHAPTER 1 disease can open up areas of cell function for basic bio￾chemical research. The relationship between medicine and biochem￾istry has important implications for the former. As long as medical treatment is firmly grounded in a knowledge of biochemistry and other basic sciences, the practice of medicine will have a rational basis that can be adapted to accommodate new knowledge. This contrasts with unorthodox health cults and at least some “alternative medicine” practices, which are often founded on little more than myth and wishful thinking and generally lack any intellectual basis. NORMAL BIOCHEMICAL PROCESSES ARE THE BASIS OF HEALTH The World Health Organization (WHO) defines health as a state of “complete physical, mental and so￾cial well-being and not merely the absence of disease and infirmity.” From a strictly 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 commen￾surate with the organism’s maximal survival in the physiologic state. However, this is an extremely reduc￾tionist view, and it should be apparent that caring for the health of patients requires not only a wide knowl￾edge of biologic principles but also of psychologic and social principles. Biochemical Research Has Impact on Nutrition & Preventive Medicine One major prerequisite for the maintenance of health is that there be optimal dietary intake of a number of chemicals; the chief of these are vitamins, certain amino acids, certain fatty acids, various minerals, and water. Because much of the subject matter of both bio￾chemistry and nutrition is concerned with the study of various aspects of these chemicals, there is a close rela￾tionship between these two sciences. Moreover, more emphasis is being placed on systematic attempts to maintain health and forestall disease, ie, on preventive medicine. Thus, nutritional approaches to—for exam￾ple—the prevention of atherosclerosis and cancer are receiving increased emphasis. Understanding nutrition depends to a great extent on a knowledge of biochem￾istry. Most & Perhaps All Disease Has a Biochemical Basis We believe that most if not all diseases are manifesta￾tions of abnormalities of molecules, chemical reactions, or biochemical processes. The major factors responsible for causing diseases in animals and humans are listed in Table 1–2. All of them affect one or more critical chemical reactions or molecules in the body. Numerous examples of the biochemical bases of diseases will be en￾countered in this text; the majority of them are due to causes 5, 7, and 8. In most of these conditions, bio￾chemical studies contribute to both the diagnosis and treatment. Some major uses of biochemical investiga￾tions and of laboratory tests in relation to diseases are summarized in Table 1–3. Additional examples of many of these uses are pre￾sented in various sections of this text. Table 1–1. The principal methods and preparations used in biochemical laboratories. Methods for Separating and Purifying Biomolecules1 Salt fractionation (eg, precipitation of proteins with ammo￾nium sulfate) Chromatography: Paper; ion exchange; affinity; thin-layer; gas-liquid; high-pressure liquid; gel filtration Electrophoresis: Paper; high-voltage; agarose; cellulose acetate; starch gel; polyacrylamide gel; SDS-polyacryl￾amide gel Ultracentrifugation Methods for Determining Biomolecular Structures Elemental analysis UV, visible, infrared, and NMR spectroscopy Use of acid or alkaline hydrolysis to degrade the biomole￾cule under study into its basic constituents Use of a battery of enzymes of known specificity to de￾grade the biomolecule under study (eg, proteases, nucle￾ases, glycosidases) Mass spectrometry Specific sequencing methods (eg, for proteins and nucleic acids) X-ray crystallography Preparations for Studying Biochemical Processes Whole animal (includes transgenic animals and animals with gene knockouts) Isolated perfused organ Tissue slice Whole cells Homogenate Isolated cell organelles Subfractionation of organelles Purified metabolites and enzymes Isolated genes (including polymerase chain reaction and site-directed mutagenesis) 1 Most of these methods are suitable for analyzing the compo￾nents present in cell homogenates and other biochemical prepa￾rations. The sequential use of several techniques will generally permit purification of most biomolecules. The reader is referred to texts on methods of biochemical research for details. ch01.qxd 2/13/2003 1:20 PM Page 2

BIOCHEMISTRY&MEDICINE3BIOCHEMISTRYNucleicProteinsLipidsacidsCarbohydrates+1+++GeneticSickle cellAthero-DiabetesdiseasessclerosismellitusanemiaMEDICINEFigure 1-1.Examples of the two-way street connecting biochemistry andmedicine.Knowledge of the biochemical molecules shown in the top part of thediagramhas clarified ourunderstandingofthediseases shown in thebottomhalf-andconversely,analysesofthediseasesshownbelowhavecastlightonmany areas ofbiochemistry.Notethatsicklecell anemia is a geneticdiseaseandthat both atherosclerosis and diabetes mellitus have genetic components.ImpactoftheHumanGenomeProject(HGP)onBiochemistry&MedicineTable1-3.SomeusesofbiochemicalRemarkable progress was made in the late 1990s in se-investigationsand laboratorytestsinquencing the human genome. This culminated in Julyrelation to diseases.2000, when leaders of the two groups involved in thiseffort (the International Human Genome SequencingUseExampleConsortiumandCelera Genomics,aprivatecompany)announced that over 90% of the genome had been se-To reveal the funda-Demonstration of the na-1.quenced.Draft versions of the sequence werepublishedmental causes andture of the genetic de-mechanisms ofdiseasesfects in cystic fibrosis.2To suggest rational treat-A diet low in phenylalanineTable1-2.Themajorcausesof diseases.All ofments of diseases basedfor treatment of phenyl-on (1)aboveketonuria.thecauses listedact by influencingthe various3.To assist in the diagnosisUse ofthe plasma enzymebiochemical mechanisms in thecell or in theofspecificdiseasescreatine kinase MBbody.!(CK-MB) in the diagnosisof myocardial infarction.Physical agents: Mechanical trauma,extremes of temper-41.Toactas screeningtestsUse of measurement offor the early diagnosisbloodthyroxineorature,suddenchangesinatmosphericpressure,radia-tion, electric shock.of certain diseasesthyroid-stimulating hor-2.Chemical agents,including drugs: Certain toxic com-mone (TSH) in the neo-natal diagnosis of con-pounds,therapeuticdrugs,etc.3.Biologicagents: Viruses, bacteria,fungi,higherforms ofgenital hypothyroidism.5.To assist in monitoringparasites.Useoftheplasmaenzyme4Oxygenlack:Lossofbloodsupply,depletionofthethe progress (eg, re-alanine aminotransferaseoxygen-carrying capacity of theblood,poisoning ofcovery,worsening,re-(ALT)inmonitoringthemission, or relapse) ofprogress of infectiousthe oxidativeenzymes5.hepatitis.Geneticdisorders:Congenital, molecular.certain diseases6.Immunologicreactions:Anaphylaxis,autoimmune6.Use of measurement ofTo assistin assessingdisease.the response of dis-bloodcarcinoembryonic7.Nutritional imbalances: Deficiencies, excesses.eases totherapyantigen (CEA) in certain8.Endocrine imbalances: Hormonal deficiencies,excesses.patients who have beentreated forcancer of the'Adapted, with permission,from Robbins SL,Cotram RS,KumarVcolon.ThePathologic BasisofDisease,3rd ed.Saunders,1984

BIOCHEMISTRY & MEDICINE / 3 BIOCHEMISTRY MEDICINE Lipids Athero￾sclerosis Proteins Sickle cell anemia Nucleic acids Genetic diseases Carbohydrates Diabetes mellitus Figure 1–1. Examples of the two-way street connecting biochemistry and medicine. Knowledge of the biochemical molecules shown in the top part of the diagram has clarified our understanding of the diseases shown in the bottom half—and conversely, analyses of the diseases shown below 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. Table 1–2. The major causes of diseases. All of the causes listed act by influencing the various biochemical mechanisms in the cell or in the body.1 1. Physical agents: Mechanical trauma, extremes of temper￾ature, sudden changes in atmospheric pressure, radia￾tion, electric shock. 2. Chemical agents, including drugs: Certain toxic com￾pounds, therapeutic drugs, etc. 3. Biologic agents: Viruses, 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 disorders: Congenital, molecular. 6. Immunologic reactions: Anaphylaxis, autoimmune disease. 7. Nutritional imbalances: Deficiencies, excesses. 8. Endocrine imbalances: Hormonal deficiencies, excesses. 1 Adapted, with permission, from Robbins SL, Cotram RS, Kumar V: The Pathologic Basis of Disease, 3rd ed. Saunders, 1984. Table 1–3. Some uses of biochemical investigations and laboratory tests in relation to diseases. Use Example 1. To reveal the funda- Demonstration of the na￾mental causes and ture of the genetic de￾mechanisms of diseases fects in cystic fibrosis. 2. To suggest rational treat- A diet low in phenylalanine ments of diseases based for treatment of phenyl￾on (1) above ketonuria. 3. To assist in the diagnosis Use of the plasma enzyme of specific diseases creatine kinase MB (CK-MB) in the diagnosis of myocardial infarction. 4. To act as screening tests Use of measurement of for the early diagnosis blood thyroxine or of certain diseases thyroid-stimulating hor￾mone (TSH) in the neo￾natal diagnosis of con￾genital hypothyroidism. 5. To assist in monitoring Use of the plasma enzyme the progress (eg, re- alanine aminotransferase covery, worsening, re- (ALT) in monitoring the mission, or relapse) of progress of infectious certain diseases hepatitis. 6. To assist in assessing Use of measurement of the response of dis- blood carcinoembryonic eases to therapy antigen (CEA) in certain patients who have been treated for cancer of the colon. Impact of the Human Genome Project (HGP) on Biochemistry & Medicine Remarkable progress was made in the late 1990s in se￾quencing the human genome. This culminated in July 2000, when leaders of the two groups involved in this effort (the International Human Genome Sequencing Consortium and Celera Genomics, a private company) announced that over 90% of the genome had been se￾quenced. Draft versions of the sequence were published ch01.qxd 2/13/2003 1:20 PM Page 3

41CHAPTER1in early 2001.It is anticipated that the entire sequence.The judicious use of various biochemical laboratorywill becompleted by2003.The implications of thistests is an integral component of diagnosis and moni-work for biochemistry, all of biology,and for medicinetoring of treatment.are tremendous, and only a few points are mentioned.Asound knowledge of biochemistry and of other rehere.Many previously unknown genes have been re-lated basic disciplines is essential for the rationalvealed; their protein products await characterization.practice of medical and related health sciences.New light has been thrown on human evolution, andprocedures for tracking disease genes have been greatlyREFERENCESrefined. The results are having major effects on areassuchasproteomics,bioinformatics,biotechnology,andFruton JS:Proteins,Enzymes, Genes:Tbe Interplay of Chemistry andpharmacogenomics.Reference to the human genomeBiology. Yale Univ Press, 1999. (Provides the historical back-will be made in various sections of this text.Theground for much of today's biochemical research.)Human Genome Project is discussed in more detail inGarrod AE: Inborn errors of metabolism. (Croonian Lectures.)Chapter 54.Lancet1908;2:1,73,142,214.International Human Genome Sequencing Consortium. Initial se-SUMMARYquencing and analysis of the human genome. Nature2001:409;860. (The issue [15 February] consists of articles。Biochemistry is the science concerned with studyingdedicated to analyses of the human genome.)the various molecules that occur in living cells andKornberg A: Basic research: The lifeline of medicine. FASEB Jorganisms and with their chemical reactions.Because1992;6:3143.life depends on biochemical reactions,biochemistryKornberg A: Centenary of the birth of modern biochemistryFASEBJ1997;11:1209.has become the basic language of all biologic sci-McKusickVA:MendelianInberitanceinMan.Catalogs of Humanences.Genes and Genetic Disorders, 12th ed. Johns Hopkins UnivBiochemistry is concerned with the entire spectrumPress, 1998. [Abbreviated MIM]of lifeforms,fromrelativelysimple viruses and bacte-Online Mendelian Inheritance in Man (OMIM): Center for Med-ria to complexhumanbeings.ical Genetics, Johns Hopkins University and National CenterBiochemistry and medicine are intimately related.for Biotechnology Information, National Library of Medi-cine, 1997.http://www.ncbi.nlm.nih.gov/omim/Health depends on a harmonious balance of bio-(The numbers assigned to the entries in MIM and OMIM will bechemical reactions occurring in the body, and diseasecited in selected chapters of this work. Consulting this exten-reflects abnormalities inbiomolecules,biochemicalsive collection of diseases and other relevant entries--specificreactions, or biochemical processes.proteins, enzymes, etc—will greatly expand the reader's·Advances in biochemical knowledge have illumi-knowledge and understanding of various topics referred tonated many areas of medicine.Conversely,the studyand discussed in this text, The online version is updated al-most daily.)of diseases has often revealed previously unsuspectedScriver CR et al (editors):The Metabolic and Molecular Bases of In-aspects of biochemistry.The determination of the se-herited Disease, 8th ed.McGraw-Hill, 2001.quence of the human genome, nearly complete, willVenter JC et al: The Sequence of the Human Genome. Sciencehavea great impact on all areas of biology,including2001;291:1304.(The issue [16 Februaryl contains theCelerabiochemistry,bioinformatics,and biotechnologydraft version and other articles dedicated to analyses of the·Biochemical approaches are oftenfundamental in il-human genome.)luminating the causes of diseases and in designingWilliams DL,MarksV:Scientific Foundations of Biochemistry inappropriate therapies.Clinical Practice,2nd ed.Butterworth-Heinemann, 1994

in early 2001. It is anticipated that the entire sequence will be completed by 2003. The implications of this work for biochemistry, all of biology, and for medicine are tremendous, and only a few points are mentioned here. Many previously unknown genes have been re￾vealed; their protein products await characterization. New light has been thrown on human evolution, and procedures for tracking disease genes have been greatly refined. The results are having major effects on areas such as proteomics, bioinformatics, biotechnology, and pharmacogenomics. Reference to the human genome will be made in various sections of this text. The Human Genome Project is discussed in more detail in Chapter 54. SUMMARY • Biochemistry is the science concerned with studying the various molecules that occur in living cells and organisms and with their chemical reactions. Because life depends on biochemical reactions, biochemistry has become the basic language of all biologic sci￾ences. • Biochemistry is concerned with the entire spectrum of life forms, from relatively simple viruses and bacte￾ria to complex human beings. • Biochemistry and medicine are intimately related. Health depends on a harmonious balance of bio￾chemical reactions occurring in the body, and disease reflects abnormalities in biomolecules, biochemical reactions, or biochemical processes. • Advances in biochemical knowledge have illumi￾nated many areas of medicine. Conversely, the study of diseases has often revealed previously unsuspected aspects of biochemistry. The determination of the se￾quence of the human genome, nearly complete, will have a great impact on all areas of biology, including biochemistry, bioinformatics, and biotechnology. • Biochemical approaches are often fundamental in il￾luminating the causes of diseases and in designing appropriate therapies. • The judicious use of various biochemical laboratory tests is an integral component of diagnosis and moni￾toring of treatment. • A sound knowledge of biochemistry and of other re￾lated basic disciplines is essential for the rational practice of medical and related health sciences. REFERENCES Fruton JS: Proteins, Enzymes, Genes: The Interplay of Chemistry and Biology. Yale Univ Press, 1999. (Provides the historical back￾ground for much of today’s biochemical research.) Garrod AE: Inborn errors of metabolism. (Croonian Lectures.) Lancet 1908;2:1, 73, 142, 214. International Human Genome Sequencing Consortium. Initial se￾quencing and analysis of the human genome. Nature 2001:409;860. (The issue [15 February] consists of articles dedicated to analyses of the human genome.) Kornberg A: Basic research: The lifeline of medicine. FASEB J 1992;6:3143. Kornberg A: Centenary of the birth of modern biochemistry. FASEB J 1997;11:1209. McKusick VA: Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders, 12th ed. Johns Hopkins Univ Press, 1998. [Abbreviated MIM] Online Mendelian Inheritance in Man (OMIM): Center for Med￾ical Genetics, Johns Hopkins University and National Center for Biotechnology Information, National Library of Medi￾cine, 1997. http://www.ncbi.nlm.nih.gov/omim/ (The numbers assigned to the entries in MIM and OMIM will be cited in selected chapters of this work. Consulting this exten￾sive collection of diseases and other relevant entries—specific proteins, enzymes, etc—will greatly expand the reader’s knowledge and understanding of various topics referred to and discussed in this text. The online version is updated al￾most daily.) Scriver CR et al (editors): The Metabolic and Molecular Bases of In￾herited Disease, 8th ed. McGraw-Hill, 2001. Venter JC et al: The Sequence of the Human Genome. Science 2001;291:1304. (The issue [16 February] contains the Celera draft version and other articles dedicated to analyses of the human genome.) Williams DL, Marks V: Scientific Foundations of Biochemistry in Clinical Practice, 2nd ed. Butterworth-Heinemann, 1994. 4 / CHAPTER 1 ch01.qxd 2/13/2003 1:20 PM Page 4

2Water&pHVictorW.Rodwell,PhD,&PeterJ.Kennelly,PhDBIOMEDICALIMPORTANCEoxygen atom pulls electrons away from the hydrogennuclei, leaving them with a partial positive charge,Water is the predominant chemical component of liv-while its two unshared electron pairs constitute a regioning organisms.Its uniquephysical properties,which inof local negativecharge.clude the ability to solvate a wide range of organic andWater, a strong dipole, has a high dielectric con-inorganic molecules, derive from water's dipolar struc.stant.As described quantitatively by Coulomb's law,ture and exceptional capacityfor forminghydrogenthe strength of interaction F berween oppositelybonds.The manner in which water interacts with a sol-charged particles is inversely proportionate to the di-vated biomolecule influences the structure of each. Anelectric constant of the surrounding medium.The di-excellent nucleophile,water is a reactant or product inelectric constant for a vacuum is unity;for hexane it ismany metabolic reactions.Water has a slight propensity1.9; for ethanol it is 24.3; and for water it is 78.5.to dissociate into hydroxide ions and protons.TheWater therefore greatly decreases theforce ofattractionacidity of aqueous solutions is generally reported usingbetween charged and polar species relative to water-freethe logarithmic pH scale. Bicarbonate and other buffersenvironments withlower dielectricconstants.Its strongnormallymaintain the pH of extracellular fluid be-dipole and high dielectric constant enable water to dis-tween 7.35 and 7.45. Suspected disturbances of acid-solve large quantities of charged compounds such asbase balance are verified by measuring the pH of arter-salts.ial blood and theCO,content ofvenous blood.Causesof acidosis (bloodpH<7.35)include diabeticketosisand lactic acidosis.Alkalosis (pH>7.45)may,for ex-WaterMoleculesFormHydrogen Bondsample,followvomitingofacidicgastriccontents.Regu-An unshielded hydrogen nucleus covalently bound tolation of waterbalance depends upon hypothalamican electron-withdrawing oxygen or nitrogen atom canmechanisms that control thirst, on antidiuretic hor-interact with an unshared electron pair on another oxy-mone(ADH),onretentionorexcretionofwaterbythegen or nitrogen atom to form a hydrogen bond. Sincekidneys, and on evaporative loss. Nephrogenic diabeteswater molecules contain both of these features,hydro-insipidus,which involves the inability to concentrategen bonding favors the self-association of water mole-urine or adjust to subtle changes in extracellular fluidcules into ordered arrays (Figure 2-2). Hydrogen bond-osmolarity,results from the unresponsiveness ofrenaling profoundly influences the physical properties oftubularosmoreceptorstoADH.water and accounts for its exceptionally high viscosity,surface tension, and boiling point. On average, eachmolecule in liquid water associates through hydrogenWATERISANIDEALBIOLOGICSOLVENTbonds with 3.5 others. These bonds are both relativelyweak and transient, with a half-life of about one mi-WaterMoleculesFormDipolescrosecond. Rupture of a hydrogen bond in liquid waterA water molecule is an irregular, slightly skewed tetra-requires only about 4.5 kcal/mol, less than 5% of thehedron with oxygen at its center (Figure 2-1). The twoenergy required to rupture a covalentOHbond.hydrogens and the unshared electrons of the remainingHydrogen bonding enables water to dissolve manytwo sp-hybridized orbitals occupy the corners of theorganic biomolecules that contain functional groupstetrahedron. The 105-degree angle between the hydro-whichcan participatein hydrogen bonding.Theoxy-gens differs slightly from the ideal tetrahedral angle,gen atoms of aldehydes, ketones,and amides providei09.5 degrees.Ammonia is also tetrahedral, with a 107.pairs of electrons that can serve as hydrogen acceptors.degree angle between its hydrogens. Water is a dipole,Alcohols and amines can serve both as hydrogen accep-a molecule with electrical charge distributed asymmetri-tors and as donors of unshielded hydrogen atoms forcally about its structure. The strongly electronegativeformation of hydrogen bonds (Figure 2-3).5

Water & pH 2 5 Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD BIOMEDICAL IMPORTANCE Water is the predominant chemical component of liv￾ing organisms. Its unique physical properties, which in￾clude the ability to solvate a wide range of organic and inorganic molecules, derive from water’s dipolar struc￾ture and exceptional capacity for forming hydrogen bonds. The manner in which water interacts with a sol￾vated biomolecule influences the structure of each. An excellent nucleophile, water is a reactant or product in many metabolic reactions. Water has a slight propensity to dissociate into hydroxide ions and protons. The acidity of aqueous solutions is generally reported using the logarithmic pH scale. Bicarbonate and other buffers normally maintain the pH of extracellular fluid be￾tween 7.35 and 7.45. Suspected disturbances of acid￾base balance are verified by measuring the pH of arter￾ial blood and the CO2 content of venous blood. Causes of acidosis (blood pH < 7.35) include diabetic ketosis and lactic acidosis. Alkalosis (pH > 7.45) may, for ex￾ample, follow vomiting of acidic gastric contents. Regu￾lation of water balance depends upon hypothalamic mechanisms that control thirst, on antidiuretic hor￾mone (ADH), on retention or excretion of water by the kidneys, and on evaporative loss. Nephrogenic diabetes insipidus, which involves the inability to concentrate urine or adjust to subtle changes in extracellular fluid osmolarity, results from the unresponsiveness of renal tubular osmoreceptors to ADH. WATER IS AN IDEAL BIOLOGIC SOLVENT Water Molecules Form Dipoles A water molecule is an irregular, slightly skewed tetra￾hedron with oxygen at its center (Figure 2–1). The two hydrogens and the unshared electrons of the remaining two sp3 -hybridized orbitals occupy the corners of the tetrahedron. The 105-degree angle between the hydro￾gens differs slightly from the ideal tetrahedral angle, 109.5 degrees. Ammonia is also tetrahedral, with a 107- degree angle between its hydrogens. Water is a dipole, a molecule with electrical charge distributed asymmetri￾cally about its structure. The strongly electronegative oxygen atom pulls electrons away from the hydrogen nuclei, leaving them with a partial positive charge, while its two unshared electron pairs constitute a region of local negative charge. Water, a strong dipole, has a high dielectric con￾stant. As described quantitatively by Coulomb’s law, the strength of interaction F between oppositely charged particles is inversely proportionate to the di￾electric constant ε of the surrounding medium. The di￾electric constant for a vacuum is unity; for hexane it is 1.9; for ethanol it is 24.3; and for water it is 78.5. Water therefore greatly decreases the force of attraction between charged and polar species relative to water-free environments with lower dielectric constants. Its strong dipole and high dielectric constant enable water to dis￾solve large quantities of charged compounds such as salts. Water Molecules Form Hydrogen Bonds An unshielded hydrogen nucleus covalently bound to an electron-withdrawing oxygen or nitrogen atom can interact with an unshared electron pair on another oxy￾gen or nitrogen atom to form a hydrogen bond. Since water molecules contain both of these features, hydro￾gen bonding favors the self-association of water mole￾cules into ordered arrays (Figure 2–2). Hydrogen bond￾ing profoundly influences the physical properties of water and accounts for its exceptionally high viscosity, surface tension, and boiling point. On average, each molecule in liquid water associates through hydrogen bonds with 3.5 others. These bonds are both relatively weak and transient, with a half-life of about one mi￾crosecond. Rupture of a hydrogen bond in liquid water requires only about 4.5 kcal/mol, less than 5% of the energy required to rupture a covalent OH bond. Hydrogen bonding enables water to dissolve many organic biomolecules that contain functional groups which can participate in hydrogen bonding. The oxy￾gen atoms of aldehydes, ketones, and amides provide pairs of electrons that can serve as hydrogen acceptors. Alcohols and amines can serve both as hydrogen accep￾tors and as donors of unshielded hydrogen atoms for formation of hydrogen bonds (Figure 2–3). ch02.qxd 2/13/2003 1:41 PM Page 5