Loss of co-linearity by modular polyketide synthases: a mechanism for the evolution of chemical diversity

Modular polyketide synthases biosynthesise natural products through successive Claisen-type condensations, where one module is responsible for one round of chain extension. This review describes recent findings where this rule of co-linearity is broken, either by one module being bypassed (skipping) or through one module being used for multiple chain extension events (stuttering).     

Priming type II polyketide synthases via a type II nonribosomal peptide synthetase mechanism

Benzoic acid priming of the enterocin and actinorhodin type II polyketide synthase complexes was accomplished in vitro via an unprecedented type II nonribosomal peptide synthetase-like mechanism involving the benzoate:acyl carrier protein (ACP) ligase EncN and the ACP EncC. The transfer of the aryl acid to the ACP is ATP-dependent, yet coenzyme A-independent, as characterized with radiolabeled substrates and protein mass spectrometry. Subsequent transport of the ACP-bound aryl group to the native enterocin and the aberrant actinorhodin ketosynthase chain length factor heterodimers was further demonstrated, thereby demonstrating the potential of this biocatalyst for engineering diverse aryl-primed aromatic polyketide agents.     

Isoxazolidine analogues of pseudouridine: a new class of modified nucleosides

A new class of modified C-nucleosides has been synthesized according to the 1,3-dipolar cycloaddition methodology. The obtained compounds are structurally related to natural pseudouridine, where the sugar moiety is replaced by an isoxazolidine ring. Different experimental conditions, and the effect of additives on the cycloaddition process, have been examined; the best results were obtained when the cycloaddition reaction was performed under microwave irradiation     

The products of 5-fluorouridine by the action of the pseudouridine synthase TruB disfavor one mechanism and suggest another

The pseudouridine synthase TruB handles 5-fluorouridine in RNA as a substrate, converting it into two isomeric hydrated products. Unexpectedly, the two products differ not in the hydrated pyrimidine ring but in the pentose ring, which is epimerized to arabinose in the minor product. This inversion of stereochemistry at C2' suggests that pseudouridine generation may proceed by a mechanism involving a glycal intermediate or that the previously proposed mechanism involving an acylal intermediate operates but with an added reaction manifold for 5-fluorouridine versus uridine. The arabino product strongly disfavors a mechanism involving a Michael addition to the pyrimidine ring.     

Structure, spectra, and rearrangement mechanism of PH2F3: revisiting a classic problem in structural inorganic chemistry

The structure, spectra, and rearrangement mechanisms of PH2F3, the first member of the PHnF5-n series and a prototype for molecules that undergo rotational isomerism, have been studied. Aided by the tools developed to compute coupled-cluster (CC) Raman intensities and NMR spin-spin couplings, a full spectroscopic characterization of PH2F3 is presented. Moreover, the structures and the energetics of the various stereoisomers are computed at the CC level (CCSD(T)) to assess the validity of proposed rearrangement mechanisms. While corroborating prior experimental IR and NMR assignments, the results are also able to remedy the "speculative" Raman and NMR assignments that lacked reliable computed values when the experiments were done. More importantly, the results identify "spectral fingerprints" that could distinguish various rotational isomers. These data, when used concurrently along with high resolution measurements, form a powerful basis for the characterization of various rotational isomers of PH2F3. A "new" stability diagram and a rearrangement path based on the computed energetic and structure data are obtained. That is far superior to what has been available in the literature.     

The type I fatty acid and polyketide synthases: a tale of two megasynthases

This review chronicles the synergistic growth of the fields of fatty acid and polyketide synthesis over the last century. In both animal fatty acid synthases and modular polyketide synthases, similar catalytic elements are covalently linked in the same order in megasynthases. Whereas in fatty acid synthases the basic elements of the design remain immutable, guaranteeing the faithful production of saturated fatty acids, in the modular polyketide synthases, the potential of the basic design has been exploited to the full for the elaboration of a wide range of secondary metabolites of extraordinary structural diversity.     

Thiol-yne coupling: revisiting old concepts as a breakthrough for up-to-date applications

Radical thiol-yne coupling (TYC) has emerged as one of the most appealing click chemistry procedures, appearing as a sound candidate for replacing/complementing other popular click reactions such as the thiol-ene coupling (TEC) and the Cu-catalysed azide-alkyne cycloaddition (CuAAC). Radical TYC is indeed a metal-free reaction suitable for biomedical applications, and its mechanistic features often make it more efficient than its TEC sister reaction and more suitable for multifaceted derivatisations in the materials chemistry and bioconjugation realms. This article reviews the fascinating results obtained in those fields in very recent years.     

Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork

This review covers advances in understanding of the biosynthesis of polyketides produced by type II PKS systems at the genetic, biochemical and structural levels.     

The SON2 mechanism : A non-oxidative reaction that is initiated by electron transfer oxidation

Under oxidizing conditions, aromatic chloro and fluoro compounds undergo what formally are typical nucleophilic substitution reactions with surprising ease. As an example, 4-fluoroanisole is converted the 4-acetoxyanisole by anodic or metal ion oxidative initiation, and the reaction is shown to be a chain process. It is proposed that a mechanism analogous to that of the reductively initiated S_RN1 mechanism operates: The substrate is oxidized to a radical cation by the initiator system, and the radical cation then undergoes ipso attack by the nucleophile. In the third step, the leaving group leaves as a species at the same oxidation level as the nucleophile, giving the radical cation of the product to be formed. A chain transfer step involving this ion and a new substrate molecule then completes the propagation sequence.Previously reported cases of this phenomenon are discussed and the individual steps of the chain reaction are considered in terms of their thermochemistry. It is concluded that the S_ON2 mechanism should be more favoured with easily oxidizable substrates.     

The hydrogenation of nitrobenzene to aniline: a new mechanism

The Haber mechanism describing the process of hydrogenating nitrobenzene to aniline is shown to be incorrect and a new mechanism is proposed.     

Methylations: a radical mechanism

On the basis of labeling experiments, Grove et?al. (2011) have shown how an electrophilic carbon (from an?RNA adenosine) can be methylated by S-adenosylmethionine-dependent methyltransferases though an original radical mechanism.     

The nitrosation of N-alkylureas: Evidence for a proton transfer mechanism

The kinetics of the nitrosation of methyl, ethyl, propyl, butyl, and allyl urea were studied by conventional and stopped-flow spectrophotometry in the presence or absence of acetate or mono-, di-, or trichloroacetate anions. In the presence of a large excess of urea, the observed rate equation was where K_a is the acidity constant of nitrous acid and K_R that of the carboxylic acid. The ureas exhibited the reactivity order methylurea ≫ (ethylurea ≅ propylurea ≅ butylurea) ≫ allylurea. Experiments in D₂O afforded values of k/k = exp(0.130hv⌅/kT)], where v⌅ is the frequency of R₃N H stretching (2700–2250 cm⁻¹) in the protonated urea. This result, the observed catalysis by carboxylate ions and the value of the Bronsted parameter β(0.45) show the rate-controlling step of these reactions to be the transfer of a proton from the protonated N-alkyl-N-nitrosourea to the solvent or to the organic anion, if present. The observed order of substrate reactivities is explicable in terms of the capacity of the protonated N-alkyl-N-nitrosourea for forming a hydrogen bond with the water molecule to which the proton will be transferred, and the degree to which the formation of such bonds is hindered by the hydrophobic alkyl chain of the nitrosourea. © 1996 John Wiley & Sons, Inc.     

The first chemical synthesis of novel MeO-3-GlcUA derivative of hyaluronan-based disaccharide to elucidate the catalytic mechanism of hyaluronic acid synthases (HASs)

The first chemical synthesis of MeO-3-GlcUAβ(1→3)GlcNAc-UDP to elucidate the catalytic mechanism of hyaluronic acid synthases (HASs) is described. Construction of the desired β(1→3)-linked disaccharide 10 was achieved very efficiently by coupling MeO-3-GlcUA donor 3 with the suitable protected GlcNTroc acceptor 4 using BF₃·Et₂O as Lewis acid. Chemoselective removal of anomeric NAP, phosphorylation, hydrogenation, coupling with UMP-morpholidate, and finally complete deprotection gave the target compound 1 in good yield.     

The photoisomerization mechanism of azobenzene: a semiclassical simulation of nonadiabatic dynamics

We have simulated the photoisomerization dynamics of azobenzene, taking into account internal conversion and geometrical relaxation processes, by means of a semiclassical surface hopping approach. Both n-->pi* and pi-->pi* excitations and both cis-->trans and trans-->cis conversions have been considered. We show that in all cases the torsion around the N==N double bond is the preferred mechanism. The quantum yields measured are correctly reproduced and the observed differences are explained as a result of the competition between the inertia of the torsional motion and the premature deactivation of the excited state. Recent time-resolved spectroscopic experiments are interpreted in the light of the simulated dynamics.     

The reaction mechanism of hydroxyethylphosphonate dioxygenase: a QM/MM study

By employing ab initio quantum mechanical/molecular mechanical (QM/MM) and molecular dynamics (MD) simulations, we have provided further evidence against the previously proposed hydroperoxylation or hydroxylation mechanism of hydroxyethylphosphonate dioxygenase (HEPD). HEPD employs an interesting catalytic cycle based on concatenated bifurcations. The first bifurcation is based on the abstraction of hydrogen atoms from the substrate, which leads to a distal or proximal hydroperoxo species (Fe-OOH or Fe-(OH)O). The second and the third bifurcations refer to the carbon-carbon bond cleavage reaction. And this is achieved through a tridentate intermediate, or employing a proton-shuttle assisted mechanism, in which the residue Glu(176) or the Fe(IV)=O group serves as a general base. The reaction directions seem to be tunable and show significant environment dependence. This mechanism can provide a comprehensive interpretation for the seemingly contradicting experimental evidences and provide insight into the development of biochemistry and material sciences.     

The mechanism of guanine alkylation by nitrogen mustards: a computational study

The thermodynamics and kinetics for the monofunctional binding of nitrogen mustard class of anticancer drugs to purine bases of DNA were studied computationally using guanine and adenine as model substrates. Mechlorethamine and melphalan are used as model systems in order to better understand the difference in antitumor activity of aliphatic and aromatic mustards, respectively. In good agreement with experiments that suggested the accumulation of a reactive intermediate in the case of mechlorethamine, our model predicts a significant preference for the formation of corresponding aziridinium ion for mechlorethamine, while the formation of the aziridinium ion is not computed to be preferred when melphalan is used. Two effects are found that contribute to this difference. First, the ground state of the drug shows a highly delocalized lone pair on the amine nitrogen of the melphalan, which makes the subsequent cyclization more difficult. Second, because of the aromatic substituent connected to the amine nitrogen of melphalan, a large energy penalty has to be paid for solvation. A detailed study of energy profiles for the two-step mechanism for alkylation of guanine and adenine was performed. Alkylation of guanine is ～6 kcal mol(-1) preferred over adenine, and the factors contributing to this preference were explained in our previous study of cisplatin binding to purine bases. A detailed analysis of energy profiles of mechlorethamine and melphalan binding to guanine and adenine are presented to provide an insight into rate limiting step and the difference in reactivity and stability of the intermediate in both nitrogen mustards, respectively.     

Insertion of organoindium carbenoids into rhodium halide bonds: revisiting a classic type of transition metal-group 13 metal bond formation

Insertion of the carbenoid group 13 metal species InCp* (Cp* = pentamethylcyclopentadienyl) and InC(SiMe3)3 into the Rh-Cl bonds of [[RhCp*Cl2]2] yields the new complexes [Cp*Rh(InCp*)3(Cl)2] 1 and [Cp*Rh(mu2-Cl)2(InC(SiMe3)3)3] 2, respectively, exhibiting novel cage-like intermetallic complexes with In-Cl-In bridges.     

Erosion of multilayered films fabricated from degradable polyamines: Characterization and evidence in support of a mechanism that involves polymer hydrolysis

Multilayered polyelectrolyte assemblies fabricated using hydrolytically degradable polyamines ( 1 – 3 ) erode gradually when incubated in physiologically relevant media. This investigation sought to characterize physically and chemically the erosion of films fabricated from these polymers and sodium poly(styrene sulfonate) (SPS) and to investigate specifically the potential role of polymer hydrolysis in governing film erosion. The characterization of erosion using reflective infrared spectroscopy revealed changes in the carbonyl region of the spectrum that were consistent with the generation of polymer hydrolysis products. To evaluate the role of the esters in these materials more directly, we also synthesized a structural analogue of polymer 2 containing amide functionality rather than ester functionality. Assemblies fabricated from this amide-containing polymer did not erode significantly or release SPS into solution when incubated in phosphate-buffered saline (PBS). Finally, we characterized the erosion of assemblies fabricated from polymer 1 in PBS buffer prepared with D₂O rather than H₂O. These assemblies eroded significantly more slowly in deuterated media than in buffer prepared with H₂O. These results, when combined, provide support for the view that polymer hydrolysis plays an important role in governing the erosion of assemblies fabricated from these degradable polymers. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5161–5173, 2006