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Robin B. Goldsmith
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# 020494
EMBARGOED BY SCIENCEz
For wire servicesand broadcastnews, February 3, 1994,3 p.m. Pacific Time
X'or print media, February 4, t994
NEW STRUCTIJRAL DETERMINATION OF' CATALYTIC ANTIBODY COI,JLD
LEAD TO IMPROVEMENTS IN SPEED AND BFFICIENCY
La Jolla, CA. - Scientistsat The ScrippsResearchInstitute(TSRI) in La Jolla, California,
have developednew insights into the structureand mode of action of catalytic
antibodies-antibodyproteinswith enzymeactivity-that could improvethe speedand
efficiency of theseproteins in catalyzingchemicalreactionsand thus their value to the
pharmaceuticaland chemicalindustries.
By comparing the three-dimensionalstructuresof an antibody and a natural enzymethat both
catalyzethe samechemicalreaction,they havebhownthat the mechanismsof catalysisfor
both proteinsare very similar. Basedon theseobservations,they can begin to fine-tune
strategiesfor developingcatalyticantibodieswith activitiesapproachingthoseof natural
erzymes.
The study, entitled Routesto Catalysis:Structureof a Catalytic Antibody and Comparison
with its Natural Counterpartappearedin the February4 issueof Science.Its authorsare
Matthew R. Haynes,Enrico A. Stura,DonaldM. Hilvert, and Ian A. Wilson. Haynesis a
graduatestudentin Dr. Wilson's laboratory;Drs. Sturaand Wilson are in the Departmentof
in the departmentsof
Molecular Biology at TSRI, and Dr. Hilvert holds appointments
MORB
Page2 -
STRUCTTJREAND FTJNCTIONOF CATALYTIC ANTIBODMS
The feasibility of developingantibodieswith catalyticpropertieswas pioneeredat TSRI in the
late 1980s.Combiningtechniquesand principlesof chemistry,molecularbiology,
immunology,and geneticengineering,this technologyholds the promiseof developing
catalystsfor many thousandsof chemicalreactions.
The technologicalimplicationsof this vastpool of potentialantibodycatalystsare enormous.
For example,many of the chemicalreactionsusedtodayto producepharmaceuticals
and other
valuablecompoundsare difficult and expensiveto run and producelow yields of product.
Indeed,somereactionschemistswould like to carry out on an industrialscaleare simply not
feasible.With the right antibodycatalysts,however,thesesamereactionscould be madeto
run swiftly, with greatprecision,and in high yield-much in the sameway that biological
reactionsoccur in the presenceof enzymes.
Catalyticantibodiesare preparedby raisingantibodiesin animalsagainstsyntheticcompounds
called transitionstateanalogues.As bondsare madeor brokenin chemicalreactions,there is
a point at which the componentsof the reactionexist in an intermediateconfiguration where
the reactioncould go either way. This molecularconfiguration,calledthe transitionstateof
the reaction,has a fleeting existenceand cannotbe isolated.However, chemistscan deduce
what the transition stateof a particular reactionmust look like and createcompoundswith
very similar shapes-transitionstateanalogues.
Enzymescatalyzeor acceleratechemicalreactionsby binding thesetransitionstatesand
stabilizingthem, therebyincreasingthe likelihoodthat the reactionwill occur. Similarly,
antibodiesthat can bind to transitionstateanaloguescan alsobind the correspondingtransition
statesthemselves.Thus, they too catalyzechemicalreactions.
MORE
Page3 -
STRUCTIJRE AND FTINCTION OF CATALYTIC ANTIBODIES
Unfortunately,the majority of the catalyticantibodiesgeneratedto datepossessbut a small
fraction of the chemicalactivity of naturalerzymes.It is a seriousproblem; in order to be
useful in biotechnologicaland industrialapplications,catalyticantibodieswill needto havefar
greateractivity.
To approachthis issue,the TSRI investigatorsmadea direct comparisonof the threedimensionalstructuresof a catalyticantibodyand an erzyme that carry out the samechemical
reaction.By so doing, they hopedto gain insight into the precisenatureof catalysisby these
different proteins,and the particulararchitecturalfeaturesof the catalyticsurfacesthat
acceleratethe chemicalreaction.
The systemthey choseto studyinvolvesa chemicalreactionin plantsand bacteriathat is
integralto the synthesisof certainamino acids.Specifically,it is the conversionof the
compoundchorismateto prephenate,an event catalyzedby the erzyme chorismatemutase.
For the past severalyears,Dr. Hilvert and his colleaguesat TSRI havecarriedout detailed
studiesof a numberof catalyticantibodieselicitedagainsta transitionstateanalogueof the
chorismate-prephenate
reaction.Using the techniqueof x-ray crystallography,Haynesand
Drs. Stura and Wilson determinedthe completethree-dimensional
structureof one of these
catalyticantibodieswith the transitionstateanalogueboundto the catalyticsite.
For comparison,they usedthe three-dimensional
structureof the enzymechorismatemutase,
also bound to the sametransitionstateanalogue,which recentlyhad beenpublishedby
investigatorsat Harvard University. The chorismatecatalyticantibodyhas aboutone ten
thousandththe catalytic activity of the natural erzyme.
MORB
Page4 -- STRUCTLJREAND FLJNCTIONOF CATALYTIC ANTIBODIES
A study of the two structures,antibody and erzyme, showedthat both appearto catalyzethe
reactionin essentiallythe sameway. This finding refutesthe suggestionby somescientists
that although enzymesand catalytic antibodiesboth may be able to carry out the same
chemicalreaction,the precisemechanisms
of catalysismay not be the same.
Also of major importancewas the identification of those structuralfeaturesof the enzymethat
most likely accountfor the much greateractivity of the enzymeas comparedto tlre antibody.
This information, they suggest,can now be usedto dramaticallyimprove the catalytic
efficiency of antibodiesby suchstrategiesas improvingthe designof transitionstate
analoguesand altering the structureof antibodyproteinsby site-directedmutagenesis
techniques.
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