Chemical Diversity in the Sialic Acids and Related -Keto Acids: An

32 Pages·2002·0.33 MB·English

Chem.Rev.2002,102,439- 469 439
r
Chemical Diversity in the Sialic Acids and Related -Keto Acids: An
Evolutionary Perspective
Takashi Angata and Ajit Varki*
GlycobiologyResearchandTrainingCenter,DepartmentsofMedicineandCellularandMolecularMedicine,UniversityofCaliforniasSanDiego,
LaJolla,California92093-0687
Received July19,2001
Contents 4. Caenorhabditis eleganssNo Sign of 455
Sialic Acid
I. Introduction 439
C. Biosynthesis of KDO in Bacteria and 456
II. Occurrence and Structural Diversity of Sialic 442 Comparison to that of Neu5Ac
Acids in Nature
D. Phylogenetic Relationships of Enzymes 456
A. Eukaryotes 443 Involved in Sialic Acid Biosynthesis
1. Animals 443 1. CMP-KDO and CMP-Neu5Ac Synthetases 456
2. Fungi 444 2. Neu5Ac(-9-phosphate) Synthetases 458
3. Plants 444 V. Biosynthesis of Modified Sialic Acids 458
4. Protozoa 444 A. CMP-Neu5Ac Hydroxylase 458
B. Bacteria 444 B. Sialic Acid O-Acetyltransferases 458
C. Archaea 445 C. Sialic Acid 8-O-Methyltransferase 459
III. Proteins That Recognize Sialic Acids 445 D. Other Modifications 459
A. Vertebrate Pathogen Lectins 445 VI. Degradation of Sialic Acids 459
1. Viruses 445 VII. Sialic Acid Metabolism Genes Shared Only 459
2. Bacteria 448 among Vertebrates and Bacteria
3. Protozoa 450 VIII. Concluding Remarks and Future Prospects 460
B. Vertebrate Endogenous Lectins 450 IX. Glossary 461
1. Complement Factor H 450 X. Footnote 463
2. Selectins 450 XI. Supporting Information 464
3. Siglecs 450 XII. References 464
4. Other Endogenous Lectins That Can 451
Recognize Sialic Acids
C. Why Do Sialic Acids Have so Many 451 I. Introduction
Structural Variations?
1. Specific Recognition by Endogenous 451 Theglycanchainsofvertebrateglycoconjugatesare
LectinssA Driving Force from Within composedmostlyoffive-andsix-carbonsugars.One
2. Evasion of Pathogens with Sialic 452 striking exception is the family of sialic acids (Sia),
Acid-Recognizing LectinssA Driving whichareR-ketoacidswithanine-carbonbackbone.
Force from Outside Several other features of sialic acids are unusual.
IV. Biosynthetic Pathways for Sialic Acids and Other 453 First, they typically occupy the distal end of glycan
R-Keto Acids chains. This “outermost” location makes them suit-
A. Biosynthesis of Neu5Ac 453 able for interaction with other cells and with envi-
1. Synthesis of ManNAc(-6-phosphate) 454 ronmentalagents,andtherearenumerousexamples
2. Synthesis of Neu5Ac 454 of such interactions (described later in this review).
Second, sialic acids are subject to a remarkable
3. Synthesis of CMP-Neu5Ac 454
numberofmodifications,generatingadiversefamily
4. Transfer of Sialic Acids to 454
ofmorethan50structurallydistinctmolecules(Table
Glycoconjugates by Sialyltransferases
1). Third, unlike the other vertebrate monosaccha-
B. Can Genomic DNA Sequences Tell Us about 454
rides, sialic acids are not ubiquitous in nature and
the Presence of Sialic Acid?
1. Methanococcus jannaschiisAn Archaeal 455 seem to be predominantly found in two distinct
branches of the tree of life: in the deuterostome
Organism with Sialic Acid?
2. Legionella pneumophilasSialic or Not 455 lineage of animals (vertebrates and a few higher
invertebrates such as starfish) and in certain types
Sialic?
3. Drosophila melanogastersIncomplete 455 of bacteria. A fourth unusual feature of sialic acids
is that they are synthesized via condensation of a
Tool Kit?
neutral six-carbon unit with the three-carbon mol-
ecule pyruvate. Finally, sialic acids are unusual in
*To whom correspondence should be addressed. Phone: (858)
534-3296.Fax: [phone].E-mail: [email protected]. the nature of their high-energy nucleotide sugar
10.1021/cr000407mCCC:$39.75 ©2002AmericanChemicalSociety
PublishedonWeb01/04/2002
440 ChemicalReviews,2002,Vol.102,No.2 AngataandVarki
Ajit Varki is currently Professor of Medicine, Professor of Cellular and
Molecular Medicine, and Director of the Glycobiology Research and
TrainingCenterattheUniversityofCalifornia,SanDiego(UCSD).Heis
Executive Director of the textbook Essentials of Glycobiology and has
servedontheEditorialBoardsoftheseveraljournals,includingtheJournal
of Biological Chemistry, The Journal of Clinical Investigation, and
Glycobiology.Dr.VarkiistherecipientofaMERITawardfromtheNIH
andanAmericanCancerSocietyFacultyResearchAwardandhasserved
ontheScientificAdvisoryBoardsoftheYerkesPrimateCenter(Emory
University)andtheComplexCarbohydrateResearchCenter(University
ofGeorgia).Significantpastappointmentsincludethefollowing: Co-Head,
UCSD Division of Hematology-Oncology (1987- 1989); President of the
SocietyforGlycobiology(1996);Editor-in-ChiefoftheJournalofClinical
Investigation(1992- 1997);theInterimDirectorshipoftheUCSDCancer
Center(1996- 1997);andPresidentoftheAmericanSocietyforClinical
Investigation (1998- 1999). Dr. Varki’s research is currently focused on
Figure1. Structuresofsialicacids: (A)Neuraminicacid
thesialicacidsandtheirrolesinbiology,evolution,anddisease. (Neu,R)H),N-acetylneuraminicacid(Neu5Ac,R)CH -
3
CO-)andN-glycolylneuraminicacid(Neu5Gc,R)HOCH-
2
CO-), (B) 2-keto-3-deoxy-D-glycero-D-galacto-nonulosonic
acid (KDN). Structures of the following sugars are also
shownforcomparison: (C)5,7-diamino-3,5,7,9-tetradeoxy-
D-glycero-D-galacto-nonulosonic acid (legionaminic acid)
derivative,(D)5,7-diamino-3,5,7,9-tetradeoxy-L-glycero-L-
manno-nonulosonicacid(pseudaminicacid)derivative,and
(E)2-keto-3-deoxy-D-manno-octulosonicacid(KDO).Note
that the configuration of legionaminic acid was recently
amended.73
one striking parallel to the sialic acids from both a
structuralandbiosyntheticpointofview.Theeight-
carbon R-keto acid KDO (2-keto-3-deoxy-D-manno-
octulosonicacid,foundinGram-negativebacteriaand
inplants;Figure1E)isformedviacondensationofa
Takashi Angata is currently a postdoctoral fellow at the Glycobiology five-carbonunit(D-arabinose)withpyruvate,andits
Research and Training Center, University of California, San Diego. His activated sugar nucleotide form is CMP-KDO. The
graduatestudyattheUniversityofTokyofocusedonthemetabolismof similaritiesinthebiosynthesisandactivationofsialic
KDN, a rare form of sialic acid. Currently he is pursuing the biological acids and KDO and the rarity of other similar
functions of the Siglec family of sialic acid-binding lectins. His future pathways raise the question of whether the two are
researchinterestincludestherolesofsialicacidsinvertebrateontogeny
evolutionarily related. This review addresses these
andphylogeny.
andotherevolutionaryissuesandprovidesanover-
donorform.Whilealltheothervertebratemonosac- view of sialic acid diversity and its distribution in
charides are activated in the form of uridine or nature.
guanine dinucleotides, e.g., GDP-Man and -Fuc, TheoriginaldiscoveryofsialicacidsbyKlenkand
UDP-Glc,-Gal,-GlcNAc,-GalNAc,-GlcUA,and-Xyl, Blixdatesbacktothe1930s(discussedinrefs1-3).
sialicacidsareactivatedascytidinemononucleotides, Although these classic works are beyond the scope
i.e., CMP-Sia molecules. ofourreview,itisworthpointingoutthatthewords
Movingbeyondvertebratesystems,onefindsmany “sialic acid” and “neuraminic acid” (the backbone of
more types of five- and six-carbon sugars and a most sialic acids) both bear the hallmarks of their
greatervarietyoflinkagesandmodificationsinsuch original discoveries: Blix isolated sialic acid from
sugars(particularlyinbacteria).However,thereare submaxillary mucin (sialos ) saliva in Greek) and
no other known nine-carbon keto sugars in nature Klenkisolatedneuraminicacidderivativefrombrain
(other than the recently described pseudaminic and glycolipids (neuro- + amine + acid). Sialic acids
legionaminic acids in bacteria, see below). There is autonomously form a pyranose (six-membered) ring
ChemicalDiversityintheSialicAcidsandRelatedR-KetoAcids ChemicalReviews,2002,Vol.102,No.2 441
Table1.SialicAcids: OccurrenceandStructuralDivergence
Compoundname Abbreviation Occurrencea
neuraminicacid Neu Vb
neuraminicacid1,5-lactam Neu1,5lactam V
5-N-acetylneuraminicacid Neu5Ac V,E,Ps,Pz,F,B
5-N-acetyl-4-O-acetylneuraminicacid Neu4,5Ac V
2
5-N-acetyl-7-O-acetylneuraminicacid Neu5,7Ac V,Pz,B
2
5-N-acetyl-8-O-acetylneuraminicacid Neu5,8Ac V,B
2
5-N-acetyl-9-O-acetylneuraminicacid Neu5,9Ac V,E,Pz,F,B
2
5-N-acetyl-4,9-di-O-acetylneuraminicacid Neu4,5,9Ac V
3
5-N-acetyl-7,9-di-O-acetylneuraminicacid Neu5,7,9Ac V,B
3
5-N-acetyl-8,9-di-O-acetylneuraminicacid Neu5,8,9Ac V
3
5-N-acetyl-4,7,9-tri-O-acetylneuraminicacid Neu4,5,7,9Ac V
4
5-N-acetyl-7,8,9-tri-O-acetylneuraminicacid Neu5,7,8,9Ac V
4
5-N-acetyl-4,7,8,9-tetra-O-acetylneuraminicacid Neu4,5,7,8,9Ac V
5
5-N-acetyl-9-O-lactylneuraminicacid Neu5Ac9Lt V
5-N-acetyl-4-O-acetyl-9-O-lactylneuraminicacid Neu4,5Ac 9Lt V
2
5-N-acetyl-7-O-acetyl-9-O-lactylneuraminicacid Neu5,7Ac 9Lt V
2
5-N-acetyl-8-O-methylneuraminicacid Neu5Ac8Me V,E
5-N-acetyl-9-O-acetyl-8-O-methylneuraminicacid Neu5,9Ac 8Me V,E
2
5-N-acetyl-8-O-sulfoneuraminicacid Neu5Ac8S V,E
5-N-acetyl-4-O-acetyl-8-O-sulfoneuraminicacid Neu4,5Ac 8S V,E
2
5-N-acetyl-9-O-phosphoneuraminicacid Neu5Ac9P Vc,d
5-N-acetyl-2-deoxy-2,3-didehydroneuraminicacid Neu2en5Ac Vd
5-N-acetyl-9-O-acetyl-2-deoxy-2,3-didehydroneuraminicacid Neu2en5,9Ac Vd
2
5-N-acetyl-2-deoxy-2,3-didehydro-9-O-lactylneuraminicacid Neu2en5Ac9Lt Vd
5-N-acetyl-2,7-anhydroneuraminicacid Neu2,7an5Ac Vd
5-N-acetylneuraminicacid1,7-lactone Neu5Ac1,7lactone V
5-N-acetyl-9-O-acetylneuraminicacid1,7-lactone Neu5,9Ac 1,7lactone V
2
5-N-acetyl-4,9-di-O-acetylneuraminicacid1,7-lactone Neu4,5,9Ac 1,7lactone V
3
5-N-glycolylneuraminicacid Neu5Gc V,Pz,F
4-O-acetyl-5-N-glycolylneuraminicacid Neu4Ac5Gc V
7-O-acetyl-5-N-glycolylneuraminicacid Neu7Ac5Gc V
8-O-acetyl-5-N-glycolylneuraminicacid Neu8Ac5Gc V
9-O-acetyl-5-N-glycolylneuraminicacid Neu9Ac5Gc V,E
4,7-di-O-acetyl-5-N-glycolylneuraminicacid Neu4,7Ac 5Gc V
2
4,9-di-O-acetyl-5-N-glycolylneuraminicacid Neu4,9Ac 5Gc V
2
7,9-di-O-acetyl-5-N-glycolylneuraminicacid Neu7,9Ac 5Gc V
2
8,9-di-O-acetyl-5-N-glycolylneuraminicacid Neu8,9Ac 5Gc V
2
7,8,9-tri-O-acetyl-5-N-glycolylneuraminicacid Neu7,8,9Ac 5Gc V
3
5-N-glycolyl-9-O-lactylneuraminicacid Neu5Gc9Lt V
4-O-acetyl-5-N-glycolyl-9-O-lactylneuraminicacid Neu4Ac5Gc9Lt V
8-O-acetyl-5-N-glycolyl-9-O-lactylneuraminicacid Neu8Ac5Gc9Lt V
4,7-di-O-acetyl-5-N-glycolyl-9-O-lactylneuraminicacid Neu4,7Ac 5Gc9Lt V
2
7,8-di-O-acetyl-5-N-glycolyl-9-O-lactylneuraminicacid Neu7,8Ac 5Gc9Lt V
2
5-N-glycolyl-8-O-methylneuraminicacid Neu5Gc8Me E
9-O-acetyl-5-N-glycolyl-8-O-methylneuraminicacid Neu9Ac5Gc8Me E
7,9-di-O-acetyl-5-N-glycolyl-8-O-methylneuraminicacid Neu7,9Ac 5Gc8Me E
2
5-N-glycolyl-8-O-sulfoneuraminicacid Neu5Gc8S V,E
5-N-glycolyl-9-O-sulfoneuraminicacid Neu5Gc9S E
5-N-(O-acetyl)glycolylneuraminicacid Neu5GcAc V
5-N-(O-methyl)glycolylneuraminicacid Neu5GcMe E
2-deoxy-2,3-didehydro-5-N-glycolylneuraminicacid Neu2en5Gc Vd
9-O-acetyl-2-deoxy-2,3-didehydro-5-N-glycolylneuraminicacid Neu2en9Ac5Gc Vd
2-deoxy-2,3-didehydro-5-N-glycolyl-9-O-lactylneuraminicacid Neu2en5Gc9Lt Vd
2-deoxy-2,3-didehydro-5-N-glycolyl-8-O-methylneuraminicacid Neu2en5Gc8Me Ed
2,7-anhydro-5-N-glycolylneuraminicacid Neu2,7an5Gc Vd
2,7-anhydro-5-N-glycolyl-8-O-methylneuraminicacid Neu2,7an5Gc8Me Ed
5-N-glycolylneuraminicacid1,7-lactone Neu5Gc1,7lactone V
2-keto-3-deoxynononicacid KDN V,B
5-O-acetyl-2-keto-3-deoxynononicacid KDN5Ac V
7-O-acetyl-2-keto-3-deoxynononicacid KDN7Ac V
9-O-acetyl-2-keto-3-deoxynononicacid KDN9Ac V
4,5-di-O-acetyl-2-keto-3-deoxynononicacid KDN4,5Ac V
2
4,7-di-O-acetyl-2-keto-3-deoxynononicacid KDN4,7Ac V
2
5,9-di-O-acetyl-2-keto-3-deoxynononicacid KDN5,9Ac V
2
7,9-di-O-acetyl-2-keto-3-deoxynononicacid KDN7,9Ac V
2
8,9-di-O-acetyl-2-keto-3-deoxynononicacid KDN8,9Ac V
2
2-keto-3-deoxy-5-O-methylnononicacid KDN5Me B
2-keto-3-deoxy-9-O-phosphonononicacid KDN9P Vc,d
aAbbreviationsused: V,vertebrates;E,echinoderms;Ps,protostomes(insectsandmolluscs);Pz,protozoa;F,fungi;B,bacteria.
bPresentonlyasboundform.cBiosyntheticintermediate.dPresentonlyasfreeform.
in solution via intramolecular hemiketal condensa- 1A,B). In natural glycoconjugates, sialic acids exist
tion and adopt a 2C chair conformation (Figure onlyintheR-configuration,exceptinthehigh-energy
5
442 ChemicalReviews,2002,Vol.102,No.2 AngataandVarki
donor form CMP-sialic acids, where the anomeric recent years. Such a “census” survey along with the
carbon is in the (cid:226)-configuration (R and (cid:226) configura- experimental evidence published in recent years
tionsrefertotheC7carbonandC1carboxylgroups indicate that sialic acids (and/or related molecules)
being in a trans and cis orientation, respectively). aremorewidelydistributedthanpreviouslythought
Sialic acids show remarkable structural diversity and possibly quite ancient in their origin. In this
innature,withthefamilycurrentlycomprisingover reviewweattempttosummarizetheserecentdevel-
50differentcompounds(Table1).Theoriginaldefini- opmentsinstudiesofthestructure,biosynthesis,and
tion of sialic acids was “neuraminic acid (5-amino- biologyofsialicacids.Wealsodiscusstheevolution-
3,5-dideoxy-D-glycero-D-galacto-2-nonulosonicacid,ab- aryoriginofsialicacids,basedonexistingdataand
breviated as Neu, Figure 1A) and its derivatives”.1,2 onourphylogeneticanalysisoftheenzymesinvolved
This definition was expanded by the discovery of intheirbiosynthesisandthatofrelatedR-ketoacids
3-deoxy-D-glycero-D-galacto-2-nonulosonicacid(or2-ke- (seeFootnotesection).Ouranalysisleadstoarather
to-3-deoxy-D-glycero-D-galacto-nononicacid,KDN,Fig- unconventionalconclusionthattheinventionofsialic
ure1B),4whichhasahydroxylgroupinplaceofthe acids may not have happened in the immediate
amino group at the C5 position. KDN is otherwise ancestor of deuterostomes (vertebrates, ascidians,
very similar to the traditionally defined sialic acids and echinoderms). Rather, it may have predated at
instructure,occurrence(ref5andcitationstherein), least the split of deuterostomes and protostomes
and its biosynthetic pathway.6-8 All other currently (arthropodsandmolluscs).Italsomaypossiblyhave
recognized sialic acids are biosynthetic derivatives initially emerged in a lineage of bacteria with later
of either N-acetylneuraminic acid (Neu5Ac, Figure transfer to eukaryotic animals. These and other
1A)orKDN(Figure1B).N-Glycolylneuraminicacid possibleevolutionaryscenariosareconsideredinthis
(Neu5Gc, Figure 1A), a major type of sialic acid review.
expressed in deuterostomes, is derived from CMP-
Our review mainly focuses on the recent publica-
Neu5Ac by the addition of an oxygen atom to the
tionsconcerningsialicacidbiologywithemphasison
N-acetyl group, catalyzed by CMP-Neu5Ac hydrox-
theproteinsinvolvedinthebiosynthesisandrecogni-
ylase.9Neuraminicacidwithanunsubstitutedamino
tionofsialicacids.Manyimportantaspects,suchas
group has been detected in some natural glycocon-
methodologiesinthedetectionandstructuralanaly-
jugatesandisconsideredtobederivedfromNeu5Ac
sis of sialic acids, are not addressed. Readers with
via enzymatic deacetylation.10 Further structural
interestsintheseaspectsareencouragedtoreferto
diversity of sialic acids is primarily generated by
certainclassicmonographs13,14aswellastotherecent
combinations of the above-mentioned variations at
encyclopedic review elaborated by Schauer and Ka-
theC5positionwithmodificationsofhydroxylgroups
merling.15Basicbackgroundconcerningglycobiology
atC4,C7,C8,andC9byacetate,lactate,sulfate,or
canbefoundinarecentlypublishedtextbook.16Some
phosphate esters or by methyl ethers. Intra- or
technical terms in the fields of genomics and phylo-
intermolecularlactonizationinvolvingthecarboxyl-
geneticsareexplainedintheGlossarysectionofthis
ateatC1andintramolecularlactamizationbetween
review.
C1andC5(incaseofNeu)addfurthervariety.Some
sialic acids (e.g., 2-deoxy-2,3-didehydro sialic acids)
arefoundonlyinfreeform,asexpectedfromthelack II. Occurrence and Structural Diversity of Sialic
of the R-keto group.11 There are some other sialic Acids in Nature
acid-like molecules with a nine-carbon backbone
found so far only in bacteria, such as derivatives of As shown in Figure 2, all cellular organisms are
legionaminicacid(Figure1C)andpseudaminicacid classified into three domains of lifeseukarya (eu-
(Figure1D).Asdiscussedbelow,thesemoleculesmay karyotes),bacteria(eubacteria),andarchaea(archae-
be synthesized via very similar biosynthetic path- bacteria). Although there is controversy over the
waystothoseofsialicacids,12raisingthepossibility exact evolutionary relationship of these three do-
of expanding the definition of sialic acids to accom- mains,17,18 it appears that the original separation of
modate them. theselifeformsisquiteancient.Generallyspeaking,
Sialic acids are critical in the development of itstillstandstobetruethattheexpressionofsialic
vertebrates, as evidenced by the fact that mouse acidistheruleonlyindeuterostomesandanexcep-
embryosengineeredtolacksialicacidexpressiondie tion among other life forms. However, the presence
well before they are born (W. Reutter, personal of sialic acids has been unequivocally shown in
communication). The expression of sialic acids was bacteriaandsomenondeuterostomeeukaryotes,and
previouslythoughttobeuniquetodeuterostomesand genomicsequencedatasuggeststhepresenceofsialic
to the pathogenic bacteria infecting these animals. acid in an archaeal organism (see below). Figure 2
However,recentstudieshaveledtothediscoveryof summarizes the occurrence of sialic acid (based on
these sugars in formerly unsuspected organisms, direct chemical analysis or indirectly based on ge-
suchascertaininsectsandfungi.Also,themolecular nomic sequences) in various organisms and their
cloning of most of the bacterial and vertebrate phylogenetic relationship. The generally accepted
enzymes involved in sialic acid biosynthesis (which nomenclatureusedtodenotethesemoleculesisalso
show significant sequence similarities) has allowed listed in Table 1. In the following sections we will
us to seek orthologous sequences in the genomes of discussthepresenceandvarietyofsialicacidsfound
otherorganisms.Theavailableinformationregarding innature,withreferencetotheenzymesinvolvedin
suchgenomicsequenceshasexpandedexplosivelyin their biosynthesis when appropriate.
ChemicalDiversityintheSialicAcidsandRelatedR-KetoAcids ChemicalReviews,2002,Vol.102,No.2 443
Figure2. “Universaltree”ofcellularorganismsandoccurrenceofsialicacids.Thetreewasconstructedfromaminoacid
sequences of elongation factors (EF-Tu and EF-1R) from various organisms using neighbor-joining method,206 and the
positionoftherootwasestimatedbythemethoddescribedintheliterature.428Expressionofsialicacids(determinedby
physicochemical methods, e.g., NMR, mass-spectrometry, etc.) is indicated with a closed circle and putative expression
(predictedfromDNAsequences)withanopencircle.Therearethreeexamplesofapparentlycompletegenomesofeukaryotes
that do not show any evidence for the genes involved in sialic acid biosynthesis: Caenorhabditis elegans (nematode),
Arabidopsisthaliana(thalecress,plant),andSaccharomycescerevisiae(baker’syeast,fungus).Therearealsoninecomplete
genomesofarchaea(asofJuly2001)thatdonotshowanyevidenceforsuchgenes.
A. Eukaryotes today.Vertebrateswerethoughttobeless“colorful”
compared with echinoderms in terms of sialic acid
1. Animals diversity, with mainly O-acetylation and occasional
lactylation (Table 1). However, a recent report em-
Deuterostomes (vertebrates, ascidians, and echi-
ployinganewderivatizationmethodhasshownthat
noderms)expressfourmajortypesofglycoconjugates
vertebrate tissues also contain small amounts of
which are expressed on the cell surface or secreted:
rather “unusual” sialic acids, such as 8-O-methyl
glycoproteins, glycolipids, proteoglycans, and glyco-
Neu5Ac.30 Of particular interest among newly dis-
sylphosphatidylinositol (GPI) anchors. With some
coveredsialicacidsareNeu1,5-lactam31andNeu5Ac
exceptions, sialic acids are expressed mostly on the
1,7-lactone.32 Both of these structures are found in
glycan chains of glycoproteins and glycolipids. In
glycoconjugates, and the former may be involved in
mostcasestheyoccupythedistal(outermost)endof
glycan chains, being commonly linked via an R2-3 regulatingrecognitionbyselectins(afamilyofsialic
linkage to Gal, via an R2-6 linkage to Gal and acidrecognizinglectins,seesectionIII.B.2),withthe
GalNAc, or via an R2-8 linkage to another sialic latter being specifically recognized by interleukin-
acid.19SuchlinkagesasR2-3linkagetoGalNAc,20,21 4.31,32Theseexamplesalsoindicatethatsubtlemodi-
R2-6linkagetoGlcNAc22,23andGlc,24R2-4linkage ficationsofsialicacidmoleculescanprofoundlyaffect
toGal25andGlcNAc,26R2-9linkagetoanothersialic biological interactions.
acid,27 and a Neu5Gc oligomer linked via hydroxyl Protostomes (arthropods and molluscs) seem to
groupofN-glycolyl28alsoexistbutarerare(someare express generally similar classes of glycoconjugates
only found, so far, in echinoderms). There are also as those of deuterostomes. In addition, some organ-
some examples in echinoderms and amphibians isms (arthropods, such as insects and crustaceans)
wherethesialicacidsarefoundasinternalresidues, expressanectoskeletonmadeofchitin(apolymerof
i.e., substituted at one or more hydroxyl groups by GlcNAc). Despite one earlier report on the presence
anothersugarotherthansialicacid.15,29These“outer” ofsialicacid(Neu5Gc)inagastropod,33protostomes
sugars may be considered as additional sialic acid were generally thought to be devoid of this class of
“modifications”. molecules. Indeed, the original extensive survey by
Deuterostomes express the highest structural di- Warren using the thiobarbituric acid test failed to
versity of sialic acids. All types of O-substitutions show a positive response in a wide variety of pro-
listed in Table 1 (acetylation, lactylation, sulfation, tostomesexamined.34Furthermore,withonepossible
methylation)canbefoundinthisgroup.Echinoderms exception,35recombinantproteinsexpressedininsect
(sea urchins, starfish, etc.) express these modified cells are not reported to have sialic acids.36,37 How-
sialic acids in rather large quantities, which made ever, recent studies have shown that some insects
identification of some of them possible in the past, mayexpressNeu5Acinastage-specificmanner.38,39
using less sensitive methods than those available Also,octopusesandsquids(belongingtothemolluscs)
444 ChemicalReviews,2002,Vol.102,No.2 AngataandVarki
have recently been shown to express gangliosides 4. Protozoa
(sialic acid-containing glycolipids).40 Perhaps sialic
acids are expressed only in a small number of It is known that some protozoa, such as Trypano-
protostomespecies.Theotherpossibilityisthatthey soma cruzi (which causes Chagas’ disease in South
are actually common in protostomes but present in America),carrysialicacids.49However,theseorgan-
verylimitedquantitiesand/orrestrictedtoparticular isms do not synthesize their own sialic acids but
tissues/stages.Thequestionalsoarisesastowhether rather “borrow” it from their host glycoproteins by
these animals actually synthesize their own sialic theactionofauniqueenzymecalledtrans-sialidase.50
acidsorsimplyutilizesialicacidassimilatedthrough The sialic acids are thought to protect these organ-
the food chain (or synthesized by a commensal isms from detection and attack by host immune
organism). In this regard, it is notable that the system.51Therearesomestudiesclaimingthepres-
genome of fruit fly Drosophila melanogaster appar- enceofsialicacids(Neu5Ac,Neu5Gc,Neu5,7Ac2,and
entlylackssomegenesofenzymesnecessaryforthe Neu5,9Ac2) on other protozoal cells, such as a slime
denovobiosynthesisofsialicacidsbutcontainssome mold Dictyostelium discoideum,52 a trypanosome
others (discussed later). Crithidia fasciculata,53 a piroplasmid Theileria ser-
genti,54 and the amoebae Entamoeba invadens and
2. Fungi E. histolytica.55,56 Whether these organisms synthe-
sizesialicacidsontheirownisanunsolvedquestion.
Therearereportsonthepresenceofsialicacidsin
Thereisinsufficientgenomicdataontheseorganisms
some pathogenic fungal cells (reviewed in ref 41),
to allow a search for genes known to be involved in
such as Candida albicans,42 Cryptococcus neofor-
thebiosynthesis,activation,ortransferofsialicacids.
mans,43 Aspergillus fumigatus,44 and Sporothrix
schenckii.45 The sialic acid species identified so far
B. Bacteria
areNeu5Ac,Neu5Gc,andNeu5,9Ac .Althoughsome
2
of these claims are based only on binding of lectins Bacteriaexpressvarioustypesofglycoconjugates,
whichcanrecognizesialicacids,othersincludemore such as capsular polysaccharides (K-antigens), lipo-
solid evidence, such as mass spectrometry.43,44 We polysaccharides (O-antigens), S-layer glycoproteins,
conducted a survey of the available genomic DNA and peptidoglycans (component of the cell wall).
sequencesofthreefungalspecies,i.e.,Saccharomyces When present, sialic acids are found mostly in cap-
cerevisiae,C.albicans(http://www-sequence.stanford. sular polysaccharides and lipopolysaccharides. Un-
edu/group/candida),andC.neoformans(http://www- likethesituationinanimalglycoconjugates,thesialic
sequence.stanford.edu/group/C.neoformans)sthelat- acidsinthesepolysaccharidesmostlyexistasinter-
ter two are still incomplete. This analysis did not nal residues, either in homopolymers (polysialic
revealanysequencessignificantlysimilartoenzymes acids) linked via R2-8 and/or R2-9 linkages or in
knowntobeinvolvedinthebiosynthesis,activation, repetitive units made of several sugar residues.
or transfer of sialic acids in bacteria and mammals. However, there are also examples of terminal sialic
However, it is possible that the expression of sialic acids in certain bacterial lipooligosaccharides.57-59
acidsinfungiisstrain-specific(asisthecaseinmany Most of these bacteria express Neu5Ac (with oc-
bacteria).Alternatively,sialicacidsmaybeacquired casionalO-acetylation,seeref60foracomprehensive
from external sources. It also cannot completely be listing), and a few synthesize KDN and its deriva-
ruledoutthatthesefungicouldhaveindependently tives.61,62 Neu5Gc has not, so far, been reported in
developedanovelpathwaytosynthesizeandexpress bacteria.
sialic acids.
Mostbacteriadonotexpresssialicacids,andeven
withinabacterialspeciessomestrainsexpresssialic
3. Plants
acidswhileothersdonot(althoughdefining“species”
With one possible exception, structural studies of in bacteria is difficult due to frequent exchange of
naturalandrecombinantplantglycoproteins46,47have geneticmaterialbetweenspecies,seerefs63and64).
shownnoevidenceofsialicacids.Therearealimited Regardless,itisofnotethatmanyofthesialicacid-
numberofreportsdescribingsialicacidinplants,of expressing bacteria are causative agents of serious
which only one appears conclusive, reporting the illness in humans and domestic animals and hence
presence of Neu5Ac in buckwheat using mass spec- became subjects of extensive studies,65 such as Es-
trometry.48 Some earlier reports on sialic acids in cherichia coli strain K1 and Neisseria meningitidis
plants may be explained by the presence of similar group B,C causing meningitis66 and Campylobacter
R-keto acids in plants, such as 3-deoxy-D-arabino- jejunicausingfood-bornegastroenteritis(somestrains
heptulosonicacid7-phosphate(DAHP,anintermedi- induce an autoimmune neurodegenerative disorder
ate in the schikimic acid pathway of the aromatic called Guillain-Barre syndrome).67 Sialic acids on
amino acid biosynthesis) and KDO (a component of the cell surface of these bacteria are thought to
cell wall polysaccharides). Both of these molecules provide a protective barrier to evade detection and
givepositivereactionsinsometraditionalcolorimet- attackbythehost’simmunesystem.Itwasoriginally
ricassaysforsialicacids.OuranalysisofplantDNA assumed that these pathogenic bacteria acquired
sequences in the GenBank database, including that theirsialicacidbiosyntheticmachineryviahorizontal
ofthalecressArabidopsisthaliana(thegenomicDNA transfer of the genes from vertebrate hosts68,69sa
of which is completely sequenced), revealed no evi- rather natural speculation given the conspicuous
dence for genes known to be involved in the biosyn- absenceofsialicacidsintheorganismsevolutionarily
thesis, activation, or transfer of sialic acids. situatedbetweenbacteriaanddeuterostomes.How-
ChemicalDiversityintheSialicAcidsandRelatedR-KetoAcids ChemicalReviews,2002,Vol.102,No.2 445
ever, there are some bacteria which express sialic numerouslectinsinnaturewhichcanrecognizesialic
acids and are not known to be pathogenic to verte- acids (Tables 2-4). These are briefly reviewed here
brates, such as some Rhodobacter species70 and to place into perspective their likely role in driving
(Sino)rhizobium meliloti.71 In addition, if bacteria theevolutionofchemicaldiversityinthesialicacids.
acquiredagenefromadeuterostomehostbylateral For convenience, we have grouped them into three
transferinthepast,thecurrentbacterialgeneshould categories: vertebrate pathogen lectins, vertebrate
look more similar to the counterpart in a current endogenous lectins, and lectins from other sources
deuterostome genome (e.g., the one in human ge- (plants, protostomes, etc.). Members of the third
nome) than to the equivalent gene in any other group have great importance as tools for sialic acid
genome, e.g., the one in Drosophila genome. (Note research. However, their natural functions are not
thatsincegenomicDNAsequencesgraduallychange clearlyunderstood(somearethoughttobeinvolved
over time, copies made most recently should look inantibacterialself-defense79,80).Thus,thisgroupis
moresimilar,comparedwiththosemadealongtime not discussed in detail.
ago). In fact, as discussed later, the bacterial genes
involved in sialic acid expression fail to show such A. Vertebrate Pathogen Lectins
an unusually close relation to vertebrate counter-
Variouspathogens(viruses,bacteria,andprotozoa)
parts.
expresslectinsthatcanrecognizesialicacids.Some
As mentioned earlier, some bacteria express dif-
pathogensusetheselectinsforrecognitionandentry
ferent kinds of 3-deoxy-2-keto-nonulosonic acids,
intothehostcells,whileothersexpresssolublelectins
namely,derivativesoflegionaminicacid(Figure1C,
with a sialic acid-binding property. In some cases,
originally discovered in Legionella pneumophila
these pathogens use not only sialic acids but also
lipopolysaccharide)andpseudaminicacid(Figure1D,
someothercellsurfacemoleculesforattachment,and
originally discovered in Pseudomonas aeruginosa
different strains show different degrees of depen-
lipopolysaccharide).Bothofthesearesimilartosialic
dence toward a particular type of such cellular
acidsintheirstructure(reviewedinref72;forcorrect
“receptors”.
configuration of legionaminic acid, see ref 73) and
probably in their biosynthesis.12 Epimers of legion-
1. Viruses
aminic acids (at C4 or C8-positions) are also re-
ported.73 Many of the bacteria expressing these Viral sialic acid-recognizing lectins are usually
sugars are pathogenic in humans; hence, a relation capable of agglutinating red blood cells (hemocytes
to the virulence is suspected.72 However, some non- in old terms) and are thus traditionally called he-
pathogenic bacteria also express these sugars, e.g., magglutinins rather than lectins. Many viruses
Sinorhizobiumfredii(asymbioticbacteriumoflegu- utilize sialic acids to facilitate attachment to host
minous plants),74 a marine bacterium Pseudoal- cells(seelistinginTable2),althoughtheirdegreeof
tromonasdistincta,75andPseudomonasfluorescens.76 dependence on sialic acids for this purpose varies.
In addition, these particular sugars have not been Hemagglutinins of influenza viruses (A, B, and C),
identifiedinvertebratetissues.Hence,theyarelikely Newcastle disease virus (NDV, an avian pathogen),
tobeantigenicinvertebrates,whichwouldhavean mousepolyomavirus,Sendaivirus(arodentpatho-
adverse effect on bacterial survival in host tissues. gen), mouse hepatitis virus, and some others have
It is therefore likely that these sugars and various been isolated and shown to bind sialic acids. Some
modifications have more to do with evading attack ofthesehemagglutinins(frominfluenzaA,C,NDV,
by bacteriophages, as suggested for Sinorhizobium andpolyomaviruses)havebeencrystallizedandtheir
K-antigens.77,78 three-dimensional structure resolved by X-ray crys-
tallography.81-85 In many other instances (e.g., ad-
C. Archaea
enovirusesandpicornaviruses),theexactmolecular
Although the structural information on archaeal natureoftheviralsialicacid-recognizinglectinshas
glycans is limited compared with those of bacteria not even been identified.
and eukaryotes, it is known that they do express Perhaps the most well-known and well-studied
glycoproteins,glycolipids,andpolysaccharides.There moleculeofthiskindistheinfluenzaAvirushemag-
havebeennopublishedstudiesconcerningthepres- glutinin. Influenza viruses show near obligatory
ence of sialic acids in archaea. However, we noted dependence on the host cell surface sialic acids for
that the genome of a hyperthermophilic archaea, infection.Sialicacidbindingpreferencesofinfluenza
Methanococcus jannaschii, contains putative genes Ahemagglutininsisolatedfromdifferenthostspecies
similar to Neu5Ac synthetase and CMP-Neu5Ac arecorrelatedwiththetypeofsialicacidsexpressed
synthetase in a gene cluster, suggesting that the on the host cells86 and even with difference in the
organism may express sialic acids or a similar sialicacidlinkage(R2-3/R2-6).Studieshaveshown
molecule. Definite chemical identification of such a that the natural reservoir of influenza viruses is in
compoundisawaited.However,thegenomesofnine variousspeciesofwildwaterfowl.87Throughaseries
otherarchaealspecies(whosecompletegenomeswere ofcross-speciesinfectionsinvolvingdomesticanimals
sequenced)donotshowevidenceforsimilarenzyme (ducks and pigs) and adaptations to the new types
genes. of sialic acids encountered in the new hosts, and/or
reassortmentofgenomicfragmentsfromhumanand
III. Proteins That Recognize Sialic Acids
birdinfluenzavirusesinpigs,whicharesusceptible
Proteins which recognize sugars (excluding anti- tobothtypesofviruses,88influenzavirusesadaptto
bodies) are collectively called lectins. There are infect humans and cause seasonal epidemics.
446 ChemicalReviews,2002,Vol.102,No.2 AngataandVarki
Table2.VertebratePathogens/CommensalOrganismsWhichRecognizeSialicAcidsa
Pathogens(lectinprotein,ifknown) Specificityb Ref
Viruses
Orthomyxoviridae
InfluenzavirusA(H)c(Fowlplaguevirus)influenzaA) variable,dependingonhostand/orstrains 86,252,253
InfluenzavirusB(H) Neu5AcR2-6Gal 254
InfluenzavirusC(HE) Neu5,9Ac 89,255
2
Paramyxoviridae
Newcastlediseasevirus(HN) Neu5Ac/Neu5GcR2-3Gal(cid:226)1-4Glc(NAc) 256,257
Sendaivirus(HN) Neu5AcR2-3Gal(cid:226)1-3GalNAc/4GlcNAc 256,258
Humanparainfluenzavirustype1(HN) Neu5AcR2-3Gal(cid:226)1-4GlcNAc 96
Humanparainfluenzavirustype3(HN) Neu5Ac/Neu5GcR2-3/6Gal(cid:226)1-4GlcNAc 96
PorcinerubulavirusLPM(HN) SiaR2-3Gal 259
Reoviridae
Reovirustype3((cid:243)1) Sia* 260,261
PorcinerotavirusgroupAOSU Neu5Gc/Neu5AcR2-3Gal(cid:226)1-4Glc(Gc>Ac) 262
PorcinerotavirusgroupCAmC-1 Sia* 263
HumanrotavirusKUN,MO GM1 264
HumanrotavirusWa Sia* 265
SimianrotavirusRRV(VP4) Sia* 266
SimianrotavirusSA11 Neu5GcR2-3Gal 267
BovinerotavirusNCDV Neu5GcR2-3Gal 267
Bluetonguevirus Neu5Ac,Neu5Gc 268
Coronaviridae
Bovinecoronavirus(Sprotein) Neu5,9Ac R2-3GalgNeu5,9Ac R2-6Gal 269,270
2 2
HumancoronavirusOC43(Sprotein) Neu5,9Ac R2-6GalgNeu5,9Ac R2-3Gal 269,270
2 2
Porcinehemagglutinatingencephalomyelitisvirus Neu5,9Ac 271
2
Porcinetransmissiblegastroenteritiscoronavirus(Sprotein) Neu5GcR2-3 272
Avianinfectiousbronchitiscoronavirus Neu5AcR2-3 273
Mousehepatitisvirus(HE) Neu4,5Ac 95
2
Adenoviridae
Adenovirustype37 SiaR2-3* 274
Adenovirustype8,19a Sia* 275
Picornaviridae
Bovineenterovirus261 Sia* 276
Humanenteroviustype70 Sia 277
Theiler’sencephalomyelitisvirusDA Sia 278
Humanrhinovirustype87 Sia* 279
Encephalomyocarditisvirus Sia 280,281
Mengoencephalomyocarditisvirus Sia* 282
Parvoviridae
Adeno-associatedvirustype4 Neu5AcR2-3Gal 283
Adeno-associatedvirustype5 Neu5AcR2-3Gal,Neu5AcR2-6Gal 283,284
Canineparvovirus Sia* 285
Bovineparvovirus Sia* 286
Polyomaviridae
Mousepolyomavirus(VP1) Neu5AcR2-3Gal(cid:226)1-3GalNAc 287,288
PolyomavirusJC SiaR2-6 289
HumanpolyomavirusBK Sia 290
Papillomaviridae
MonkeyB-lymphotropicpapovavirus Sia 291,292
Herpesviridae
Humancytomegalovirus Neu5Ac>Neu5Gc 293
Mousecytomegalovirus Neu5Ac(virulence-associated) 294
Rhabdoviridae
Rabiesvirus Sia* 295
Vesicularstomatitisvirus Sia* 296
Hepdnaviridae
HepatitisBvirus(smallSprotein) Neu5Ac 297
Bacteriasadhesinsorwholecells
Proteobacteria(Gram-negative)
E.coli(SfaI,II;commonsubunitSfaS) Neu5GcR2-3Gal,Neu5AcR2-8Neu5Ac 298,299
E.coli(K99fimbriae) Neu5GcR2-3Gal(cid:226)1-4Glc 104,105
E.coli(F41fimbriae) Sia 300
E.coli(CFAI) Sia* 301,302
E.coli(CFAII;CS2protein) Sia(Neu5Gc>Neu5Ac) 303
Helicobacterpylori Neu5AcR2-3Gal 304,305
Neisseriasubflava(Sia-1adhesin) Neu5AcR2-3Gal(cid:226)1-4Glc 306
Pseudomonasaeruginosa sialylLex 307
SiaR2-6 308
Haemophilusinfluenzae GD2,GD1a,GD1b 309,310
Haemophilusinfluenzae(HMW1agglutinin) SiaR2-3 311
Bordetellabronchiseptica Neu5Ac 312
Bordetellaavium GD1a,GT1b 313
Pasteurellahaemolytica(adhesin) GlcNAc>Neu5Ac 99
ChemicalDiversityintheSialicAcidsandRelatedR-KetoAcids ChemicalReviews,2002,Vol.102,No.2 447
Table2(Continued)
Pathogens(lectinprotein,ifknown) Specificityb Ref
Bacteriasadhesinsorwholecells
Moraxellacatarrhalis GM2 314
Actinobacillusactinomycetemcomitans Sia* 315
Gram-positivebacteria
Streptococcussanguis(SSP-5) Neu5AcR2-3Gal(cid:226)1-3GalNAc 316,317
Streptococcusmitis Neu5AcR2-3Gal(cid:226)1-3GalNAc 317
Streptococcusgordonii Neu5AcR2-3 318
Streptococcusmutans(PAcprotein) SiaR2-6 319
Streptococcussuis Neu5AcR2-3(Gal(cid:226)1-4GlcNAc(cid:226)1-3)n 320
Streptococcuspneumoniae(CpbA) SiaR2-6Gal(cid:226)1-4Glc? 321
Staphylococcusaureus Sia,sulfatedsugar? 322
Ureaplasmaurealyticum Sia* 323
CFB/greensulfurbacteria
Bacteroidesfragilis Neu5Ac?***,d 324
Spirochaeta
Treponemadenticola Neu5Ac?***,d 325
Treponemapallidum Neu5Ac*** 326
Mycoplasma
Mycoplasmapneumoniae(hemagglutinin) Neu5AcR2-3(Gal(cid:226)1-4GlcNAc(cid:226)1-3)n 327
Mycoplasmabovis Sia,sulfatedsugar?** 328
Mycoplasmagallisepticum Sia* 329
Bacteriastoxins
Clostridiumtetani(tetanustoxin) GD1b,GT1b 330
Clostridiumbotulinum(neurotoxin,typeA-F) GQ1b,GT1b,GD1a 331-333
Clostridiumperfringens((cid:228)toxin) GM2 334
Clostridiumperfringens((cid:15)toxin) Sia* 335
Vibriocholera(choleratoxin) GM1 330,336
Vibriomimicus(hemolysin) GD1a,GT1b 337
Vibrioparahemolyticus(thermostabledirecthemolysin) GT1 338
E.coli(heat-labileenterotoxin) GM1 330
E.coli(heat-stableenterotoxinb) sulfatide,gangliosides? 100
Bordetellapertussis(pertussistoxin) GD1a;Neu5AcR2-6Gal(cid:226)1-4GlcNAc 339,340
Staphylococcusaureus(Rtoxin) Neu5AcR2-3Gal(cid:226)1-4GlcNAc(cid:226)1-3Gal(cid:226)1-4Glc 341
Staphylococcusaureus((cid:231)hemolysin,leucocidin) GM1 342
Protozoa
Plasmodiumfalciparum(EBA-175) Neu5AcR2-3Gal 108
Plasmodiumfalciparum(BAEBL) Sia* 112
Tritrichomonasmobilensis(TML) Neu5Ac>Neu5Gc*** 343
Tritrichomonasfoetus(TFL) Neu5Ac(cid:25)Neu5Gc*** 113
Tritrichomonassuis Sia?***,d 344
Entamoebahistolytica(toxin) Sia 345
Toxoplasmagondii Sia* 346
Fungi
Aspergillusfumigatus Sia 347
Penicilliummarneffei Neu5Ac*** 348
Chrysosporiumkeratinophilum Neu5Ac*** 349
Anixiopsisstercoraria(Aphanoascusfulvescens) Neu5Ac*** 349
Microsporumsp.(7species) Sia 350
Trichophytonsp.(5species) Sia 350
Epidermophytonfloccosum Sia 350
aThelistcompiledhereisdeliberatelyinclusive,consideringallreportsthatsuggestmicrobialrecognitionofsialicacids,including
invitroexperimentsinvariousdirectandindirectformats.Inmanycases,thebiologicalrelevanceofsialicacidbindingtoinvivo
infection process has not been proven. In some instances sialic acids only represent one of several factors involved in initial
interactions of microbes with vertebrate cells. Also, due to strain-to-strain difference in cellular “receptor” preference, the fact
thatonestrainusessialicacidforcelladhesiondoesnotnecessarilymeanthattheotherstrainsofthesamemicrobealsoutilize
sialicacids.Forexample,among102typesofhumanrhinovirusestested,type87istheonlyonewhichrequiressialicacidascell
surfacereceptor.279bTheasterisks(*)indicatethecriteriausedintheoriginalliteraturetoclaimsialicacidrecognitionbythe
pathogen(lectin): *,sialidasetreatmentofhostcells/erythrocytesreducebinding/hemagglutinationbythepathogen(lectin);**,
asialo-counterpart of the glycoconjugate (used as competitive inhibitor) is less effective than intact one in inhibiting binding/
hemagglutination by the pathogen (lectin); ***, Neu5Ac (or other mono/oligosaccharide) inhibits binding/hemagglutination by
thepathogen(lectin).Noasterisksareattachedwhenmorethanonecriteriawasusedtoprovesialicacidrecognitionormore
detailedanalysis(e.g.,TLC-overlay)wasemployedtoanalyzebindingspecificity.Sia)sialicacid,typenotspecified.Incases
where the specificity is indicated only as Sia, binding of pathogens to sialic acids were determined by criteria * and/or ** as
above. In cases in which the evidence is even less robust, we list the item with a question mark (?).cH, hemagglutinin; HE,
hemagglutinin-esterase; HN, hemagglutinin-neuraminidase.dSialic acid significantly inhibits hemagglutination/binding by
pathogen(lectin),butsialidasetreatmentoferythrocytes/hostcellsdoesnotinhibitorevenenhancehemagglutination/binding.
Among other related molecules, the influenza C bindstoNeu5,9Ac ,butalsohasanenzymeactivity
2
virus hemagglutinin-esterase is notable for being to destroy the 9-O-acetyl ester.90 This protein has
specific for 9-O-acetylated sialic acids.89 It not only provenusefulasaprobeforstudying9-O-acetylated
448 ChemicalReviews,2002,Vol.102,No.2 AngataandVarki
Table3.VertebrateLectinsWhichRecognizeSialicAcids
Names(synonyms) Expression(source)a Bindingspecificity Ref
Selectins
E-selectin(ELAM-1,CD62E) activatedendothelium sialylLex,sialylLea 119,351
L-selectin(MEL14antigen,CD62L) leucocyte 6¢-sulfosialylLex,heparansufate 119,351
P-selectin(GMP-140,PADGEM,CD62P) activatedendothelium, sialylLex,sialylLea,heparansulfate 119,351
platelet
Siglecs
Siglec-1(sialoadhesin) macrophage Neu5AcR2-3Gal>Neu5AcR2-6Gal 149,352
Siglec-2(CD22) B-cell SiaR2-6Gal 353,354
Siglec-3(CD33) myeloidprecursor,Mob SiaR2-6GalgSiaR2-3Gal 149,355
Siglec-4(MAG) glialcells Neu5AcR2-3Galoncomplexgangliosides 356,357
Siglec-5 Mo,Gr SiaR2-6Gal(cid:25)SiaR2-3Gal,Neu5AcR2-8 149,358
Siglec-6(OB-BP1) placenta,B-cell SiaR2-6GalNAc 359
Siglec-7(AIRM-1) NKcells,Mo,Gr SiaR2-6Gal(cid:25)SiaR2-3Gal(3-Igisoform) 360
SiaR2-6Gal(2-Igisoform) 361
Siglec-8 eosinophil,basophil SiaR2-3GalgSiaR2-6Gal 362
Siglec-9 Mo,Gr SiaR2-6Gal(cid:25)SiaR2-3Gal 142,363
Siglec-10 B-cell SiaR2-6Gal(cid:25)SiaR2-3Gal 364
Siglec-11 ? Neu5AcR2-8Neu5Ac unpublished
Others
ComplementfactorH blood Sia;C7-C9sidechainisapartofepitope 365,366
CD83 dendriticcell Sia 143
L1 mouseneuron Neu5AcR2-3(onCD24) 144
Interleukin-1R blood Neu5AcR2-3Gal(cid:226)1-4GlcNAc,biantennary 32
Interleukin-1(cid:226) blood Neu5AcR2-3Gal(cid:226)1-Cer(GM4) 32
Interleukin-2 blood GD1b 367
Interleukin-4 blood Neu5Ac1,7lactone 32
Interleukin-7 blood Neu5AcR2-6GalNAc 32
Laminin extracellularmatrix Neu5AcR2-3Gal(cid:226)1-4GlcNAc(R2-3>R2-6) 145
Sialicacid-bindingprotein endometrium Neu5Gc>Neu5Ac 368
Sarcolectin placenta Neu5Ac,Neu5Gc 147
Calreticulin ovineplacenta Neu5Gc>Neu5Ac,preferO-acetyl 146
Sialicacid-bindingprotein ratuterus Sia 369
Calcyclin bovineheart Neu5Gc 148
Sialicacid-bindingprotein frogegg Sia 370
Gangliosidebindingprotein* ratbrainmyelin gangliosides(GT1b,GQ1b,GD1b) 371,372
Hemagglutinin* ratbrain Neu5Ac,Neu5Gc 373
aExpression(source)isinhuman,unlessotherwisestated.bMo,monocyte;Gr,granulocyte.cMostoftheproteinslistedhere
areclonedand/orpurifiedtohomogeniety,exceptfortheentitiesmarkedwithanasterisk(*).
sialic acids.91-94 Mouse hepatitis virus also has a adhesin,99orsulfatedsugars,aswiththeE.coliheat-
hemagglutinin-esterase, which is specific to sialic stable enterotoxin b.100
acidssubstitutedbyO-acetylgroupattheC4position Bacterialadhesinsareoftenexpressedinastrain-
(Neu4,5Ac2).95 Another prominent example of such specific way and can influence the range of tissues
bifunctional (receptor-recognition/destruction) pro- the strain can infect or colonize.101 Such examples
teins are the hemagglutinin-neuraminidases of include Helicobacter pylori102,103 and E. coli strain
NDV84 and parainfluenza viruses.96 At first glance K99.104,105Theformerisanetiologicalagentofpeptic
it appears irrational that a bifunctional protein ulcers in humans, and the latter causes lethal
carriestwo“contradictory”functions.However,inthe dysenteryamongpigletsandcalves.H.pyloriexpress
case of influenza A virus which carry separate twodifferentadhesins(inanenvironment-dependent
hemagglutininandneuraminidaseproteins,thebal- manner) which can recognize sialic acids.102,103 De-
ance between these two functions appears to be spite detailed analyses on ligand structural prefer-
important for efficient viral replication, which in- ence of these adhesins, their exact role in the
volves numerous cycles of host cell attachments establishmentofinfectionisnotyetunderstood.The
internalization, amplification, and assemblysand adhesinsexpressedbyE.coliK99strainshowshigh
detachment from the host cell.97,98 specificitytowardNeu5GcR2-3Gal(cid:226)1-4Glcstructure
onglycolipids,whichisabundantlyexpressedinthe
2. Bacteria
gastrointestinal tract of piglets.106
Some bacterial pathogens interact with host cells Cholera toxin, produced by Vibrio cholerae, is a
in a sialic acid-dependent manner. The involved classic example of soluble sialic acid-binding lec-
lectinsareattachedtothebacterialsurfaceandare tins.107 It is composed of five B subunits and an A
typicallycalledadhesins.Theidentityoftherecogni- subunit. The B subunits show specific binding to a
tion molecule is uncertain in many cases. There are sialylatedglycolipid(gangliosideGM1),deliveringthe
also soluble bacterial lectins, which are typically Asubunittothecytosol.Thisinturncausesoverac-
toxins. Although many have high specificity toward tivation of an intracellular signaling pathway (ade-
sialicacids,somearenotasspecific,e.g.,recognizing nylatecyclase,producingcyclicAMP)ingastrointes-
also GlcNAc, as with the Pasteurella haemolytica tinal epithelial cells, causing severe diarrhea and