Table Of ContentAnimal Lectins: Form, Function and Clinical
Applications
.
G.S. Gupta
Animal Lectins: Form,
Function and Clinical
Applications
In Collaboration with Anita Gupta
and Rajesh K. Gupta
Principalauthor
G.S.Gupta,Ph.D.
PanjabUniversity
Chandigarh160014
India
ISBN978-3-7091-1064-5 ISBN978-3-7091-1065-2(eBook)
DOI10.1007/978-3-7091-1065-2
SpringerWienHeidelbergNewYorkDordrechtLondon
LibraryofCongressControlNumber:2012945422
#Springer-VerlagWien2012
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Foreword I
Lectinsaretypicallycarbohydrate-bindingproteinsthatarewidelydistributedinNature.With
thegrowinginterestinthefieldofglycobiology,thebodyofresearchrelatedtoanimallectins
has grown at an explosive rate, particularly in the past 25 years. However, the Lectinology
fieldisstillrelativelyyoung,nascent,andevolving.“AnimalLectins:Form,Functionand
ClinicalApplications”presentsthemostup-to-dateanalysisofthesecarbohydrate-binding,
andpotentiallylifesavingproteinsintwocomprehensivevolumes.Lectionologyisanexciting
areaofresearchthathashelpedimmenselyinourunderstandingofhost-pathogeninteractions.
Importantly,C-typelectinscanactaspattern-recognitionreceptors(PRR)thatsenseinvading
pathogens.
The interactions between lectins and carbohydrates have been shown to be involved in
diverse activities such as opsonizationof microbes, cell adhesion andmigration,cellactiva-
tionanddifferentiation,andapoptosis.Developmentsintheareaoflectinresearchhasopened
anewaspectinstudyingtheimmunesystem,andatthesametime,providednewtherapeutic
routesforthetreatmentandpreventionofdiseases.
Thispresentbookonanimallectinsdiscussesthebiochemicalandbiophysicalpropertiesof
animal lectins at length along with their functions in health and diseases. Importantly, the
potentialinterrelationshipsbetweenlectinsoftheinnateimmunesystemandlatentvirusesthat
reside within host cells, sometimes integrated into the genome have been beautifully
highlighted. These interactions help to explain autoimmune diseases and shed light on the
developmentofcancerdiagnostics.Thepresentbookonanimallectinspresentsnewinsights
intothebiologicalrolesofmostanimallectins,includingtheirroleinpreventionofinfections
through innate immunity. The contents of “Animal Lectins: Form, Function and Clinical
Applications”providefunctionalexplanationfortheenormousdiversityofglycanstructures
foundonanimalcells.Therearestillseveralotherareaswhereinlectinsandtheirspecificities
are not well defined and the biological functions of the interactions remain elusive, thereby
underscoring the need for further research. The book offers novel ideas for students of
Immunology, Microbiology, as well as young researchers in the area of Biochemistry.
Icongratulatetheauthorsincompletingthistrulyenormoustask.
Prof.N.K.Ganguly,MD,DSc(hc),FMedSci(London),
FRCPath(London),FAMS,FNA,FASc,FNASc,
FTWAS(Italy),FIACS(Canada),FIMSA
President,JIPMER
FormerDirectorGeneral,ICMR
Pondicherry,India FormerDirector,PGIMER,Chandigarh
v
.
Foreword II
Lectins are proteinsthatbind tosoluble carbohydratesaswell astothefunctionalgroups of
carbohydratechainsthatarepartofaglycoproteinorglycolipidfoundonthesurfacesofcells.
Lectinsareknowntobewidespreadinnatureandplayaroleininteractionsandcommunica-
tionbetweencellstypicallyforrecognition.Carbohydratesonthesurfaceofonecellbindto
the binding sites of lectins on the surface of another cell. For example, some bacteria use
lectinstoattachthemselvestothecellsofthehostorganismduringinfection.Bindingresults
from numerous weak interactions which come together to form a strong attraction. A lectin
usually contains two or more binding sites for carbohydrate units. In addition, the
carbohydrate-binding specificityofacertainlectin is determinedby the amino acidresidues
that bind to the carbohydrates. Most of the lectins are essentially nonenzymic in action and
nonimmune in origin. They typically agglutinate certain animal cells and/or precipitate
glycoconjugates. Plant lectins are highly resistant to breakdown from heat or digestion.
Theyprovideadefenseforplantsagainstbacteria,viruses,andotherinvaders,butcancreate
problemsforhumans.Inanimals,lectinsregulatethecelladhesiontoglycoproteinsynthesis,
controlproteinlevelsinblood,andbindsolubleextracellularandintracellularglycoproteins.
Also,intheimmunesystem,lectinsrecognizecarbohydratesfoundspecificallyonpathogens
orthosethatarenotrecognizableonhostcells.Embryosareattachedtotheendometriumof
theuterusthroughL-selectin.Thisactivatesasignaltoallowforimplantation.E.coliareable
toresideinthegastrointestinaltractbylectinsthatrecognizecarbohydratesintheintestines.
The influenza virus contains hemagglutinin, which recognizes sialic acid residues on the
glycoproteinslocatedonthesurfaceofthehostcell.Thisallowsthevirustoattachandgain
entry into the host cell. Clinically, purified lectins can be used to identify glycolipids and
glycoproteinsonanindividual’sredbloodcellsforbloodtyping.
ThejourneyofAnimalLectins:Form,Function,andClinicalApplications,essentiallythe
Encyclopedia of Animal Lectins, starts with an introductory chapter on lectin families, in
general, followed by specific animal lectin families, such as intracellular sugar-binding ER
chaperones,calnexinandcalreticulin;theP-typelectinsworkingintheendocyticpathway,the
lectins of ERAD pathway, and the complex mannose-binding ERGIC-53 protein and its
orthologs circulating between the ER, ERGIC, and the Golgi apparatus; and the fairly small
galectinsthataresynthesizedinthecytosolbutmaybefoundatmanylocations.Chapterson
R-type lectin families, pentraxins, siglecs, C-type lectins, regenerating gene family,
tetranectin group of lectins, ficolins, F-type lectins, and chi-lectins have covered the up-to-
dateliteratureonthesubjectandcontainillustrationsoftheirstructures,functions,andclinical
applications.Theemerginggroupofannexinsaslectinshasbeengivenaplaceasaseparate
family.
The C-type lectins comprising 17 subfamilies such as collectins, selectins, NK cell lectin
receptors, latest discoveries of lectins on dendritic cells and others form the backbone of
Volume2.Thechaptersarewellwritten,althoughthereisvariabilityonhowtheyarefocused.
Most of the chapters focus on lectin structures, functions, their ligands, and their medical
vii
viii ForewordII
relevance in terms of diagnosis and therapy. The journey ends with five reviews on clinical
applications of lectins with a survey of literature on endogenous lectins asdrug targets.This
mayreflectstateoftheartineachareaortheinterestsoftheauthor(s).
Inpost-genomicyears,withthehumangenomesequenceathand,acompleteoverviewof
many human lectin genes has become available, as illustrated by C-type lectin domain 3D
structureshavingaslittleas30%aminoacidsequencesimilarity.Themajoreffortinthefuture
will be on elaboration of similar studies on other families of lectins with carbohydrate
specificitiesandinvivolectin–ligandinteractions.Inthisrespect,furtherwritingswillbring
thereadertotheforefrontofknowledgeinthefield.Thus,onthirstoflearningaboutanimal
recognitionsystems,AnimalLectins:Form,Function,andClinicalApplicationsisanexcel-
lent reference book for those studying biochemistry, biotechnology, and biophysics with a
specialization in the areas of immunology, lectinology, and glycobiology as well as for
pharmacy students involved in drug discoveries through lectin–carbohydrate interactions.
Both novice and advanced researchers in biomedical, analytical, and pharmaceutical fields
needtounderstandanimallectins.
T.P.Singh,F.N.A.,F.A.Sc.,F.N.A.Sc.,F.T.W.A.S
DBT-DistinguishedBiotechnologyResearchProfessor
DepartmentofBiophysics,
AllIndiaInstituteofMedicalSciences,NewDelhi,India
Preface
Lectins are phylogenetically ancient proteins that have specific recognition and binding
functions for complex carbohydrates of glycoconjugates, that is, of glycoproteins,
proteoglycans/glycosaminoglycans, and glycolipids. They occur ubiquitously in nature and
typicallyagglutinatecertainanimalcellsand/orprecipitateglycoconjugateswithoutaffecting
theircovalentlinkages.Lectinsmediateavarietyofbiologicalprocesses,suchascell–celland
host–pathogen interactions, serum–glycoprotein turnover, and innate immune responses.
Although originally isolated from plant seeds, they are now known to be ubiquitously
distributedinnature.Thesuccessfulcompletionofseveralgenomeprojectshasmadeamino
acidsequencesofseverallectinsavailable.Theirtertiarystructuresprovideagoodframework
upon which all other data can be integrated, enabling the pursuit of the ultimate goal of
understanding these molecules at the atomic level. With growing interest in the field of
glycobiology,thefunction–structurerelationsofanimallectinshaveincreasedatanexplosive
rate, particularly in the last 20 years. Since lectins mediate important processes of adhesion
and communication both inside and outside the cells in association with their ligands and
associatedco-receptorproteins,thereisaneedofareferencebookthatcandescribeemerging
applicationsontheprinciplesofstructuralbiologyofanimallectinsatonepoint.Nobookhas
ever described in a coordinated fashion structures, functions, and clinical applications of 15
families of animal lectins presently known. Therefore, with the increasing information on
animallectinsinbiomedicalresearchandtheirtherapeuticapplications,writingofacompre-
hensive document on animal lectins and associated proteins in the form of Animal Lectins:
Form, Function, and ClinicalApplications has been the main objective ofthe present work.
The entire manuscript has been distributed into two volumes in order to produce an easily
readable work with easy portability. Volume 1 comprises most of the superfamilies (Chaps.
1–21)oflectins,excludingC-typelectinsorC-type-lectin-likedomain.Involume2,wehave
mainly focused on C-type lectins, which have been extensively studied in vertebrates with
widerclinicalapplications(Chaps.22–46).
AnimalLectins:Form,Function,andClinicalApplicationsreviewsthecurrentknowledge
of animal lectins, their ligands, and associated proteins with a focus on their structures and
functions, biochemistry and patho-biochemistry (protein defects as a result of disease), cell
biology(exocytosisandendocytosis,apoptosis,celladhesion,andmalignanttransformation),
clinicalapplications,andtheirinterventionfortherapeuticpurposes.Thebookemphasizeson
theeffectorfunctionsofanimallectinsininnateimmunityandprovidesreviews/chapterson
extracellularanimallectins,suchasC-typelectins,R-typelectins,siglecs,andgalectins,and
intracellularlectins,suchascalnexinfamily(M-type,L-type,andP-type),recentlydiscovered
F-box lectins, ficolins, chitinase-like lectins, F-type lectins, and intelectins, mainly in
vertebrates. The clinical significance of lectin–glycoconjugate interactions has been
exemplified by inflammatorydiseases,defectsof immune defense, autoimmunity,infectious
diseases, and tumorigenesis/metastasis, along with therapeutic perspectives of novel drugs
thatinterferewithlectin–carbohydrateinteractions.
Basedontheinformationgatheredonanimallectinsinthisbook,avarietyofmedicaland
other applications are in the offing. Foremost among these is the lectin-replacement therapy
forpatientssufferingfromlectindeficiencydefects.Wehavepointedouttheadvancementsof
ix
x Preface
suchstudieswheresuchprogresshasbeenmade.Otherusesindifferentstagesofdevelopment
are antibacterial drugs; multivalent hydrophobic carbohydrates for anti-adhesion therapy of
microbial diseases; highly effective inhibitors of the selectins for treatment of leucocyte-
mediatedpathogenicconditions,suchasasthma,septicshock,stroke,andmyocardialinfarc-
tion; inhibitors of the galectins and other lectins involved in metastasis; and application of
lectinsforfacileandimproveddiseasediagnosis.RecentadvancesinthediscoveryofM6PR-
homologousproteinfamily(Chap.5),lectinsofERADpathway,F-boxproteinsandM-type
lectins (Chap. 6), and mannose receptor–targeted drugs and vaccines (Chaps. 8 and 46) can
formthebasisofcutting-edgetechnologyindrugdeliverydevices.
Based on the structures of animal lectins, classified into at least 15 superfamilies, C-type
lectins and galectins are the classical major families. Galectins are known to be associated
withcarcinogenesisandmetastasis.Galectin-3isapleiotropiccarbohydrate-bindingprotein,
involved in a variety of normal and pathological biological processes. Its carbohydrate-
binding properties constitute the basis for cell–cell and cell–matrix interactions (Chap. 12)
andcancerprogression(Chap.13).Studiesleadtotherecognitionofgalectin-3asadiagnos-
tic/prognosticmarkerforspecificcancertypes,suchasthyroidandprostate.Ininterferingwith
galectin–carbohydrateinteractionsduringtumorprogression,acurrentchallengeisthedesign
of specific galectin inhibitors for therapeutic purposes. Anti-galectin agents can restrict the
levelsofmigrationofseveraltypesofcancercellsandshould,therefore,beusedinassociation
with cytotoxic drugs to combat metastatic cancer (Chap. 13). The properties of siglecs that
makethemattractiveforcell-targetedtherapieshavebeenreviewedinChaps.16,17,and46.
F-type domains are found in proteins from a range of organisms from bacteria to
vertebrates, but exhibit patchy distribution across different phylogenetic taxa, suggesting
that F-type lectin genes have been selectively lost even between closely related lineages,
thus making it difficult to trace the ancestry of the F-type domain. The F-type domain has
clearly gained functional value in fish, whereas the fate of F-type domains in higher
vertebrates is not clear, rather it has become defunct. Two genes encoding three-domain
F-type proteins are predicted in the genome of the opossum (Monodelphis domestica), an
early-branching mammal. There is plenty of scope to discover F-type lectins in mammalian
vertebrates(Chap.20).SincethereportsontheC-reactiveprotein(CRP)asacardiovascular
marker (Chap. 8), novel biomarkers in cardiovascular and other inflammatory diseases have
emergedinrecentyears.ThesubstantialknowledgeonCRPisnowbeingcomplementedby
newmarkerssuchasYKL-40,amemberofchi-lectinsgroupofCTLD(Chap.19).TheYKL-
40 (chitinase-3-like protein 1, or human cartilage glycoprotein-39) displays a typical fold of
family18glycosylhydrolasesandisexpressedandsecretedbyseveraltypesofsolidtumors,
including glioblastoma, colon cancer, breast cancer, and malignant melanoma. Chitinase-3-
like protein 1 was recently introduced into clinical practice; yet its application is still
restricted.
In volume 2, we have mainly focused on C-type lectins, which have been extensively
studiedinvertebrates.AC-typelectinisatypeofcarbohydrate-bindingproteindomainthat
requirescalciumforbindinginteractionsingeneral.Drickameretal.classifiedC-typelectins
into seven subgroups (I to VII) based on the order of the various protein domains in each
protein. This classification was subsequently updated in 2002, leading to seven additional
groups (VIII to XIV). A further three subgroups (XV to XVII) were added recently. The C-
typelectinssharestructuralhomologyintheirhigh-affinitycarbohydraterecognitiondomains
(CRDs) and constitute a large and diverse group of extracellular proteins that have been
extensively studied. Their activities have been implicated as indispensable players in carbo-
hydraterecognition,suggestingtheirpossibleapplicationindiscriminationofvariouscorrel-
ative microbes and developing biochemical tools. The C-type lectins, structurally
characterized by a double loop composed of two highly conserved disulfide bridges located
atthebasesoftheloops,arebelievedtomediatepathogenrecognitionandplayimportantroles
intheinnateimmunityofbothvertebratesandinvertebrates.Alargenumberoftheseproteins
