Ein synthetisches Modell für die Aktivstelle der Coenzym‐B₁₂‐abhängigen Methylmalonyl‐CoA‐Mutase

Abstract

A synthetic model of the active site of the coenzyme BIZ dependent methylmalonyl-Coh mutase SummaryThe synthesis of a bridged cobaloxime with a built-in methylmalonic ester moiety is described. 2-Brommethyl-2-methylmalonic acid dichloride (5) afforded upon reaction with 5-heptin-1-01 (4) the corresponding diester 6 . Subsequent treatment of 6 with ozone, dimethylsulfide and hydroxylamine hydrochloride led to the pentadentate ligand: 10-brommethy1-10-methy1-9,1 l-dioxo-8,12-dioxa-nonadecane-2,3,17,18-tetraone tetraoxime (8). Reaction of 8 with cobalt (11) chloride, pyridine and sodium borohydride furnished in 7% yield the bridged cobaloxime 10, which was spectroscopically characterized. Short term irradiation of 10 in methanol caused the exchange of the axial pyridine ligand by a solvent molecule affording 10a, the structure of which has been determined by X-ray crystallography. Long term irradiation of 10 in methanol or ethanol led to irreversible cleavage of the Co, C-bond. Upon alkaline hydrolysis the degradation product afforded methylsuccinic acid in 82-95% yield. No incorporation of solvent protons into this product could be observed. Implications of these findings for the mechanism of the coenzyme-B 12 catalysed rearrangement of methylmalonyl-CoA are discussed.Wahrend die Wirkungsweise der meisten Coenzyme in den funfziger Jahren aufgeklart werden konnte, blieb diejenige des Coenzym-B 12 trotz intensiver Forschung bis vor kurzem im Dunkeln. Als Hauptursache muss wohl das Fehlen von Analogien in der (meta1L)organischen Chemie angesehen werden. Die ersten erfolgreichen chemischen Modelle bestanden aus Kobaltkomplexen, in denen das <<Substrat)) kovalent an das Metallatom gebunden wurde [ 1-31. Photolytische oder thermische Spaltung der Co, C-Bindung bewirkte eine Umlagerung des substratahnlichen Molekelteils in einem fur die B12-abhangigen Reaktionen charakteristischen Sinne. Allerdings waren die Ausbeuten an Umlagerungspro-

Bridged (β-alkoxyalkyl)CoIII(salen) complexes by intramolecular alkoxycobaltation of unactivated alkenes: new models for coenzyme B12

“…2 A considerable amount of methylsuccinic acid was isolated by Rétey et al after photolysis and saponification of a methylmalonate bridged cobaloxime. 3 These studies demonstrate that one of the important functions of the holoenzyme may be to keep the substrate close to the cobalt centre of the coenzyme during reaction, thereby moderating the reactivity of radical intermediates and allowing cobalt to assist in group migration. Indeed, recent EPR studies of the B 12 -dependent carbon skeleton rearrangement of glutamate to methylaspartate have demonstrated 'communication' between Co II and the 4-glutamyl radical over a distance of ca.…”

Model Studies for the Coenzyme‐B12‐Catalyzed Methylmalonyl→Succinyl Rearrangement. The Importance of Hydrophobic Peripheral Associations

“…IR (CHCI,): 3040-3020m, 2930s, 2860(CHCI,): 3040-3020m, 2930s, .q 1745(CHCI,): 3040-3020m, 2930s, , 1675s: 14603, 1440m, 1380m, 1285s, 1265 S-Dodecyl 0-Methyl 2-(Bromomethyl)-2-methylmono1hiomalonate ( = Methyl 2-(Bromomethyl)-3-(dodecylthio)-2-methyl-3-oxopropanoa~e ; 5b). Methyl 3-bromo-2-(chlorocarbonyl)-2-methylpropanoate ( = methyl 2-(bromomethyl)-3-chloro-2-methy1-3-oxopropanoate; 4) [24] (1.46 g, 6 mmol) was added dropwise to dodecane-Ithiol (1.8 g, 6 mmol) and Et,N (2 ml) in toluene (10 ml), and the mixture was stirred under N, for 18 h. It was then diluted with H,O and extracted with AcOEt ( 3~) .…”

Photolytic and thermal properties of a new series of intramolecular bridged alkyl cobaloxime complexes

“…In 1980 the first kinds of bridged organocobalt(III) complexes were synthesized and the products of 1,2-rearrangement reaction from photolysis were characterized by Rétey et al 13,14 However, in the past years only a few of cobaloximes, Cosalen and Cocosta complexes with bridged structures have been reported. [15][16][17][18][19][20] It is well recognized that the necessary step in the coenzyme B 12 dependent enzymatic reactions is homolytic cleavage of the Co-C bond, generating a Co(II) species and a 5-deoxyadenosyl radical. Like the above enzyme reactions, photolysis or thermolysis of the 5-adenosylocobalamin and its analogues leads to homolytic cleavage of the Co-C bond.…”