Total Synthesis, Structure, and Biological Activity of Adenosylrhodibalamin, the Non‐Natural Rhodium Homologue of Coenzyme B₁₂

Abstract

B12 is unique among the vitamins as it is biosynthesized only by certain prokaryotes. The complexity of its synthesis relates to its distinctive cobalt corrin structure, which is essential for B12 biochemistry and renders coenzyme B12 (AdoCbl) so intriguingly suitable for enzymatic radical reactions. However, why is cobalt so fit for its role in B12‐dependent enzymes? To address this question, we considered the substitution of cobalt in AdoCbl with rhodium to generate the rhodium analogue 5′‐deoxy‐5′‐adenosylrhodibalamin (AdoRbl). AdoRbl was prepared by de novo total synthesis involving both biological and chemical steps. AdoRbl was found to be inactive in vivo in microbial bioassays for methionine synthase and acted as an in vitro inhibitor of an AdoCbl‐dependent diol dehydratase. Solution NMR studies of AdoRbl revealed a structure similar to that of AdoCbl. However, the crystal structure of AdoRbl revealed a conspicuously better fit of the corrin ligand for RhIII than for CoIII, challenging the current views concerning the evolution of corrins.

Die Hydrogenobyrsäure‐Struktur enthüllt den Corrin‐Liganden als entatisches Zustandsmodul zur Steigerung der Katalyseaktivität von B12‐Cofaktoren

“…Eine ähnliche Situation existiert in Coenzym F 430 , einem Ni-Corphinoid, in dem aber eine radiale Spannung durch Fehlanpassung der Grçßen des koordinierten Ni-Ions und des porphyrinoiden Makrocyclus zustande kommt [4a, 29] Die Verfügbarkeit der metallfreien Hby çffnete die Tür zur direkten Herstellung von Übergangsmetallanaloga der Cobalamine,d er Metbalamine (Metbls), einem "heiligen Gral" der bioanorganischen Chemie. Wien eulich mit AdoRhbl,d em Rh III -Analog von AdoCbl, [9] beschrieben, sind geeignete strukturierte Metblspotentielle "Antivitamine B 12 ", die in der biologischen Bildgebung oder als neuartige Antibiotika wirken kçnnen. Wien eulich mit AdoRhbl,d em Rh III -Analog von AdoCbl, [9] beschrieben, sind geeignete strukturierte Metblspotentielle "Antivitamine B 12 ", die in der biologischen Bildgebung oder als neuartige Antibiotika wirken kçnnen.…”

“…[2b,9] Kürzlich haben wir von rekombinanten E.-coli-Stämmen berichtet, welche metallfreie Corrine liefern wie Hydrogenobyrinsäure-a,c-diamid (HBAD). [9,10] Normalerweise wird Cobalt in HBAD im aeroben B 12 -Biosyntheseweg eingebaut. [2] Einige Purpur-Schwefel-Bakterien produzieren jedoch cobaltfreie Corrine,wenn diese ohne Cobalt kultiviert werden, [11] unter ihnen auch eine Verbindung,d ie vorläufig als Hby identifiziert wurde, [11b,c] 1,3 Hby mit inneren H-Atomen an N1 und N3, wurden nicht detektiert (Abbildung 2).…”

Partial Synthesis of Coenzyme B12 from Cobyric Acid

“…An analogous synthesis strategy may also be helpful in the preparation of other transition metal analogues of the cobalamins, i.e ., of ‘metbalamins’ carrying other metals than (the cobalamin's) cobalt. Some of such structural similars of vitamin B 12 ( 1 ) or of coenzyme B 12 ( 2 ) are in the focal point of current B 12 ‐research and may represent effective ‘antivitamins B 12 ’. [ ][ ] …”

“…The strategy of the pre-coordination of the B 12nucleotide moiety 5, considered here, has similarly been employed recently in the last step of the total synthesis of 5 0 -deoxyadenosyl-rhodibalamin (AdoRhbl), the rhodium homologue of coenzyme B 12 (AdoCbl, 2), from 5 0 -deoxyadenosyl-rhodibyric acid (AdoRhby, the Rh-analogue of AdoCby, 3). [39] An analogous synthesis strategy may also be helpful in the preparation of other transition metal analogues of the cobalamins, [40] i.e., of 'metbalamins' carrying other metals than (the cobalamin's) cobalt. Some of such structural similars of vitamin B 12 (1) or of coenzyme B 12 (2) [39] are in the focal point of current B 12 -research [41] and may represent effective 'antivitamins B 12 '.…”

“…[39] An analogous synthesis strategy may also be helpful in the preparation of other transition metal analogues of the cobalamins, [40] i.e., of 'metbalamins' carrying other metals than (the cobalamin's) cobalt. Some of such structural similars of vitamin B 12 (1) or of coenzyme B 12 (2) [39] are in the focal point of current B 12 -research [41] and may represent effective 'antivitamins B 12 '. [41] [42] The biosynthetic completion of AdoCbl (2) from AdoCby (3) depends upon several enzyme catalyzed steps [8] [9] and does not involve direct attachment of the complete B 12 -nucleotide 5 to AdoCby (3).…”