176036-37-6Relevant articles and documents
Thioester hydrolysis and C-C bond formation by carboxymethylproline synthase from the crotonase superfamily
Batchelar, Edward T.,Hamed, Refaat B.,Ducho, Christian,Claridge, Timothy D. W.,Edelmann, Mariola J.,Kessler, Benedikt,Schofield, Christopher J.
, p. 9322 - 9325 (2008)
(Chemical Equation Presented) Enzyme in action: Labeling studies and the finding that carboxymethylproline synthase catalyzes production of deuterated (2S,5S)-6,6′-dimethyl-trans-carboxymethylproline (3) from dimethylmalonyl-CoA (1) and labeled l-pyrroline-5-carboxylate (2) limit possible mechanisms of C-C bond formation and thioester hydrolysis. A key feature in the catalysis is that intermediates are stabilized by hydrogen bonds in the oxy-anion hole of the enzyme (dark curve in scheme).
Crotonase catalysis enables flexible production of functionalized prolines and carbapenams
Hamed, Refaat B.,Henry, Luc,Gomez-Castellanos, J. Ruben,Mecinovic, Jasmin,Ducho, Christian,Sorensen, John L.,Claridge, Timothy D. W.,Schofield, Christopher J.
supporting information; scheme or table, p. 471 - 479 (2012/03/07)
The biocatalytic versatility of wildtype and engineered carboxymethylproline synthases (CMPSs) is demonstrated by the preparation of functionalized 5-carboxymethylproline derivatives methylated at C-2, C-3, C-4, or C-5 of the proline ring from appropriately substituted amino acid aldehydes and malonyl-coenzyme A. Notably, compounds with a quaternary center (at C-2 or C-5) were prepared in a stereoselective fashion by engineered CMPSs. The substituted-5-carboxymethyl-prolines were converted into the corresponding bicyclic β-lactams using a carbapenam synthetase. The results demonstrate the utility of the crotonase superfamily enzymes for stereoselective biocatalysis, the amenability of carbapenem biosynthesis pathways to engineering for the production of new bicyclic β-lactam derivatives, and the potential of engineered biocatalysts for the production of quaternary centers.
Definition of the common and divergent steps in carbapenem β-lactam antibiotic biosynthesis
Bodner, Micah J.,Li, Rongfeng,Phelan, Ryan M.,Freeman, Michael F.,Moshos, Kristos A.,Lloyd, Evan P.,Townsend, Craig A.
experimental part, p. 2159 - 2165 (2012/05/20)
Approximately 50 naturally occurring carbapenem β-lactam antibiotics are known. All but one of these have been isolated from Streptomyces species and are disubstituted structural variants of a simple core that is synthesized by Pectobacterium carotovorum
Carboxymethylproline synthase catalysed syntheses of functionalised N-heterocycles
Hamed, Refaat B.,Mecinovic, Jasmin,Ducho, Christian,Claridge, Timothy D. W.,Schofield, Christopher J.
supporting information; experimental part, p. 1413 - 1415 (2010/06/12)
The utility of wild-type and variant carboxymethylproline synthases for biocatalysis was demonstrated by preparing functionalised 5-, 6- and 7-membered N-heterocycles from amino acid aldehydes and (alkylated) malonyl-coenzyme A derivatives; the N-heterocycles produced were converted to the corresponding bicyclic β-lactams by a carbapenem synthetase. The Royal Society of Chemistry 2010.
Synthesis of regio- and stereoselectively deuterium-labelled derivatives of l-glutamate semialdehyde for studies on carbapenem biosynthesis
Ducho, Christian,Hamed, Refaat B.,Batchelar, Edward T.,Sorensen, John L.,Odell, Barbara,Schofield, Christopher J.
supporting information; experimental part, p. 2770 - 2779 (2009/09/07)
l-Glutamate semialdehyde (l-GSA) is an intermediate in biosynthetic pathways including those leading to the carbapenem antibiotics. We describe studies on asymmetric deuteration or hydrogenation of appropriate didehydro-amino acid precursors for the stereoselective synthesis of C-2- and/or C-3-[2H]-labelled l-GSA suitable for use in mechanistic studies. Regioselective deuterium incorporation into the 5-position of l-GSA was achieved using a labelled form of the Schwartz reagent (Cp2Zr 2HCl). 4,4-Dideuterated and fully backbone deuterated l-GSAs were prepared. The application of the labelled l-GSA derivatives to biosynthetic studies was exemplified by the chemo-enzymatic preparation of selectively deuterated trans-carboxymethylprolines using two different carboxymethylproline synthases (CarB and ThnE), enzymes that catalyse early steps in the biosynthesis of two carbapenems: (5R)-carbapenem-3-carboxylate and thienamycin, respectively. The Royal Society of Chemistry 2009.
Synthesis of deuterium labelled L- and D-glutamate semialdehydes and their evaluation as substrates for carboxymethylproline synthase (CarB) - Implications for carbapenem biosynthesis
Sorensen, John L.,Sleeman, Mark C.,Schofield, Christopher J.
, p. 1155 - 1157 (2007/10/03)
Carboxymethylproline synthase was shown to condense L-glutamate semialdehyde with malonyl-coenzyme A to produce (2S,5S)-carboxymethylproline, while incubation of D-glutamate semialdehyde results only in uncoupled turnover of malonyl-CoA. The Royal Society of Chemistry 2005.
