Cobamides, a uniquely diverse family of enzyme cofactors related to vitamin B12, are produced exclusively by bacteria and archaea but used in all domains of life. While it is widely accepted that cobamide-dependent organisms require specific cobamides for their metabolism, the biochemical mechanisms that make cobamides functionally distinct are largely unknown. Here, we examine the effects of cobamide structural variation on a model cobamide-dependent enzyme, methylmalonyl coenzyme A (CoA) mutase (MCM). The in vitro binding affinity of MCM for cobamides can be dramatically influenced by small changes in the structure of the lower ligand of the cobamide, and binding selectivity differs between bacterial orthologs of MCM. In contrast, variations in the lower ligand have minor effects on MCM catalysis. Bacterial growth assays demonstrate that cobamide requirements of MCM in vitro largely correlate with in vivo cobamide dependence. This result underscores the importance of enzyme selectivity in the cobamide-dependent physiology of bacteria. IMPORTANCE Cobamides, including vitamin B12, are enzyme cofactors used by organisms in all domains of life. Cobamides are structurally diverse, and microbial growth and metabolism vary based on cobamide structure. Understanding cobamide preference in microorganisms is important given that cobamides are widely used and appear to mediate microbial interactions in host-associated and aquatic environments. Until now, the biochemical basis for cobamide preferences was largely unknown. In this study, we analyzed the effects of the structural diversity of cobamides on a model cobamide-dependent enzyme, methylmalonyl-CoA mutase (MCM). We found that very small changes in cobamide structure could dramatically affect the binding affinity of cobamides to MCM. Strikingly, cobamide-dependent growth of a model bacterium, Sinorhizobium meliloti, largely correlated with the cofactor binding selectivity of S. meliloti MCM, emphasizing the importance of cobamide-dependent enzyme selectivity in bacterial growth and cobamide-mediated microbial interactions.
Objectives To understand the relationship between age, frailty and overactive bladder (OAB). Methods This is a prospective study of individuals age ≥65 presenting to an academic urology practice between December 2015 and July 2016. All patients had a Timed Up and Go Test (TUGT), a parsimonious measure of frailty, on intake and were thereby categorized as fast (≤10 sec), intermediate (11-14 sec) and slow (≥15 sec). The TUGT and other clinical data were abstracted from the electronic medical record (EMR) using direct queries. Logistic regression was used to examine the relationship between frailty and the diagnosis of OAB, adjusting for age, gender and race. Results Our cohort included 201 and 1162 individuals with and without OAB, respectively. Individuals with OAB had slower TUGTs (13.7 ± 7.9 sec) than their non-OAB counterparts (10.9 ± 5.2 sec), p<0.0001, with 32.3% and 11.0% of OAB and non-OAB individuals being categorized as slow, or frail. In multivariable analysis, slower TUGT was a significant predictor of OAB (adjusted OR 3.0; 95% CI 2.0-4.8). Age was not independently associated with this diagnosis (p values >0.05 for each age group). Conclusions Patients with OAB are statistically significantly frailer than individuals seeking care for other non-oncologic urologic diagnoses. Frailty, when adjusted for age, race and gender, is a statistically significant predictor of OAB. Furthermore, frailty should be considered when caring for older patients with OAB and OAB should be assessed when caring for frail older patients.
Objectives To evaluate the prevalence of frailty, a known predictor of poor outcomes, among patients presenting to an academic non-oncologic urology practice and to examine whether frailty differs among patients who did and did not undergo urologic surgery. Methods The Timed up and Go Test (TUGT), a parsimonious measure of frailty, was administered to patients ages ≥ 65. The TUGT, demographic data, urologic diagnoses and procedural history were abstracted from the medical record into a prospective database. TUGT times were categorized as nonfrail (≤10 sec), prefrail (11–14 sec) and frail (≥15 sec). These times were evaluated across age and urologic diagnoses and compared between patients who did and did not undergo urologic surgery using chi-square and t-tests. Results The TUGT was recorded for 78.9% of patient visits from December 2015 to May 2016. For 1089 patients, average age was 73.3 ± 6.3 years; average TUGT time was 11.6 ± 6.0 sec; 30.0% were categorized as prefrail and 15.2% as frail. TUGT times increased with age, with 56.9% of patients age 86 and over categorized as frail. Times varied across diagnoses (highest average TUGT was 14.3 ± 11.9 sec for patients with urinary tract infections), however no difference existed between patients who did and did not undergo surgery (p = 0.94). Conclusions Among our population, prefrailty and frailty were common, TUGT times increased with age and varied by urologic diagnosis, but did not differ between patients who did and did not undergo urologic surgery, presenting an opportunity to consider frailty in preoperative surgical decision making.
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