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Preparation of Tetrapyrrole-Amino Acid Covalent Complexes

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Preparation of Tetrapyrrole-Amino Acid Covalent Complexes I'lunt I'ht.siol.Ritx ltt'nt. 1996. -14 (3). 393-39lt Preparation of tetrapyrrole-amino acid covalent complexes Leszek Fiedorl'2*, Varda Rosenbach-Belkinl, Maruthi Sail and Avigdor Scherzl I BiochernistryDepartment. The Weizn-rannInstitute of Science.76100 Rehovot.Israel. I Prcscntaddress: Institute of Molecular BiologSr.Ja-ciellonian University. Al. Mickiewicza 3. 3 l- 120 Cracow. Poland. ':'Author to whom correspondenceshould bc addrcsscd(fax +48-12-336907:E-mail fiedor@)mol.uj.edu.pl) Abstract The presentedsynthetic approach towards chcn'rical modifications of chlorophylls(Chls) provides a perspectivcto construct model systems. where tetrapyrrole-aminoacid and tetrapyrrole-peptideinteractions coulcl be studied in covalent rnodel compor,rncls. The approach relies on thc lact that in Chls the | 7r propionic rcid sidc chain docs not participatc in the tetrapl'rroleii--electron system. It makes use of a plant enzvmechlolophyllase (EC 3.1.1.1,+).which lrr lilo and in yitrc catalysesreactions at this sidc function. The transesterilicationand hyclrolysisenzymatic rerctions are useful on a preparativescale. ln the transesterificationreaction. a desiredamino acid rcsiduc posscssirrgprimary hydloxyl group can be directly attachedto the propiorric acid side chain o1' Chl. This mcthod allows to replace the phytyl moiety in Chls n'ith seline. The r:rtherreaction. enzyrratic hydrolysis of Chls, yields chlorophyllides and opens a convenientroutc fbr furthcr rnodifications.If sufliciently mild synthetic mcthodsarc uscd. such as catalysisw,ith ,l-dimethyl arnino pyridine or activationwith N-hvdroxvsuccinimide.an arrino acid or peptide residuecan be covalentlybound to chlorophyllides' carboxylic group. lear,'ingthe essentialclectlonic structure of Chl intact. The activation w'ith N-hydroxvsuccininridcallows fbr the coupling cvrn in aqueous rncdia. Followinc these two metl.rods.the chlorophyllideswere linked e.g. to tyrosine or melanocytestirnulating horrnone (rr-'l,7-MSH;. The spectralf'eatures of thesenrodel cornpounds indicate a lbrmation of a ground statecharge transl'er complex betweenthe tetrapl,rrolcand amino acid moieties.Thirnks to the high stereospecilicityof chlorophyllase.the describedurodel compounds are the non-primediastereisomers. They have chemicnlfeatures of both Chl and amino acid and thus can be uscd as modulesto build more cornplicatednrodel svstems. Kel rvords Chlorophi,ll. chloropht'llase.chlorophyllides. nlrdel compoundssynthesis. interaction with arnino acids.char-rrc transfcr complex. Abbreviations Bchla. bactcriochlorophvlla; Chla. chlorophl'll a: Chlase, chlorophyllase;Chlide, chlorophyllidcl DCC. dicl'clohexylcarbodiimide:DMAP. .l-dimethyl amino pyridine: HPLC. hi-ch pressure licluid chromatography:IR. infra-red; LHC, light harvesting complexl MSH. melanocytestimLrlating hormone: NHS. N-hyclroxysuccinimide;PDT, photodynarnictherapy: Phco. pheophytinl Phide. pheophorbidc:RC. reaction centlel THF. tetrahyclrofuran:Tl-C. thin layer chrontatoglaphy. INTRODUCTION undergo certain modificationsto suit their functions in yit,o.It becameevident that this tunin-uof pigment In natural systems interacting with li-rrht. the properties is achieved by the interactions of the tetrapyrrolesplav a specialrole by virtue ol'their light pigmentswith their environment,which in most cases absorbin-eproperties. However. these properties ur consistsof proteins.The plant and bacterialphotosyn- lrlo difl'ermarkedly fion thoseof isolatedpigments in thetic systemsare well known exampleswhere such organicmedia. This is becausethe pigmentproperties interactionsoccLrr. The chloroohvlls.embedded in the Plant Phr,siol.Biochern.. 09flI 9.1ltl/96/03/:1i-1.(Xyaal Ciauthicr-Villals L. F'iedor el a/. proteinmatrix closelyinteract with variousamino acid ln this respect,the enzymatic catalysisappears to residues(Deisenhofer and Michel. lc)89;McDermott be a promising approach towards the synthesisof et al.,1995).These interactions ale involvednot only covalent tetrapyrrole-aminoacid/peptide complexes. in maintainingthe structureof the photosyntheticrc'rLc- Thanks to the unique f'eaturesof enzymes. l.c. tion centresand light harvestingcomplexes (Zuber and high selectivity. specificity and good yields of the Brr-rnisholz.199 l: McDermott d/ ul.. 1995)but also catalysedreactions. the use of enzymaticmethods in in the tuning of pignent propertics.This was shown organicsynthesis receives much attention(Zaks. 1990; elegantly by site-directedr-nutagenesis of particular Hal-ea5,1992). ln application to Chl modifications, arninoacid residuesin severalbacterial RCs (Coleman the plant enzyme chlorophyllasehas been fbund to and Youvan. I990; Bylina and Youvan. 199I), be a convenientsynthetic tool (Michalski.1988). The fbllowed by spectroscopicor redox mcasurements. enzyne is known to catalyse in v'ivo and irt t'ittrt The presenceol'some amino acid residuesprofor-rndly the reactions at the propionic acid side chain of influences the ultrafhst electron transf-er process various Chls and their derivatives(Willstaedter and (DiMagno and Norris. 1993). AlthoLrghin such Stoll, l9l3; Fiedoret al.. 1992).As we have shown experimentsthe involvement of certain amino acid previously (Fiedor et al., 1992), in the hydrolysis. into the electrontransf'er or other processesis clearly transesterificationand reesterificationof this side shown. the exact mechanismsol' that involvement tunction. Chlase shows high stereospecificityand are not understood yet. This is due to the high catalyses the production of only the non-prime complexity of the natural systemsand the dilliculty Chl diastereoisomers.Here we describe the use of in spotting these weak single pigment-an'rinoacid Chlaseand other syntheticmethods in constructionof interactions.superimposed on the backgroundwhich chlorophyll-aminoacid/peptide covalent cornpounds. is a sum of many suchinteractions. Therefbre. it seems Thesemethods enabled us to synthesizethe covalent reasonableto investi-{atethe specific tetrapyrrole- complexesof Chls c.g. with the amino acids serine arninoacid and tetrapyrrole-peptideinteractions in less and tyrosine and a 14 amino acid peptide o-4,7- complicatedmodel systems.provided an appropriute MSH (melanocytestirnulating hormone). These model systemcan be constructed.ln tirct, a grcat eflbrt has compounds were characterizedby various spectral been put into the developrnentof artificial covalent techniques,such as absorptionand emissionspectro- model compoundsand other model systems.as they scopies.The model compoundscontaining aromatic proved to be very helpfLrlin studiesof rnany aspects amino acids,show occurrenceof char-oetransf'er com- of photosyntheticsystems (Wasielewski, 1992). In plexes betweenChla and these amino acid residues. order to achievedesired mirrricking effects in model Serine-(B)Chlidewas recently characterizedas effi- systems.each of their componentsmust preserveall cient photcrsensitizerfbr PDT (Fiedor et al., 1993lr. their structuraland chemicalcharacteristics. crucial to allow the specific interacticlnsto occur. Attempting to model the interacfionsbetween the photosynthetic RESULTS AND DISCUSSION pigmentsand arclmaticamino acids which are tound in the RC, in particular those that may all-ect Transesterification reaction the electron transf'er process. requires that thesc moleculesshould be brought into close contact and The Chlase catalysed transesterificationreaction their (stereo)electronicstructures need to be intact. was used to synthesizeSer-Chlide and Ser-Bchlide However. from the synthetic point of view it ntay esters. Almost pure non-prine epimeric forms of appear to be difficult. Due to the prcsence of a the pigmentswere producedwith yields up to JOC/a. labile centralmagnesium ion, the caseol'oxidation. The purificationof the transesterifiedcompounds was epimerizationand isocyclic ring opening, etc., Chls achievedon a CM-Sepharosecolumn or by reversed are known to be chemicallyunstable. Therefore. or.rly phaseHPLC. Thesesimple model compoundsposses very mild syntheticprocedures can be applied in the chernical f-eaturesof both Chl and the arnino acid constructionof model systemswhich contain Chls. and therefbrecan be used as modulesin cclnstructicln This seemsto be a sevefeobstacle since out of many of rrore advanced model systems. They are water- syntheticmodel systemsconstructed up to now only soluble and spectrclscopicallyresemble parent Chls f'ewaddress the aspectsof Chl-aminoacid interactions (see below). Recently, they were characterizedas (seee.g. Boxer, 1983;Verchere-Beaur et ttl., 1990). very efTectivephotosensitizers for PDT (Fiedor er a/.. Plunt Phvsiol. BioL'lterrt. Preparation of tetrapyrrole 395 1993).lmportantly, in comparisonto hematoporphyrin derivative, these compounds administeredinto the living organismsare expectedto undergomuch faster it biodegradation(Spikes and Bommer. l99l). I tt I I it Hydrolysis of chlorophylls , rl The chlorophyllideswere obtainedon a preparative lr scaleby enzymatichydrolysis of variouschlorophylls, ,l using Chlase.The productswere purified by column I chromatography on CM-Sepharose. The enzyme hydrolysesand produceswith very high yields (up 300 430 560 690 820 950 Io 90c/c)only the non-prinrediastereoisomers ol' the Wavelength Inrn I pigrnents(Fiedor et ul.. 1992). Figure l. Ab.utrption .\pe(tftt ol Scr-Chlide und Ser-lJchlide in Modifications at the 172 carboxylic group of Chlides Ser-Chlideand Ser-Bchlidein methanol.are shown Thc l7- earboxylic group in chlorophyllides is in figure l. The spectra are almost identical
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