Rapamycin biosynthesis: Elucidation of gene product function

The function of gene products involved in the biosynthesis of the clinically important polyketide rapamycin were elucidated by biotransformation and gene complementation.     

Exponentially long time stability near an equilibrium point for non–linearizable analytic vector fields

We study the orbit behaviour of a germ of an analytic vector field of We prove that if its linear part is semisimple, non–resonant and verifies a Bruno–like condition, then the origin is effectively stable: stable for finite but exponentially long times.Received: July 5, 2004; revised: December 9, 2004     

Aging of cholinesterases phosphylated by tabun proceeds through O-dealkylation

Human butyrylcholinesterase (hBChE) hydrolyzes or scavenges a wide range of toxic esters, including heroin, cocaine, carbamate pesticides, organophosphorus pesticides, and nerve agents. Organophosphates (OPs) exert their acute toxicity through inhibition of acetylcholinesterase (AChE) by phosphorylation of the catalytic serine. Phosphylated cholinesterase (ChE) can undergo a spontaneous, time-dependent process called "aging", during which the OP-ChE conjugate is dealkylated. This leads to irreversible inhibition of the enzyme. The inhibition of ChEs by tabun and the subsequent aging reaction are of particular interest, because tabun-ChE conjugates display an extraordinary resistance toward most current oxime reactivators. We investigated the structural basis of oxime resistance for phosphoramidated ChE conjugates by determining the crystal structures of the non-aged and aged forms of hBChE inhibited by tabun, and by updating the refinement of non-aged and aged tabun-inhibited mouse AChE (mAChE). Structures for non-aged and aged tabun-hBChE were refined to 2.3 and 2.1 A, respectively. The refined structures of aged ChE conjugates clearly show that the aging reaction proceeds through O-dealkylation of the P(R) enantiomer of tabun. After dealkylation, the negatively charged oxygen forms a strong salt bridge with protonated His438N epsilon2 that prevents reactivation. Mass spectrometric analysis of the aged tabun-inhibited hBChE showed that both the dimethylamine and ethoxy side chains were missing from the phosphorus. Loss of the ethoxy is consistent with the crystallography results. Loss of the dimethylamine is consistent with acid-catalyzed deamidation during the preparation of the aged adduct for mass spectrometry. The reported 3D data will help in the design of new oximes capable of reactivating tabun-ChE conjugates.     

Characterisation of dolomites before and after reactivity measurement with HCl solution

The aim of this study was to compare different types of dolomites through batch reactivity experiments between HCl and dolomite powders, and ex‐situ characterisation of the particles before and after dissolution. Sedimentary dolomites were observed to have higher initial reactivities than metamorphic ones with sufficiently low calcite concentrations (<6% according to our regression model). In addition, the initial reactivities of the metamorphic dolomites were dependent on calcite concentration and could exceed those of the sedimentary dolomites. A regression model is presented for the dependence of initial reactivity on mineral composition and type of origin (sedimentary/metamorphic). The samples with the highest initial reactivities had also the largest BET (Brunauer, Emmet, Teller) surface areas obtained with nitrogen physisorption. Yet our data indicates that mineral composition of the dolomite has a greater influence on the initial reactivity than the BET surface area. Furthermore, it was found that the surface of sedimentary dolomites, unlike the surface of metamorphic dolomites, becomes porous during dissolution. Copyright © 2014 John Wiley & Sons, Ltd.     

XPS and SEM study of calcite bearing rock powders in the case of reactivity measurement with HCl solution

The dissolution of seven natural limestones and calcareous rocks in hydrochloric acid solution was examined to investigate their capability for wet flue gas desulphurisation. All samples were crushed, ground and sieved to a size‐fraction of 150–250 µm. Thereafter they were subjected to a dissolution experiment utilising stepwise titration with hydrochloric acid. The dissolution rates of three calcareous rocks were found to be controlled by reaction kinetics, while the limestones showed mass transfer control. The surface characterisation was implemented before and after dissolution experiments using X‐ray photoelectron spectroscopy and scanning electron microscopy. Additional characterisation was carried out with X‐ray diffraction, X‐ray fluorescence and polarizing microscope. Initial reactivities have been shown to decrease in the order limestone, calcareous rock with high calcium concentration, calcareous rock with low calcium concentration. Coarse grain structure is proposed to decrease the initial reactivity. Copyright © 2011 John Wiley & Sons, Ltd.     

Quantum computation with programmable connections between gates

A new model of quantum computation is considered, in which the connections between gates are programmed by the state of a quantum register. This new model of computation is shown to be more powerful than the usual quantum computation, e.g. in achieving the programmability of permutations of N different unitary channels with 1 use instead of N uses per channel. For this task, a new elemental resource is needed, the quantum switch, which can be programmed to switch the order of two channels with a single use of each one.     

Engineered biosynthesis of hybrid macrolide polyketides containing D-angolosamine and D-mycaminose moieties

The glycosylation of natural product scaffolds with highly modified deoxysugars is often essential for their biological activity, being responsible for specific contacts to molecular targets and significantly affecting their pharmacokinetic properties. In order to provide tools for the targeted alteration of natural product glycosylation patterns, significant strides have been made to understand the biosynthesis of activated deoxysugars and their transfer. We report here efforts towards the production of plasmid-borne biosynthetic gene cassettes capable of producing TDP-activated forms of D-mycaminose, D-angolosamine and D-desosamine. We additionally describe the transfer of these deoxysugars to macrolide aglycones using the glycosyl transferases EryCIII, TylMII and AngMII, which display usefully broad substrate tolerance.