The realm of natural products of early diverging fungi such as Mortierella species is largely unexplored. Herein, the nonribosomal peptide synthetase (NRPS) MalA catalysing the biosynthesis of the surface-active biosurfactants, malpinins, has been identified and biochemically characterised. The investigation of the substrate specificity of respective adenylation (A) domains indicated a substrate-tolerant enzyme with an unusual, inactive C-terminal NRPS module. Specificity-based precursor-directed biosynthesis yielded 20 new congeners produced by a single enzyme. Moreover, MalA incorporates artificial, click-functionalised amino acids which allowed postbiosynthetic coupling to a fluorophore. The fluorescent malpinin conjugate penetrates mammalian cell membranes via an phagocytosis-mediated mechanism, suggesting Mortierella oligopeptides as carrier peptides for directed cell targeting. The current study demonstrates substrate-specificity testing as a powerful tool to identify flexible NRPS modules and highlights basal fungi as reservoir for chemically tractable compounds in pharmaceutical applications.Specificity profiling of a nonribosomal peptide synthetase of an early diverging fungus revealed high substrate flexibility. Feeding studies with click-functionalised amino acids enabled the production of fluorescent peptides targeting macrophages.相似文献
We here outline the importance of open-source, accessible tools for computer-aided drug discovery (CADD). We begin with a discussion of drug discovery in general to provide context for a subsequent discussion of structure-based CADD applied to small-molecule ligand discovery. Next, we identify usability challenges common to many open-source CADD tools. To address these challenges, we propose a browser-based approach to CADD tool deployment in which CADD calculations run in modern web browsers on users’ local computers. The browser app approach eliminates the need for user-initiated download and installation, ensures broad operating system compatibility, enables easy updates, and provides a user-friendly graphical user interface. Unlike server apps—which run calculations “in the cloud” rather than on users’ local computers—browser apps do not require users to upload proprietary information to a third-party (remote) server. They also eliminate the need for the difficult-to-maintain computer infrastructure required to run user-initiated calculations remotely. We conclude by describing some CADD browser apps developed in our lab, which illustrate the utility of this approach. Aside from introducing readers to these specific tools, we are hopeful that this review highlights the need for additional browser-compatible, user-friendly CADD software. 相似文献
This paper investigates the influences of wind speed and of heat-convection coefficient on the temperature prediction of a slab. Numerical calculation of a slab temperature found that wind speed varies the slab temperature in a degree of 2–10 °C. More varying degrees occur at midday and in sunny day but less, at midnight and in a cloud day. These degrees also depend on the used heat-convection coefficients, which have different values in different models. Special emphases are paid to unearth the correlation between different heat convection coefficients and find the best alternative in the slab-temperature prediction. 相似文献
A new preparative column for the vortex counter-current chromatograph was fabricated by making many (966) cylindrical separation units to a high-density polyethylene disk and then threading them with 6–40 taps. The resulting column had a total capacity of 364 mL. The performance of this vortex column was examined with three different two-phase solvent systems each using a set of suitable test samples: hexane–ethyl acetate–methanol–0.1 M hydrochloric acid (1:1:1:1, v/v) for the separation of DNP-amino acids; 1-butanol–acetic acid–water (4:1:5, v/v) for the separation of dipeptides; and hexane–acetonitrile–water (20:15:2, v/v) for the separation of Sudan dyes. Most of the separations show high partition efficiency of over a thousand theoretical plates, as expected based on the results previously obtained in preliminary separations with a small column. Overall, the results of the present study suggest that further improvement of the partition efficiency can be obtained by the modifying column configuration.
The temperature field generated by the sudden application of a far-field mechanical loading of a periodically layered composite with an interfacial crack or with a cracked layer parallel to the interfaces is determined. As a result of the crack’s existence, the periodicities of the structure and the thermoelastic field are lost. The complexity of the resulting problem is resolved by the combined application of the representative cell method and the full (two-way) dynamic thermomechanical equations. In the former analysis, due to the loss of periodicity the dynamic thermoelastic Green’s functions are generated, in conjunction with the double finite discrete Fourier transform. In the latter one, the transformed displacements and temperature are expressed by second-order expansions and the strong-form of the elastodynamic and energy equations together with the various interfacial and the so called Born–von Karman boundary conditions are imposed in the average sense (in the transform domain). The results exhibit the induced temperature field at any point in the plane of the crack. The generated temperature fields show the cooling and heating zones in both Mode I and Mode II deformations. In addition, the adiabatic assumption (according to which the heat conduction is a priori ignored) is assessed by comparing the computed temperature field with the corresponding one based on the full thermomechanical coupling. 相似文献
We present herein our results on the nucleophilic addition of imidazole to a range of arylselanylalkynes by simple heating in DMF without any additives to give (Z)-1-(1-organyl-(2-arylselanyl)vinyl)-1H-imidazoles. The reactions were performed under mild conditions with a range of arylselanylalkynes in good yields and with high regio- and stereoselectivity to give the respective (Z)-arylselanyl alkene as the only isomer. 相似文献
In (3)He magnetic resonance images of pulmonary air spaces, the confining architecture of the parenchymal tissue results in a non-Gaussian distribution of signal phase that non-exponentially attenuates image intensity as diffusion weighting is increased. Here, two approaches previously used for the analysis of non-Gaussian effects in the lung are compared and related using diffusion-weighted (3)He MR images of mechanically ventilated rats. One approach is model-based and was presented by Yablonskiy et al., while the other approach utilizes the second order decay contribution that is predicted from the cumulant expansion theorem. Total lung coverage is achieved using a hybrid 3D pulse sequence that combines conventional phase encoding with sparse radial sampling for efficient gas usage. This enables the acquisition of nine 3D images using a total of only approximately 1 L of hyperpolarized (3)He gas. Diffusion weighting ranges from 0 s/cm(2) to 40 s/cm(2). Results show that the non-Gaussian effects of (3)He gas diffusion in healthy rat lungs are directly attributed to the anisotropic geometry of lung microstructure as predicted by the Yablonskiy model, and that quantitative analysis over the entire lung can be reliably repeated in time-course studies of the same animal. 相似文献