Structural Studies of Modular Nonribosomal Peptide Synthetases.

The non-ribosomal peptide synthetases (NRPSs) are a family of modular enzymes involved in the production of peptide natural products. Not restricted by the constraints of ribosomal peptide and protein production, the NRPSs are able to incorporate unusual amino acids and other suitable building blocks into the final product. The NRPSs operate with an assembly line strategy in which peptide intermediates are covalently tethered to a peptidyl carrier protein and transported to different catalytic domains for the multiple steps in the biosynthesis. Often the carrier and catalytic domains are joined into a single large multidomain protein. This chapter serves to introduce the NRPS enzymes, using the nocardicin NRPS system as an example that highlights many common features to NRPS biochemistry. We then describe recent advances in the structural biology of NRPSs focusing on large multidomain structures that have been determined.

Structural advances toward understanding the catalytic activity and conformational dynamics of modular nonribosomal peptide synthetases.

Covering: up to fall 2022.Nonribosomal peptide synthetases (NRPSs) are a family of modular, multidomain enzymes that catalyze the biosynthesis of important peptide natural products, including antibiotics, siderophores, and molecules with other biological activity. The NRPS architecture involves an assembly line strategy that tethers amino acid building blocks and the growing peptides to integrated carrier protein domains that migrate between different catalytic domains for peptide bond formation and other chemical modifications. Examination of the structures of individual domains and larger multidomain proteins has identified conserved conformational states within a single module that are adopted by NRPS modules to carry out a coordinated biosynthetic strategy that is shared by diverse systems. In contrast, interactions between modules are much more dynamic and do not yet suggest conserved conformational states between modules. Here we describe the structures of NRPS protein domains and modules and discuss the implications for future natural product discovery.

Fear of Falls Following an Online Exercise Program for Aging Adults.

Individuals who participate in regular exercise tend to report a lower fear of falling; however, it is unknown if this fear can be reduced following an online fall prevention exercise program. The main purpose of this study was to test if offering a peer-led fall prevention exercise program online reduced the fear of falling and if this potential improvement was greater than when the program was offered in person. The secondary objectives were to describe participants' characteristics when participating online, the rate of falls and the context in which falls occur. A total of 85 adults aged 69.0 ± 7.8 years participated in the program offered online (n = 44) and in-person (n = 41). No significant differences in fear of falling before and after participation in the program were reported for either group: online (20.7 ± 5.1-21.8 ± 5.5) and in-person (20.6 ± 5.1-21.2 ± 5.3). Online participants reported a greater proportion of falls (n = 9; 20.5% vs. n = 4; 9.8%; p = .14), mostly occurring outdoors (n = 7) (77.8). A properly designed study is needed to test if the rate of falls is greater when an exercise program is offered online.

Intensity of acute aerobic exercise but not aerobic fitness impacts on corticospinal excitability.

Aerobic exercise (AE) modulates cortical excitability. It can alter both corticospinal excitability and intra-cortical networks, which has implications for its use as a tool to facilitate processes such as motor learning, where increased levels of excitability are conducive to the induction of neural plasticity. Little is known about how different intensities of AE modulate cortical excitability or how individual-level characteristics impact on it. Therefore, we investigated whether AE intensities, lower than those previously employed, would be effective in increasing cortical excitability. We also examined whether the aerobic fitness of individual participants was related to the magnitude of change in AE-induced cortical excitability. In both experiments we employed transcranial magnetic stimulation to probe corticospinal excitability before and after AE. We show that 20 min of continuous moderate- (40% and 50% of heart rate reserve, HRR), but not low- (30% HRR) intensity AE was effective at increasing corticospinal excitability. We also found that while we observed increased corticospinal excitability following 20 min of continuous moderate-intensity (50% HRR) AE, aerobic fitness was not related to the magnitude of change. Our results suggest that there is a lower bound intensity of AE that is effective at driving changes in cortical excitability, and that while individual-level characteristics are important predictors of response to AE, aerobic fitness is not. Overall these findings have implication for the way that AE is used to facilitate processes such as motor learning, where increased levels of cortical excitability and plasticity are favourable.

Comparison of bilateral and unilateral contractions between swimmers and nonathletes during leg press and hand grip exercises.

The bilateral limb deficit (BLD) is defined as the reduction in force production during bilateral compared with summed unilateral contractions of homologous muscles. The underlying mechanism for the BLD has been elusive to determine. The purpose of this study was to examine the presence of the BLD during maximal isometric leg press and handgrip exercises in female swimmers (n = 9, mean age = 20.1 ± 1.3 years) and nonathletes (n = 9, mean age = 21.7 ± 1.3 years) to gain further insight into this phenomenon. Force and electromyography (EMG) measures were collected from participants under bilateral and unilateral conditions for handgrip and leg press exercises. Bilateral limb ratios (BLR) were calculated for swimmers (BLRS) and nonathletes (BLRNA). A deficit was found for swimmers and nonathletes in leg force (BLRS = 79.84% ± 13.09% and BLRNA = 81.44% ± 19.23%) and leg EMG (BLRS = 88.45% ± 15.41% and BLRNA = 94.66% ± 13.62%); however, no BLD was seen in hand force (BLRS = 98.30% ± 11.21% and BLRNA = 95.91% ± 11.04%) and hand EMG (BLRS = 102.42% ± 11.20% and BLRNA = 103.30% ± 16.50%). Furthermore, no significant differences were found between groups for leg force, leg EMG, hand force, and hand EMG. In conclusion, a BLD was detected for both groups during bilateral isometric leg press. This suggests that while the BLD may be affected by neural influences, there may other factors involved such as postural stability requirements to perform the exercise.