The structure of flavin‐dependent tryptophan 7‐halogenase RebH

Abstract

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.

A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins

“…In contrast, our current study focuses on flavin-dependent halogenases, which employ FAD as a cofactor and use a halide anion and molecular oxygen to produce hypochlorous acid as a halogenating agent. Protein crystallography greatly helped in understanding the structural basis of regioselective formation of the carbon-halogen bond (50)(51)(52)(53). A. mellea halogenase genes encode the signature motif GW(A/V)W(F/L)I.…”

Development of Halogenase Enzymes for Use in Synthesis

“…133 This electrophilic chlorine species is believed to be ultimately responsible for aromatic substitution of the substrate to generate the Wheland intermediate (23), which is then deprotonated by a conserved glutamate residue to afford chlorinated product (24, Figure 12). 114,131,[133][134][135] Positioning of this active site lysine relative to substrate is therefore believed to control which position of the substrate is halogenated.…”

An Unusual Flavin-Dependent Halogenase from the Metagenome of the Marine Sponge Theonella swinhoei WA

“…Both constructs produced little soluble protein when expressed in Escherichia coli unless the chaperone proteins GroEL/S, DnaK/J and GrpE were coexpressed. Though the production of many other halogenases in heterologous expression hosts do not require the use of chaperones; [29][30][31][32] chaperones GroEL/S has previously been reported to improve the solubility and yield of RebH when produced in E. coli.…”