Development of a Second Generation Coenzyme A Analogue Synthon

Abstract

We have previously reported a general synthetic approach to analogues of coenzyme A (CoA) which involves enzymatic synthesis of a general CoA analogue synthon having a thioester linkage in place of the amide bond nearest the thiol group (Martin et al. J. Am. Chem. Soc. 1994, 116, 4660). We report here the synthesis of a second CoA analogue synthon 1c which has the amide bond more distant from the thiol group replaced with a thioester. This analogue was prepared by nonenzymatic synthesis of a racemic phosphopantetheine analogue followed by enzymatic conversion to the corresponding CoA analogue. Stereochemical analysis showed that the natural enantiomer of the phosphopantetheine analogue was selectively converted to product by the enzyme phosphopantetheine adenylyltansferase, yielding a product that possessed the desired stereoconfiguration. Reaction of the new synthon 1c with a primary amine results in amide bond formation to form the CoA analogue of interest. This new methodology provides access to an even broader array of CoA analogues modified in the beta-alanylcysteamine moiety. This has been demonstrated in the synthesis of an analogue having an extra methylene group in the beta-alanine moiety and two analogues in which the amide bond nearest the thiol group is replaced with a pair of methylene groups.

An in vitro synthetic biosystem based on acetate for production of phloroglucinol

“…To decrease costs, in vitro biosystem should be operated continuously which can realize the minimal addition of feedstock chemicals. Considering that the consumption of expensive ATP and CoA will increase production costs, low-cost ATP regeneration module need to be designed, and also low-cost and high-stability CoA analogues need to be explored or synthetized [ 32 ]. Another possible solution is the construction of efficient enzyme cascade and substrate channeling for in vitro biosynthesis in order to overcome the typical disadvantages for in vitro biotransformation [ 5 , 33 ] (e.g.…”

Polymeric redox-responsive delivery systems bearing ammonium salts cross-linked via disulfides

“…The cross-linking agent N , N’ -bis(4-chlorobutanoyl)cystamine ( CL 1 ) was synthesized by using the reaction of cystamine dihydrochloride and 4-chlorobutanoyl chloride [49]. Polycationic hydrogels where obtained by adding CL 1 to a solution of poly(DEAAm- co -DMAEMA) and potassium iodide in acetone at 80 °C.…”

Protein Chemistry on the Surface of Living Cells

“…If needed, more complex CoA derivatives are accessible via synthetic routes developed by the group of Drueckhammer. [38] Beside their promiscuity toward different labels, ACP fusions of cell-surface proteins can be used for studying the dynamics of their distribution on and in the cell. Specifically, the membrane impermeability of PPTases and CoA derivatives limits the labeling to proteins that are already displayed on the cell surface during incubation and leaves unlabeled those proteins that are either still in the secretory pathway or already internalized.…”