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

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

Synthesis, spectral characterization and crystal structure of Chlororhodibalamin: A synthesis platform for rhodium analogues of vitamin B12 and for Rh-based antivitamins B12

Chlororhodibalamin (ClRhbl), a rhodium analogue of vitamin B12 (cyanocobalamin), was prepared in 84% yield by metalation of the metal-free B12 ligand hydrogenobalamin using the RhI-complex [Rh(CO)2Cl]2. ClRhbl was identified and characterized by UV/Vis, circular dichroism, high-resolution mass and heteronuclear NMR spectra. The RhIII-corrin ClRhbl features the 'base-on' architecture of vitamin B12. X-ray analysis of single crystals of ClRhbl have revealed its detailed 3D-geometry and close structural similarity to the CoIII-analogue chlorocobalamin (ClCbl). ClRhbl is a versatile starting material for the preparation of other rhodibalamins, among them the organometallic derivatives adenosylrhodibalamin and methylrhodibalamin, the Rh analogues of the important coenzyme and cofactor forms of B12, adenosylcobalamin and methylcobalamin

The Hydrogenobyric Acid Structure Reveals the Corrin Ligand as an Entatic State Module Empowering B12‐Cofactors for Catalysis

The B12 cofactors instill a natural curiosity regarding the primordial selection and evolution of their corrin ligand. Surprisingly, this important natural macrocycle has evaded molecular scrutiny, and its specific role in predisposing the incarcerated cobalt-ion for organometallic catalysis has remained obscure. Herein, we report the biosynthesis of the cobalt-free B12 corrin moiety, hydrogenobyric acid (Hby), a compound crafted through pathway redesign. Detailed insights from single crystal X-ray and solution structures of Hby have revealed a distorted helical cavity, redefining the pattern for binding cobalt-ions. Consequently, the corrin ligand coordinates cobalt-ions in de-symmetrized ‘entatic’ states, thereby promoting the activation of B12-cofactors for their challenging chemical transitions. The availability of Hby also provides a route to the synthesis of transition metal analogs of B12

Profiling Trait Anxiety: Transcriptome Analysis Reveals Cathepsin B (Ctsb) as a Novel Candidate Gene for Emotionality in Mice

Behavioral endophenotypes are determined by a multitude of counteracting but precisely balanced molecular and physiological mechanisms. In this study, we aim to identify potential novel molecular targets that contribute to the multigenic trait “anxiety”. We used microarrays to investigate the gene expression profiles of different brain regions within the limbic system of mice which were selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, and also show signs of comorbid depression-like behavior

Co–C Bond Energies in Adenosylcobinamide and Methylcobinamide in the Gas Phase and in Silico

Essential to biological activity of adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl) is the Co–C bond cleavage step. Hence, we report an accurate determination of the homolytic gas-phase Co–C bond dissociation energies in the related adenosyl- and methylcobinamides (41.5 ± 1.2 and 44.6 ± 0.8 kcal/mol, respectively) utilizing an energy-resolved threshold collision-induced dissociation technique. This approach allows for benchmarking of electronic structure methods separate from (often ill-defined) solvent effects. Adequacy of various density functional theory methods has been tested with respect to the experimentally obtained values

Development and Validation of a Prognostic Model to Predict Overall Survival in Multiple System Atrophy

BackgroundMultiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. ObjectiveTo enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. MethodsMSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. ResultsA total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. ConclusionThe nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients

Axial motor clues to identify atypical parkinsonism: A multicentre European cohort study

Objective: Differentiating Parkinson's disease (PD) from atypical parkinsonian disorders (APD) such as Multiple System Atrophy, parkinsonian type (MSA-p) or Progressive Supranuclear Palsy (PSP-RS) can be challenging. Early signs of postural Instability and gait disability (PIGD) are considered clues that may signal presence of APD. However, it remains unknown which PIGD test – or combination of tests – can best distinguish PD from APD. We evaluated the discriminative value of several widely-used PIGD tests, and aimed to develop a short PIGD evaluation that can discriminate parkinsonian disorders. Methods: In this multicentre cohort study patients were recruited by 11 European MSA Study sites. Patients were diagnosed using standardized criteria. Postural instability and gait disability was evaluated using interviews and several clinical tests. Results: Nineteen PD, 21 MSA-p and 25 PSP-RS patients were recruited. PIGD was more common in APD compared to PD. There was no significant difference in axial symptoms between PSP-RS and MSA-p, except for self-reported falls (more frequent in PSP-RS patients). The test with the greatest discriminative power to distinguish APD from PD was the ability to perform tandem gait (AUC 0.83; 95% CI 71–94; p < 0.001), followed by the retropulsion test (AUC 0.8; 95% CI 0.69–0.91; p < 0.001) and timed-up-and-go test (TUG) (AUC 0.77; 95% CI 0.64–0.9; p = 0.001). The combination of these three tests yielded highest diagnostic accuracy (AUC 0.96; 95% CI 0.92–1.0; p < 0.001). Conclusions: Our study suggests that simple “bedside” PIGD tests – particularly the combination of tandem gait performance, TUG and retropulsion test – can discriminate APD from PD

The natural history of multiple system atrophy: a prospective European cohort study

Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA