Chemoenzymatic synthesis of SAM analogs This study highlights a broadly applicable platform for the facile syntheses of SAM analogs that is directly compatible with downstream SAM utilizing enzymes. The ability to couple SAM synthesis and utilization in a single vessel circumvents issues associated with rapid SAM analog decomposition and thereby opens the door to the further interrogation of a wide range of SAM utilizing enzymes. As a proof of concept for the feasibility of natural product ‘alkylrandomization’, the coupled strategy was used to generate a small set of indolocarbazole analogs in conjunction with the rebeccamycin O-methyltransferase RebM.

Objective To study the relative risk (RR) of all‐cause and cause‐specific mortality in rheumatoid arthritis (RA) associated with body mass index (BMI), and to quantify the clinical and outcome consequences of abnormal BMI. Methods We studied mortality in 24,535 patients over 12.3 years, dividing patients into 3 age groups, <50, 50–70, and >70 years and fit Cox regression models separately within each age stratum. We used BMI categories of <18.5 kg/m2 (underweight), 18.5 to <25 kg/m2 (normal weight, reference category), 25 to <30 kg/m2 (overweight), and ≥30 kg/m2 (obesity). Results BMI ≥30 kg/m2 was seen in 63–68% and underweight in ∼2%. Reduction in the RR (95% confidence interval [95% CI]) for all‐cause (AC) and cardiovascular mortality was seen for overweight (AC 0.8 [95% CI 0.8, 0.9]) and obese groups (AC 0.8 [95% CI 0.7, 0.8]), with and without comorbidity adjustment. Underweight was associated with increased mortality risk (AC 1.9 [95% CI 1.7, 2.3]). By contrast, obesity produced profound changes in clinical variables. Compared with normal weight, the odds ratio in the obese group was 4.8 for diabetes mellitus, 3.4 for hypertension, 1.3 for myocardial infarction, 1.4 for joint replacement, and 1.9 for work disability. Total semiannual direct medical costs were $1,683 greater, annual household income $6,481 less, pain scores 1.1 units higher, Health Assessment Questionnaire 0.28 higher, and EuroQol utility 0.7 units lower in the obese. Conclusion Overweight and obesity reduce the RR of all‐cause and cardiovascular mortality across different age groups and durations of RA. By contrast, overweight and obesity are associated with substantial increased risks of comorbidity, total joint replacement, greater pain, medical costs, and decreased quality of life.

This study highlights the biochemical and structural characterization of the L-tryptophan C-6 C-prenyltransferase PriB from Streptomyces sp. RM-5-8. PriB was found to be uniquely permissive to a diverse array of prenyl donors and acceptors including the antibiotic daptomycin (Cubicin®). This study also highlights two additional PTs (FgaPT2 and CdpNPT) as catalysts for daptomycin prenylation where novel prenylated daptomycins also displayed improved antibacterial activities over the parent drug.

Glycosyltransferases (GTs) are ubiquitous in nature and are required for the transfer of sugars to a variety of important biomolecules. This essential enzyme family has been a focus of attention from both the perspective of a potential drug target as well as a catalyst for the development of vaccines, biopharmaceuticals and small molecule therapeutics. This review attempts to consolidate the emerging lessons from Leloir (nucleotide-dependent) GT structural biology studies and recent applications of these fundamentals toward rational engineering of glycosylation catalysts.