Alterations in the bidirectional interactions between the intestine and the nervous system have important roles in the pathogenesis of irritable bowel syndrome (IBS). A body of largely preclinical ...evidence suggests that the gut microbiota can modulate these interactions. A small and poorly defined role for dysbiosis in the development of IBS symptoms has been established through characterization of altered intestinal microbiota in IBS patients and reported improvement of subjective symptoms after its manipulation with prebiotics, probiotics, or antibiotics. It remains to be determined whether IBS symptoms are caused by alterations in brain signaling from the intestine to the microbiota or primary disruption of the microbiota, and whether they are involved in altered interactions between the brain and intestine during development. We review the potential mechanisms involved in the pathogenesis of IBS in different groups of patients. Studies are needed to better characterize alterations to the intestinal microbiome in large cohorts of well-phenotyped patients, and to correlate intestinal metabolites with specific abnormalities in gut–brain interactions.
Deprotonated glutathione is among the most potent biological nucleophiles and plays an important physiological role in cellular detoxification by forming covalent conjugates with Michael acceptors. ...The electrophilicity E of various Michael acceptors was characterized recently according to the Patz–Mayr relation lg k2=sN(N+E). We now determined the nucleophilic reactivity (N, sN) of glutathione (GSH) in aqueous solution at 20 °C to connect published GSH reactivities (kGSH) with Mayr's electrophilicity scale (E). In this way, electrophilicities E of more than 70 Michael acceptors could be estimated, which can now be used to systematically predict novel reactions with the multitude of nucleophiles whose nucleophilicity parameters N/sN are known.
Connected: The nucleophilicity parameters N and sN of glutathione (GSH) were determined in aqueous solution at 20 °C to link published GSH reactivities (lg kGSH) with Mayr's electrophilicity scale (E). The electrophilic reactivities of Michael acceptors determined in kinetic chemoassays can now be compared with reactivities of neutral and cationic electrophiles characterized on the E scale.
Kinetics of the reactions of isocyanates, isothiocyanates, carbodiimides, carbon disulfide, and carbon dioxide with carbanions or enamines (reference nucleophiles) have been measured photometrically ...in acetonitrile or DMSO solution at 20 °C. The resulting second-order rate constants and the previously published reactivity parameters N and s N of the reference nucleophiles were substituted into the correlation log k 2(20 °C) = s N(N + E) to determine the electrophilicity parameters of the heteroallenes: TsNCO (E = −7.69) ≫ PhNCO (E = −15.38) > CS2 (E = −17.70) ≈ PhNCS (E = −18.15) > PhNCNPh (E = −20.14) ≫ CyNCNCy (E ≈ −30). An approximate value could be derived for CO2 (−16 < E < – 11). Quantum chemical calculations were performed at the IEFPCM(DMSO)/B3LYP‑D3/6‑311+G(d,p) level of theory and compared with experimental Gibbs activation energies. The distortion–interaction model was used to rationalize the different reactivities of O- and S-substituted heteroallenes. Eventually it is demonstrated that the electrophilicity parameters determined in this work can be used as ordering principle for literature-known reactions of heteroallenes.
Amino acid biosynthesis initiates with the reductive amination of α‐ketoglutarate with ammonia to produce glutamate. However, the other α‐keto acids derived from the glyoxylate and Krebs cycles are ...converted into amino acids by transamination, rather than by reductive amination. Why is only one amino acid synthesized by reductive amination and not the others? To explore this question, we quantified the inherent reactivities of keto acids in nonenzymatic reduction and reductive amination by using BH3CN− as a model nucleophile. Biological α‐keto acids were found to show pronounced nonenzymatic reactivity differences for the formation of amino acids (α‐ketoglutarate<oxaloacetate≈pyruvate≪glyoxylate). Accordingly, the flow of ammonia passes through the least reactive α‐keto acid of the Krebs cycle. One possible explanation for this choice is the position of the corresponding amino acid, glutamate, at the top of the thermodynamic landscape for subsequent transamination reactions.
Why does biochemical amino acid synthesis proceed the way it does? Kinetic and mechanistic experiments with a model hydride donor were used to determine the intrinsic electrophilic reactivities of keto acids in reduction and reductive amination reactions. Comparing the nonenzymatic reactivity trends with those found in biology provides new insight into the structure of amino acid metabolism.
Under enzyme catalysis, adenosine triphosphate (ATP) transfers a phosphoryl group to canonical ribonucleotide diphosphates (NDPs) to form ribonucleotide triphosphates (NTPs), the direct biosynthetic ...precursors to RNA. However, it remains unclear whether the phosphorylation of NDPs could have occurred in water before enzymes existed and why an adenosine derivative, rather than another canonical NTP, typically performs this function. Here, we show that adenosine diphosphate (ADP) in the presence of Fe3+ or Al3+ promotes phosphoryl transfer from acetyl phosphate to all canonical NDPs to produce their corresponding NTP in water at room temperature and in the absence of enzymes. No other NDPs were found to promote phosphorylation, giving insight into why adenosine derivatives specifically became used for this purpose in biology. The metal–ADP complexes also promote phosphoryl transfer to ribonucleoside monophosphates (NMPs) to form a mixture of the corresponding NDPs and NTPs, albeit less efficiently. This work represents a rare example in which a single nucleotide carries out a function critical to biology without enzymes. ADP–metal complexes may have played an important role in nucleotide phosphorylation in prebiotic chemistry.
A quantitative Lewis acidity/basicity scale toward boron‐centered Lewis acids has been developed based on a set of 90 experimental equilibrium constants for the reactions of triarylboranes with ...various O‐, N‐, S‐, and P‐centered Lewis bases in dichloromethane at 20 °C. Analysis with the linear free energy relationship log KB=LAB+LBB allows equilibrium constants, KB, to be calculated for any type of borane/Lewis base combination through the sum of two descriptors, one for Lewis acidity (LAB) and one for Lewis basicity (LBB). The resulting Lewis acidity/basicity scale is independent of fixed reference acids/bases and valid for various types of trivalent boron‐centered Lewis acids. It is demonstrated that the newly developed Lewis acidity/basicity scale is easily extendable through linear relationships with quantum‐chemically calculated or common physical–organic descriptors and known thermodynamic data (ΔHBF3
). Furthermore, this experimental platform can be utilized for the rational development of borane‐catalyzed reactions.
Loose or Lewis? A comprehensive set of experimental equilibrium constants reveals the strength of interactions between boron‐centered Lewis acids and N‐, O‐, S‐, and P‐centered Lewis bases. Data analysis shows that two‐parameter Equation (1) enables Lewis adduct formation to be straightforwardly predicted for borane/Lewis base couples. Experimental data can be supplemented by quantum‐chemical calculations for a rational design of borane‐catalyzed reactions.
Equilibrium constants for the associations of 17 diaryliodonium salts Ar2I+X– with 11 different Lewis bases (halide ions, carboxylates, p-nitrophenolate, amines, and tris(p-anisyl)phosphine) have ...been investigated by titrations followed by photometric or conductometric methods as well as by isothermal titration calorimetry (ITC) in acetonitrile at 20 °C. The resulting set of equilibrium constants K I covers 6 orders of magnitude and can be expressed by the linear free-energy relationship lg K I = s I LAI + LBI, which characterizes iodonium ions by the Lewis acidity parameter LAI, as well as the iodonium-specific affinities of Lewis bases by the Lewis basicity parameter LBI and the susceptibility s I. Least squares minimization with the definition LAI = 0 for Ph2I+ and s I = 1.00 for the benzoate ion provides Lewis acidities LAI for 17 iodonium ions and Lewis basicities LBI and s I for 10 Lewis bases. The lack of a general correlation between the Lewis basicities LBI (with respect to Ar2I+) and LB (with respect to Ar2CH+) indicates that different factors control the thermodynamics of Lewis adduct formation for iodonium ions and carbenium ions. Analysis of temperature-dependent equilibrium measurements as well as ITC experiments reveal a large entropic contribution to the observed Gibbs reaction energies for the Lewis adduct formations from iodonium ions and Lewis bases originating from solvation effects. The kinetics of the benzoate transfer from the bis(4-dimethylamino)-substituted benzhydryl benzoate Ar2CH–OBz to the phenyl(perfluorophenyl)iodonium ion was found to follow a first-order rate law. The first-order rate constant k obs was not affected by the concentration of Ph(C6F5)I+ indicating that the benzoate release from Ar2CH–OBz proceeds via an unassisted S N1-type mechanism followed by interception of the released benzoate ions by Ph(C6F5)I+ ions.
Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts, and thus their pre-enzymatic ...function remains unclear. Since metal ions are known to catalyze metabolic reactions in the absence of enzymes, here we explore the influence of metal ions on coenzyme catalysis under conditions relevant to the origin of life (20–75 °C, pH 5–7.5). Specifically, Fe or Al, the two most abundant metals in the Earth’s crust, were found to exhibit substantial cooperative effects in transamination reactions catalyzed by pyridoxal (PL), a coenzyme scaffold used by roughly 4% of all enzymes. At 75 °C and 7.5 mol % loading of PL/metal ion, Fe3+-PL was found to be 90-fold faster at catalyzing transamination than PL alone and 174-fold faster than Fe3+ alone, whereas Al3+-PL was 85-fold faster than PL alone and 38-fold faster than Al3+ alone. Under milder conditions, reactions catalyzed by Al3+-PL were >1000 times faster than those catalyzed by PL alone. Pyridoxal phosphate (PLP) exhibited similar behavior to PL. Experimental and theoretical mechanistic studies indicate that the rate-determining step in the PL-metal-catalyzed transamination is different from metal-free and biological PL-based catalysis. Metal coordination to PL lowers the pK a of the PL-metal complex by several units and slows the hydrolysis of imine intermediates by up to 259-fold. Coenzymes, specifically pyridoxal derivatives, could have exhibited useful catalytic function even before enzymes.
PDF
