Essentials of Medical Biochemistry With Clinical Cases http://booksite.elsevier.com/9780124166875 Essentials of Medical Biochemistry, Second edition N. V. Bhagavan and Chung-Eun Ha Resources for Professors: Multiple choice questions and answers. All figures and tables from the book available as PowerPoint slides. Essentials of Medical Biochemistry With Clinical Cases Second Edition N. V. Bhagavan Chung-Eun Ha AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON(cid:129)NEWYORK(cid:129)OXFORD PARIS(cid:129)SANDIEGO(cid:129)SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO AcademicPressisanimprintofElsevier AcademicPressisanimprintofElsevier 525BStreet,Suite1800,SanDiego,CA92101-4495,USA 32JamestownRoad,LondonNW17BY,UK 225WymanStreet,Waltham,MA02451,USA Firstedition2011 Secondedition2015 Copyrightr2011,2015ElsevierInc.Allrightsreserved. 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BritishLibraryCataloguing-in-PublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary LibraryofCongressCataloging-in-Publication Data AcatalogrecordforthisbookisavailablefromtheLibraryofCongress ISBN:978-0-12-416687-5 ForinformationonallAcademicPresspublications visitourwebsiteatstore.elsevier.com PrintedandboundinChina 15 16 17 18 19 10 9 8 7 6 5 4 3 2 1 Publisher:JaniceAudet AcquisitionEditor:JillLeonard EditorialProjectManager:PatGonzalez ProductionProjectManager:MelissaRead Designer:MariaInesCruz Preface Much of the content and concepts for the second edition biology as they relate to health and disease. Biochemistry, of Essentials of Medical Biochemistry: With Clinical therefore,isnotatopiclimitedtotextbooksorlaboratories; Cases were derived from the first edition, but this latest life depends on it. This is illustrated by the clinical cases edition has been extensively re-designed in an effort to that we have presented immediately following the chapter better integrate the principles of biochemistry into disci- material.Thesecaseswereabstractedfrompreviouslypub- plines of basic and clinical sciences. The goal is to foster lished articles that describe actual clinical conditions. This a more comprehensive understanding of health and servesasareminderoftheimportanceofmedicalbiochem- disease. We hope that we have accomplished this task by istry,anditaidsthestudentindevelopingtheirskillsinthe making the principlesofbiochemistry andmolecularbiol- diagnosticacuityandsubsequenttreatment. ogymoreclinicallyrelevantandapplicable. We hope students cultivate a full understanding of the Unique features of this textbook include: for each pathophysiologic processes of the body by examination at chapter,alistofkeypointswhichoutlinethemainconcepts the molecular level, in an effort to accomplish the overall or questions that will be discussed in the chapter, followed goal of logical clinical problem-solving, with a compas- by the text and a list of required readings in some chapters. sionateunderstandingofhumanailment. Thetextalsoincludessupplementalreferenceswhereappro- We also promote problem-solving skills that are based priate, to encourage readers to continue learning beyond the on accurate and current information. In almost every chap- chapter material. Most chapters include actual clinical cases ter, we have listed required reading references as well as with teaching points that pertain to the subject matter of the a enrichment reference list at the end of the text, so that chapter. This textbook has also been revised to include the the student may refer to the original literature. We hope latestresearchonvariousaspectsofbiochemistryandmole- that students can develop skills in the understanding of cularbiologytopicsthathaveemergedsincethefirstedition. evidence-basedmedicine. Every effort has been made to create an enjoyable Asclinicians,academicians,andresearchers,theauthors and educational learning experience for the student. andtheirassociatesintheproductionofthistextbookfirmly Biochemistry has often been perceived as a topic of rote believethatthenewformatofourtextencouragesstudents memorizationofreactions and pathways, but herewepres- toembracemedicalbiochemistryandapplyitsprinciplesto ent a well-organized and a systematic mosaic of basic and all areas of medicine. The versatility of this textbook also clinical sciences, which altogether clearly illustrates the makes it appropriate for use by students pursuing various interconnectedness between biochemistry and molecular disciplinesinbasicandclinicalsciences. xvii Acknowledgments We are grateful to our collaborative authors for their con- LIST OF AUTHORS tributions and sharing their knowledge and insights. We 1. NadhipuramV.Bhagavan,Ph.D.,F.A.C.B. also appreciate their cooperation during the lengthy writ- EmeritusProfessor ingandproductionprocess. DepartmentofAnatomy,Biochemistry,andPhysiology The preparation of this text required collective efforts JohnA.BurnsSchoolofMedicine andcollaborationofmanyindividuals.Weareindebtedand UniversityofHawaiiatManoa appreciative of several individuals who contributed to the Chapters1(cid:1)4,8(cid:1)18,20,25(cid:1)32,and35(cid:1)37 book as reviewers of selected chapters, served as consul- 2. Chung-EunHa,Ph.D. tants, provided constructive suggestions and academic AssociateProfessor support. These individuals are Stacey A.A. Honda, Jodi DepartmentofNativeHawaiianHealth Matsuura-Eaves, Brock Kaya, Stanley Loo, Carlos Rios, JohnA.BurnsSchoolofMedicine Lourna M. Murakami, Leslie Y. Uyeno, Karen Higa, Gale UniversityofHawaiiatManoa Fugitani, Charity Saludares, Miki Loscalzo, Ji-Sook Ha, Chapters21(cid:1)24 ScottLozanoff,KarenYamaga,KumarBhagavan,Kimberly 3. WilliamGosnell,Ph.D. Yamauchi, Celeste Wong, Winona K. Lee, Keawe’aimoku AssistantProfessor Kaholokula,MariC.Kuroyama,andMichaelD.Black.We DepartmentofTropicalMedicine,MedicalMicrobiology, aregratefultoKentonKramerforreviewingandproofread- andPharmacology ing several chapters and providing many constructive sug- JohnA.BurnsSchoolofMedicine gestions for improving the text. One of the authors, Craig UniversityofHawaiiatManoa M. Jackson, particularly thanks M. Peter Esnouf for always Chapter33 constructiveandvaluableadvice. 4. CraigM.Jackson,Ph.D.,FNACB,FAAAS(Chem) The production of this manuscript, which involved a FormerlyProfessor,BiologicalChemistry myriad of processes, required the contributions from AssociateProfessor,WashingtonUniversity, many dedicated individuals. James Ha and Jennifer Ha St.Louis,MO were responsible for transforming the rough manuscript SanDiego,CA into its final form and we appreciate their vital contribu- Chapters5,6,34 tion. Other individuals who assisted in this process are 5. NicoleMahealaniLum,D.O. Michael Tabacchini, Teri Laupola, Anastacia Guittap, and ResidentPhysician TriciaYamaguchi. FamilyMedicineResidencyProgram The acquisition of current information in the process DepartmentofFamilyMedicineandCommunityHealth of development of our manuscript was aided and assisted JohnA.BurnsSchoolofMedicine by the staff of the John A. Burns School of Medicine UniversityofHawaiiatManoa Health Science Library. The persons involved in this pro- Chapter19 cesswereVirginiaTanji,LeahGazan,andHildaBaroza. From Elsevier staff we received continued encourage- Dr.Lumalsopreparedthefollowingclinical cases: ment and support from Elizabeth Gibson, Jill Leonard, CC4.1,4.2;CC7.1(cid:1)3;CC10.1(cid:1)10.3; and Pat Gonzalez. They helped us in maintaining sche- CC11.1(cid:1)11.5;CC17.1;CC19.1,19.2;CC26.1,26.3; dules for the manuscript preparation, and assisted us in CC27.1;CC29.1;CC30.1;CC31.1,31.2; manyways,whichmovedtheprojectforward. CC32.1(cid:1)32.3;CC35.1(cid:1)35.3;CC37.1,37.2. xix Chapter 1 The Human Organism: Organ Systems, Cells, Organelles, and Our Microbiota KeyPoints ORGAN SYSTEMS: INTEGRATED 1. Thehumanorganismishierarchicallyorganized;atthe FUNCTION AT THE HIGHEST LEVEL highestlevel,itisorganizedintoorgansystemsclassically relatedtofunctionsandanatomicalstructures. The highest level of integrated functionality in humans is 2. Distinctionsamongorgansaretheconsequenceoftheir the organ system; these systems have been structurally specializedtissuesandcellsthatareproducedduring recognized for thousands of years but recognized for their embryonicdifferentiation,aprocessthatbeginsafter functional importance for only a few hundred. The 11 fertilizationofanovumbyaspermatozoonandcontinues organsystemsofhumansareasfollows: forsomeorgansforatimepost-partum. 3. Cellsarethebasicbuildingblocksfororgansandtissuesin (cid:1) Skeletal—bones, cartilage, and ligaments. This system alllivingsystems. provides the framework and physical form for the 4. Biochemicalprocesseswithincells,andthuswithinorgan body. systems,includemetabolism,growth,reproduction, (cid:1) Integumentary—skin, hair, and nails. This system pro- mutation,response,self-destruction,andevolution. vides a barrier between the outside world and the 5. Thebodyofanadultconsistsofmorethan200differentiated body. andthusspecializedcelltypes. (cid:1) Muscular—skeletal, cardiac, and smooth muscle. This 6. Specializedstructureswithfunctionaldistinctions, system enables movement of the body, skeleton, and organelles,existwithcellsandconstrainparticular internalorgans. biologicalprocessesthatcreateuniquefunctionsthatconfer (cid:1) Digestive—mouth,stomach,smallandlargeintestines, metabolicefficiencyandcellularintegrity.Intracellular colon, and anus. This system provides the pathway for organellesworkinterdependentlytodegrade,synthesize, transport,andexcreteintracellularproducts. food ingestion and processing to extract nutrients and 7. Cellularshapeandabilitytoexchangesubstanceswiththe thus energy, and an environment in which symbiosis circulatoryandothertransportsystemsarederivedfromthe occurs with microorganisms that convert foodstuffs cellularmembranesandintracellularmembranous into nutrients absent from the foodstuffs but required structures. forsurvival. a. Mitochondriaaretheprimarysourcesofenergyforcells, (cid:1) Cardiovascular or circulatory—heart, arteries, veins, organs,andthelivinganimal. and lymphatic vessels. This is the transportation sys- b. Thenucleusprovidesthegeneticandgeneticexpression tem by which nutrients and oxygen are exchanged systemsthatenablegrowth,celldivision,andcell withboththelungsandcellswithinorgans. differentiation. (cid:1) Respiratory—lungs with their alveolar sacs, trachea, 8. Stemcells,auniqueprecursortoallcelltypes,tissues,and nasal orifices, and diaphragm. This is the system for organtypes,arecapableofrepairingdamagedordefective cells,tissues,andorgans. oxygen exchange with the atmosphere and specialized 9. Thehumanbodyiscolonizedbymicroorganismsatseveral musclethatenablesbreathing. locations.Themicrobiotaisprimarilyinthedistalintestine (cid:1) Excretory—kidneys and ureters, bladder, and urethra. withinthegastrointestinaltract.Gastrointestinalmicrobes Thisis the system for waste removal from nutrient uti- contributetothehostasbothsymbioticandpathogenic lization and organ and cell renewal as well as for agentsinmanyphysiologicalprocesses. maintainingelectrolytebalance. N.V.BhagavanandC.-E.Ha:EssentialsofMedicalBiochemistry,Secondedition.DOI:http://dx.doi.org/10.1016/B978-0-12-416687-5.00001-4 ©2015ElsevierInc.Allrightsreserved. 1 2 EssentialsofMedicalBiochemistry (cid:1) Nervous—brain,spinalcord,nerves,andsomereceptors. middle ear; the liver and gall bladder; the urinary tract This system provides cognition and electrical signal/ abovetheurethra;bones;joints;muscles;blood;thelinings informationprocessing and transmission,and acts as the around the lungs; and cerebrospinal fluid. Intestinal colon control center for the other organ systems of the human contains numerous microorganisms, and they are collec- animal. tively known as microbiota. Humans and microorganisms (cid:1) Endocrine—glands and secretory tissues. This system have a symbiotic relationship. A population of normal provides for chemical signaling via transport using the healthy microbiota is essential for the maintenance of opti- circulatorysystem,asecondcontrolsystem. malhostphysiologybyprovidingnutrientsandenergybal- (cid:1) Reproductive—testes, ovaries, uterus, genitalia. This ance. In germ-free mice, changes in the microbial flora is the system by which the species ensures continua- have ameliorated obesity. Fecal flora from healthy persons tionofitself. has been used to re-establish normal microbiota in a recur- (cid:1) Immune—white blood cell types, thymus, spleen. This rent Clostridium difficile enteric infection. Diet, the quality is the system by which protection from pathogens of the gut microbiota, and genetic makeup of the host all enablessurvival. may play a role in producing a proatherosclerotic metabo- lite known as trimethylamine-N-oxide (TMAO) leading Organs are composed of cells that compartmentalize to cardiovascular disease. Recent studies have revealed thelower-levelfunctionsthatare thebasisfororganfunc- that dietary sources of carnitine and phosphatidylcho- tion in living organisms. These are, in turn, composed of line (lecithin) are converted to trimethylamine by gut organelles that further compartmentalize the biochemical microbes, which in turn enter the enterohepatic blood cir- reactions and processes that are highly evolved and spe- culation followed by its conversion to TMAO by hepatic cialized to produce the chemical substances needed to flavin-containing monooxygenases. Colon epithelial bar- create these structures and to extract energy to drive the rier damage can provoke infection and inflammation chemicalreactionsandmechanicalactionswhichthevari- and may lead to a spectrum of diseases. (These aspects, ous organ systems provide. Normal health and disease along with required reading references, are discussed in diagnosis are related to the organ systems of humans, and Chapter11). thus the primary sections and chapters of this biochemical All bacteria belong to the super kingdom called textaresimilarlyorganized. prokaryotes. Yeasts, molds, and protozoa are also single- celled organisms, but their cellular structures and func- tions are more complex than those of bacteria. These CELLS: STRUCTURES AND FUNCTIONS organisms belong to the other super kingdom called The unifying principle of biology is that all living eukaryotes, along with all higher plants and all multicel- organisms from the smallest and least complex (bacte- lular animals. A prokaryote cell has no true nucleus or ria) to the largest (whales) and most complex (humans) specialized organelles in the cytoplasm. Bacteria repro- are composed of cells. The precise location of cells in duce asexually by cell division (fission). Because mito- the multicellular organisms and the location of intracel- chondria (discussed later) have many properties in lular organelles within cells are vital in normal develop- common with bacteria, it suggests that bacteria-like ment and function. During injury, wound repair, or organisms were assimilated into eukaryotic cells early in morphogenesis, the precise location and migratory pat- theirevolution. terns of cells in multicellular organisms involve several All eukaryotic cells have a well-defined nucleus sur- strategies, which include establishment of gradient of rounded by a nuclear membrane and cytoplasm containing small molecules, regulatory networks, and genetic diver- organelles that perform specialized functions. All eukary- sity [1]. The membrane trafficking and metabolites to oticsomaticcellsreproducebythecomplexmechanismsof correct intracellular locations are precisely regulated. mitosisandcytokinesis.Germinalcells(spermandova)are Defects in the membrane trafficking lead to pathological formedbyaslightlydifferentmechanismcalledmeiosis. consequences [2]. Althoughthe size andcomplexityof eukaryotic organ- In the simplest forms of life, such as bacteria, cellular isms differ enormously (e.g., amoeba, fly, worm, crab, organization and biochemical functions are relatively bird, dog, dolphin, chimpanzee, human being), the basic uncomplicated and are primarily devoted to growth and organization and chemistry of their individual cells are reproduction. As a consequence, bacteria have evolved to quite similar. Sequencing of the nuclear DNA of many survive and thrive in the widest range of environments different organisms has shown remarkable conservation imaginable—soil, rivers and oceans, hot springs, and fro- of key genes and proteins among widely dissimilar organ- zen land,aswellasinmostareas ofthehumanbody.The isms. In some cases a protein produced by a human gene only regions of the body that are normally sterile are the will function just as well when the human gene is respiratory tract below the vocal chords; the sinus and swappedforthecomparablegeneinyeast. TheHumanOrganism:OrganSystems,Cells,Organelles,andOurMicrobiota Chapter | 1 3 Properties of “Living” Cells Evolution The human body actually contains billions of both prokary- As aresultofmutation andothergeneticmechanisms, the otic and eukaryotic cells that perform metabolic functions, genetic information, chemical reactions, and other proper- manyofthemsynergistic.Thus,bacteriainthehumanbody ties of organisms change (evolve) over time. Some of the arejustasessentialtothehealthandsurvivalofapersonas inherited changes that occur in organisms make some areherorhisowncells(discussedearlier).Althoughnosin- individuals better able to survive and reproduce in partic- gledefinitionservestodistinguish“living”from“nonliving,” ularenvironments.Evolutioncausespopulationsoforgan- bothprokaryoticandeukaryoticcellssharecertainproperties isms to evolve over time; somebecome extinct and others thatdistinguishthemfromnonlivingmatter. developintonewspecies. First proposed in the 1800s, the cell theory of life is Metabolism now well integrated into biological sciences and medicine. Ingeneral,thecelltheorystatesthat(1)allorganismscon- The sum of all chemical reactions in cells that maintain sist of one or more cells; (2) cells are the smallest units life is metabolism. Living cells extract energy from the characteristic of life; and (3) all cells arise from pre- environment to fuel their chemical reactions; the metabo- existing cells. How the first cells(s) arose on Earth is still lism of dead or dying cells is significantly different from matter of intense scientific research, speculation, and that of healthy cells. Bacteria generally extract the chemi- controversy. cals they need from their immediate environment; human cells obtain essential chemicals and nutrients via the cir- culatory system. The ultimate source of energy for all plants and animals is sunlight, which is used directly by Structures and Organelles in Eukaryotic Cells plantsandindirectlybyanimalsthatconsumeplants. Cytosol Growth The intracellular aqueous compartment that surrounds all of the subcellular organelles is known as cytosol. As a result of the utilization of energy and the synthesis The content of cytosol includes ionic compartment and ofnewmolecules,cellsincreaseinsizeandweight. macromolecular enzyme units. The cytosolic components participateintheosmoregulation,extracellulartransduction Reproduction events, and transport and delivery of metabolites to All cells reproduce by giving rise to identical copies of selected cellular locations and several metabolic pathways. themselves. As a result of growth, cells reach a size that The metabolic pathways of cytosol involve interdepen- triggers reproduction and the production of progeny cells. dence of organelles. For example, synthesis of glucose For example, prokaryotes divide asexually while eukar- (gluconeogenesis), heme, urea, and pyrimidines requires yotesarecapableofsexualreproduction. enzymes located in both cytosol and mitochondria. Some metabolic pathways occur entirely in the cytosol, such as Mutation glycolysis and hexose monophosphate (HMP) shunt pathways. Intheprocessofgrowthandreproduction,cellsoccasionally The metabolic pathways are organized and located at undergo a mutation that is a permanent heritable change in specific sites of the cytosol. The organization and inte- the genetic information in the cell’s DNA. Such mutations gration of feedback loops of proteins that participate in that arise in sperm or ova are called germinal mutations, specific pathways and signaling networks are facilitated andthese may lead to hereditary disorders.Thosethatarise by scaffolding proteins [3,4]. Cytosolic metabolic path- in body cells other than sperm or ova are called somatic ways are regulated depending on the availability of nutri- mutations; these mutations may alter normal cell growth ents and oxygen supply. This is illustrated in the and reproduction, and may underlie the development of circulating red blood cells (RBCs). During the relative cancer (unregulated cell growth), aging, or other derange- deoxygenated state of hemoglobin, glycolysis operates to mentsofcellularfunctions. produce ATP and 2,3-diphosphoglycerate (2,3-DPG). ATP provides energy and 2,3-DPG facilitates oxygen Response delivery to tissues from oxyhemoglobin. During the oxy- All living cells and multicellular organisms respond to genated state of hemoglobin, glucose oxidation is shunted environmental stimuli that change chemical reactions to the HMP pathway for the production of NADPH and and behaviors. Stimuli that evoke cellular responses glutathione (GSH), both of which are required to protect include light, nutrients, noxious chemicals, stress, and the RBCs from oxidative stress (discussed in Chapters 12 other environmentalfactors. and 26). 4 EssentialsofMedicalBiochemistry Alleukaryoticcellspossesscharacteristicstructuresand are in a dynamic state of degradation and renewal. Skin organelles (see Figure 1.1). The shape and size of eukary- cells and gastrointestinal epithelial cells, for example, are otic cells differ markedly depending on their functions, but destroyedandreplacedonaregularbasis.Ifportionsofthe all are much larger than even the largest prokaryote. Most liveraredamagedbydiseaseorsurgicalremoval,theorgan eukaryotic cells contain all of the structures shown in will regrow to its original size. Table 1.1 lists the primary Figure 1.1, but there are exceptions. Non-motile cells usu- functions of the specialized structures and organelles in a ally lack a flagellum or cilia; the nuclei of red blood cells generalized animal cell. The size of cellular organelles is areextrudedafterbeingsynthesizedinbonemarrowbefore subject to nutrient availabilities, metabolic demands, and they enter the circulation; the nuclei also are digested in stressfulconditions[6]. the outermost layer of skin cells. Cilia are sensory orga- Cells of every adult multicellular organism trace their nelles and possess hair-like microtubular structures. They ancestry to the zygote, the first cell of a new individual participate in signaling pathways, which include detections that is formed by union of sperm and egg. During devel- of external signals and their integrations into metabolic opment, cells undergo repeated mitosis and division and functions. Ciliary dysfunction due to genetic defects can ultimately differentiate into specialized cells that have result in a wide variety of developmental and degenerative structures and functions specific to the needs of each disorders known asciliopathies[5]. Mostcells in thebody tissueororganinthebody. Golgi Plasma apparatus membrane Ribosomes Cytoplasm Lysosome Rough endoplasmic reticulum Peroxisome Mitochondrion Nucleus Nuclear envelope Nucleolus Microtubule Microfilament Smooth endoplasmic reticulum Centriole FIGURE1.1 Schematicrepresentationofaeukaryoticanimalcellshowingcharacteristicstructuresandorganelles.