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Synthesis of Sugars by Aldolase-Catalyzed, Condensation Reactionsl

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Synthesis of Sugars by Aldolase-Catalyzed, Condensation Reactionsl [teprirrtt'cllrotn-l'he.l,,lrn)rrl .l ( )rgrrnri( i]r,rnr.1r\ l1l'r ('ollrright G) llls:i lrr tht,.-\rneritun ( iit.rnitirlS,r'it, lv rtrrl rt-1rrnrl{.(ll,\ ,,l I itt,t oltr rigftt ()$'lter. Synthesis of Sugars by Aldolase-Catalyzed, Condensation Reactionsl Chi-Huey Wong and George M. Whitesides* Departmentsof Chemistry,Massachusetts Institute of Technologyand Haruard Uniuersity, Cambridge,Massachusetts 02138 ReceiuedMarch 15. 1983 Dihydroxyacetone phosphate was prepared in 2OGmmol scale from dihydroxyacetone by two procedures: reaction with phosphorus oxytrichloride and glycerol kinase catalyzed phosphorylation using ATP with in situ regeneration of ATP by phosphoenolp5rruvateor acetyl phosphate. Dihydroxyacetone phosphate was converted to fructose 6-phosphatein 80% yield by exposureto a mixture of co-immobilizedtriosephosphate isomerase and aidolase followed by acid hydrolysis of the condensation product fructose 1,6-bisphosphate. Fructose 6-phosphate was subsequentlyconverted by chemical and enzymatic schemesinto fructose, glucose6-phosphate, and glucose. Practical procedures are described for the preparation of o- and l-glyceraldehyde 3-phosphate and foiseveral hexoseslabeled with 13Cin the C-2 and C-2,5 positions. Introduction reactions as a route to isotopically labeled and uncommon The work reported in this manuscript is part of a pro- sugarson scalesfrom 0.01to 1 mol. The aldolaseused in gram to evaluate the potential of aldolase-catalyzedaldol this work (from rabbit muscle,E.C. 4.1.2.13)is commer- cially available. It is inexpensive,and it has high specific (1) Supported by the National Institutes of Health Grant GM-26b48. activity and good stability. It requiresdihydroxyacetone Inquiries should be addressedto G.M.W. at Harvard Universitv. phosphate(DHAP)2 as one substrate,but will accept a 0022-3263i 8:r i 1948-iti99$01 .5f) i 0 .c 1983American Chemical Societr \\'r 'ng \\'hitesides 3200 J. Org.Chem., Vol. 48, No. 19,1983 ancl Table I. Kinetic Parameters of Aldolase from N{uscle antl Y eiLst " rabbit muscle Yeast substrate K-, mM v K*, mNI Aldol Cleavage b 1" -fructose 1, 6-bisphosphate 0.006 1c 0.36 D 0.13 0.002 -sorbose 1,6-bisPhosPhate 0.o44 0.1 L 0.0002 1-phosphate 0.6 0.02 0.2 L-sorbose 1.0 0.000.1 D -fructose 1 -phosPhate 6.3 0.01 D -fructose 6-phosPhate 0.0001 Aldol Condensation 1.0(0.4)" 2.4 dihydroxyacetone PhosPhate 2.0 3.0 * D-glYceraldehYde-3-P 4.0 2.8 t D .t, -giYceraldehYde 0.1 0.1f i- D,L-lactaldeirYde f I D.L -.r-hydroxybutyraldehycie 0.1 dihydrnxyacetone sulfate i3 ) r + D,L -glYceraldehYde-3-P < 0.0001 dihydroxyacetone .< -t D -glyceraldehYde-3-P 0.0001 phosphate (2) acetol 0.0006 + o -glyceraldehyde-3-P <0.0003 -phosphonate 4-l'rydroxy-3-oxo-1, i 1 ) o.4e '' + tr -glyceraldehyde-3-P 0.L l-9-A 3185-92) a numben cited are from: Richardsand Pottet (Richar&, o. C-; Rutter' w. J "I Broi gt:,l] The -glyceraldehyde3-phoaphate' ii6" unlessotherwise indicated. The f- OH,qi rn* aetlrmined in the presenceof D ' D "i i.-8. Biochem.Biophls ResCommun lil6' 69' 844-51 rrmolmin v - v^-.. Mariensen,';il;o;;i;i;-;T. Irl.; vra,isout-. r.(-42 in I'his ,"J??;'r;'. ;;'' oi 'stfiblins,D B.iichem't ts14, I4t' ?25-8 Determined ;; (DHAP or diirvdroxy- i"i""r-t"ir.' 'ift" ufa"ivO" *"."ptoi".,,v-. *as iO -l,i'.na tn" concentmtion of donor acetonesulfate) was ".n-"."it"iio"20 mM, PH "r ?.0 li i'ltr.'tiilai irn,t i',itz.5'nttrttt'I\t'parati'i.rtrs <lf Scireme L st,ereochetni5try of li'eactions (latiil'zed br i'ir;'nrc i)ri-rr rtl'ir\\ iict'l,rrlel)trosphlrtt' Rabbit \luscle Altiola*st' l -, - 7 -^-,^6 ? \ QPO1H riO^-=. ---R ! t{ fr PEP HO-!-_{'-CP \ pCC I -!2 l:( a, H r ,____=x I - z Ac \ I:^c^ \..'r\ v . ^- - ll ^ Av' H03PO--,'xt'!rh ' DHAP Acp R WidelY vorioble {R'l R 60% f rom POCI3(not !sololed ) R'= H,OH { a') d--l rom ATP (isoloted) + HOi 807" f -oH o- Norrow specificirY Po- previously in small-scale (-2 mmol) svntheses ut'1:r(l-la- { I PO-"{"' beled fructoseand glucose.s Its utilitv for larger scalework has not been explored. wide variety of aldehydes as the second.3 The stereo- These methods should be useful in the svnthesisof chemistry of the aldol condensation catalyzed by this en- certain simple sugarsand in the preparation of isotopically zyme is indicated in Scheme I; the two new chiral centers labeledsugars for use in biochemistry,metabolism, and are formed enantiospecifically.4 Aldolase has been used physiology. Results (2) Abbreviations: AcP, acetyl phosphate; DHA, dihydroxyacetone; -P, FDP, o-fructose 1,6-bisphosphate;F-O-p, o-fructose 6-phosphate;F- 1 The enzyme aldolase from rabbit muscle or yeast is o-fructose 1-phosphatb; G-6-P, n-glucose 6-phosphat".;-.Gq'glycer- - Table I summarizesdata on Gd-^3-P,'glyceraldehyde3-phosphate; Gr- 1-P, (B) - g-lycerol1 highly specific for DHAP. "ld"hydu; -P, 1-plo-sptrate; change in the f norptt"t"; PEP, p"hosphoenolpyruvate;-S- 1 L-sorbose su-bstratespecificity.3 In general, any bK, gly""rokinase; GPDH, glycerophosphatedehydrogenase; HK, hexo- of DHAP greatly reduces reactivity in the al- phosph-oglucoisomerase; structure tinaJe; GluDH, glutamic dehydrogenase;PGI, reaction. The phosphonate analogue Pase, potato acid"phosphatase;PK, pyruvate kinase; T?I, triosephosphate dolase-catalyzed isomerase. 4-hydroxy-3-oxol-phosphonate' 1, providesan exception: (3) In addition to the substrates described in Table I, the aldolase from this substanceis 10% as active as DHAP. Acetol phos- ,"u'bit muscle also accepts the following aldehydes using DHAP as as DHAP, while di- not available for the reactions: form- phate 2 is about 0.017oas active reactant, but kinetic data are the aldehyde, glycolaldehyde,t--glycidaldehyde (O'Connell, E' L'; Rose, I' A' irydroxyacetone monosulfate (3) is not a substrate for J. Bi;t. Ciem.1973, i't8,22t541'1, t--threose(Jones, J. K. N.; Matheson, muscle enzvme. N. K. Con. J. Chem.1959, 37, 1?54-6),n-ribose, L-arabinose, D-lyxose, and n-xylose (Jones,J. K. N.; Stephton, H. H. Ibtd. 1960,38, 753-60)' ih" from peas has been reported to accept: glycolic aldehyde Soc. 1958,80' 5835'4' (Hough,L.;Jones,"trry*. i. X. f. J. Chern.Soc. 1952,4A47-52), o,i--lactaldehyde (4) Rose,l. A. J. Am. Chem. A. S.; Cadman,E.; Pierce,J.; Haves,M L'; Barker, R' igo"gt, L.';.Iones, J. K. N. Ibid. 1952,4052-5),and o-erythrose(Hough, i5) Serianni, 1982,89, 83:92 and referencescited therein' L.: Jones.J. K. N. Ibid. 1952,342'-5) Methods Enzvmol. Aldolase-Catalyzed Condensations J. Org. Chem., Vol.48, ftlo.19, 1983 3201 III. Synthesesof Fructose 1'6'Bisphosphate, oa RR Scheme H O--,.$ HaP (OH )2 Fructose 6-Phosphate, Fructose, Glucose x o-,2\zoii t ox ), G-Phosphate,and Glucose DHAP I a rpr ^ It P x o-t=\-oe +-i--+ o\,.:\-.o e9 AR --- H-._,A..--.OP(0H)2 HO-_-x.-,.osoH DHAP 0 (. o'oo,or" : I ,;t":-t-t OP Dihydroxyacetone Phosphate. We have examined /oH two routes from dihydroxyacetone (DHA) to DHAP FDP "oas-t/xo{4 'oP (SchemeIi). Fcir most preparationscarried out on scales procedure on chemical I H+(oowexso) up tri several moles, the based I phosphorylationis the more convenienl (especiallyfor i 86% preparationof PEP or Acl) are not OH laboratoriesin which OP /oN routine). The deficienciesof the c:hemicaltrlroi:edttre are Pqse H ,'o'^.- -p -.--- r: a-- r that it generatesrelatively dilute sohitionso1'prodttct and r i.-r-. uo-\-i iCC"/" Lox f-hatimpurities remaining from the chemicalsteps n'ra1' -ctl comJlhcateworkup. F urther, becausethe product solutirltr ti r PGl,66% from this chemicairoute containsphosphate, isolation and I purificationof the DHAP from it are ir,convenient.It is Pose (o"-o '*'ititout ,o' -- bestused directly irr subsequenttransfortnatiorts G-6-P ,o--(-5,,_Ho\4_oH rdFv"'[Nft-o, isolation. The puritl' of the I)HAI' prepared bv this procedureseerns. however, to be perfectly'acceptable in the enzymaticreact.ions we have explored. SchemeIV. Synthesesof (2''3C,)Glucose and The biochemicalroute to DHAP is basedon the enzy- (2,5-1'C.)Glucose anti Intermediates(Heary Circles matic phosphorylationof DHA bv ATP with in situ co- lndicate Positionsof '3C Label) factor regeneration. This proceduregives a product that oH ,i *3* ,^, ^ r) xr can either be isoiated in relatively high purity (80-90% ) HCHO o:^\n \^--'H or used in situ. The enzymatic procedure using PEP as 2)H;ti' ffik," pH t.7 pH r.7 I the ultimate phosphorylating agent is somewhat more Prl,/Bo3O4 Pd,/Bq3O4 | ^ convenient than that based on AcP, becausePEP has eo% sz% | NoBHo | 82 greater stability in solution than AcP.6'7 The procedures "t" are otherwise comparable. ADP'PEP oH rF.r,€r-re r-,--\-./.\-,/v. I -1p p* , HVSJH D- and l-Glyceraldehyde and I)- and t.-Glycer- ----. Of Gt,, <--. - NAD 89% aldehyde 3-Phosphate. Thesethree-carbon substances '),,,oruou I GPDH condensewith DHAP in aldolase-catalvzedreactions and NH: ) \ruADn/Y yield hexosephosphates: the stereochemistrvat C-5 i-s crKG "' defined by the chirality of the glyceraldehyde.Procedures for preparing each are summarized in Table II. D- Glyceraldehyde(D-Gd) can be prepared in 82% enan- tiomeric excess(ee) by selectivephosphorylation of r,-Gd in a mixture of D-Gd and l-Gd using glycerokinase(GK). It can also be prepared by treatment of o-glyceraldehyde 3-phosphate(D-Gd-3-P) with acid phosphatase(Pase, E.C.
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