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Reference: Crouch, Nicholas., (1988). The mechanism of the enzymatic ring expansion of penicillin N to deacetoxycephalosporin C. DPhil. University of Oxford.Citable link to this page:


The mechanism of the enzymatic ring expansion of penicillin N to deacetoxycephalosporin C

Abstract: The order of events in the Deacetoxycephalosporin C/Deacetylcephalosporrn C Synthetase (DAOC/DAC Synthetase) catalysed ringexpansion of penicillin N to deacetoxycephalosporin C has been investigated bythe use of labelled/unlabelled penicillin N mixed competitive kinetic isotope effectexperiments, in which the labelled penicillin N substrates were either labelled inthe pro R- and pro S-methyl groups or at C-3. In addition, to assisting in thedetermination of the position of the first irreversible event in this reaction,deuteration at C-3 gave rise to a bifurcation of the natural biosynthetic pathwaywhich led to enhanced production of the shunt metabolite, (2R,3S,6R,7R)-l-aza-3-methyl-3-hydroxy-7-[(5R)-5-amino-5-carboxy-pentanamido]-8-oxo-5-thiabicyclo[4.2.0]octane-2-carboxylate.The biosynthetic precursor to the 3S-hydroxycepham shunt metabolite hasbeen investigated and the origin of the 3S-hydroxyl oxygen atom has beendetermined by the use of labelling studies with 18O2 and shown to be derived frommolecular oxygen.13C-labelling studies are described which indicate that the ring expansionprocess is stereospecific to within the limits of the detection system employed.These experiments confirm earlier investigations but, in addition to improvingupon the assessment of the degree of stereospecificity, have shown that the 3S-hydroxycepham shunt metabolite is produced with the same stereospecificity asthat observed for the usual biosynthetic products, DAOC and DAC.Chapter 5 describes an investigation of the anomalous C-2 deuteriumexchange detected in DAOC produced by incubation of di-(2H3-methyl)-penicillinN with DAOC/DAC synthetase. The preliminary results from this study indicate thatinitially exchange occurs stereospecifically with the pro R C-2 deuterium atombeing replaced by a hydrogen atom.The origins of the unusual tripeptides L-α-aminoadipyl-L-serinyl-D-valine(L,L,D-ASV), α-aminoadipyl-serinyl-isodehydrovaline (ASdV) and α-aminoadipyl-cysteinyl-β-hydroxyvaline (AC-[β-OH]-V) isolated from Penicillium chrysogenumand Cephalosporium acremonium, have been examined by the use of variously13C-labelled L,L,D-α-aminoadipyl-cysteinyl-valine (L,L,D-ACV) and D,L,D-α-aminoadipyl-cysteinyl-valine (D,L,D-ACV) tripeptide isotopomers. The initialresults obtained from this investigation may be considered as circumstantialevidence that ASdV is formed by the action of IPNS upon L,L,D-ACV.Finally, various substrate analogues have been prepared and evaluated assubstrates for the ring expansion and hydroxylation activities of the bifunctionalDAOC/DAC synthetase enzyme.

Type of Award:DPhil Level of Award:Doctoral Awarding Institution: University of Oxford Notes:This thesis was digitised thanks to the generosity of Dr Leonard Polonsky.


Baldwin, Jack E.More by this contributor



Professor J. E. BaldwinMore by this contributor


 Bibliographic Details

Issue Date: 1988Identifiers

Urn: uuid:de3e54eb-b4b5-4673-a863-3c094cc1456d

Source identifier: 602819996 Item Description

Type: Thesis;

Language: eng Subjects: Penicillin Ring formation (Chemistry) Cephalosporins Tiny URL: td:602819996


Autor: Crouch, Nicholas. - institutionUniversity of Oxford facultyMathematical and Physical Sciences Division - - - - Contributors Baldw



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