Nicotinamide adenine dinucleotide (NAD)؉ -dependent sirtuins have been identified to be key regulators in the lifespan extending effects of calorie restriction (CR) in a number of species. In this study we report for the first time that promotion of the NAD ؉ -dependent sirtuin, SIRT1-mediated deacetylase activity, may be a mechanism by which CR influences Alzheimer disease (AD)-type amyloid neuropathology. Most importantly, we report that the predicted attenuation of -amyloid content in the brain during CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1 expression/activity through mechanisms involving the regulation of the serine/threonine Rho kinase ROCK1, known in part for its role in the inhibition of the non-amyloidogenic ␣-secretase processing of the amyloid precursor protein. Conversely, we found that the expression of constitutively active ROCK1 in vitro cultures significantly prevented SIRT1-mediated response, suggesting that ␣-secretase activity is required for SIRT1-mediated prevention of AD-type amyloid neuropathology. Consistently we found that the expression of exogenous human (h) SIRT1 in the brain of hSIRT1 transgenics also resulted in decreased ROCK1 expression and elevated ␣-secretase activity in vivo. These results demonstrate for the first time a role for SIRT1 activation in the brain as a novel mechanism through which CR may influence AD amyloid neuropathology. The study provides a potentially novel pharmacological strategy for AD prevention and/or treatment.Sirtuins are a family of NAD ϩ -dependent histone/protein deacetylases that are highly conserved in their catalytic domains and are distributed across all kingdoms of life (1-4). These enzymes utilize NAD ϩ as a substrate to catalyze deacetylation of specific acetylated-protein substrates (1, 5). Sirtuins can deacetylate a variety of substrates and are, therefore, involved in a broad range of physiological functions, including control of gene expression, metabolism, and aging (6). Accumulating evidence implicates sirtuins in calorie restriction (CR)-mediated health effects including increased organism longevity in yeast, worms, flies, and mammals (1-4, 6). Mammalian genomes encode seven distinct sirtuins (SIRT1-SIRT7). SIRT1 is induced by CR 4 in several tissues and has been implicated in various effects such as stress resistance, reduced apoptosis, and metabolic changes associated with CR (1). SIRT1 is also expressed in the developing and the adult mammalian brain (7). Based on these considerations and on the evidence that CR prevents AD-type amyloid neuropathology in animal models (8, 9), we sought to test the hypothesis that CR may reduce AD-type amyloid neuropathology through mechanisms involving promotion of SIRT1. The relevance of CR treatment in experimental models of AD to human pathology is supported by recent epidemiological evidence suggesting that humans who maintain a low calorie diet have a reduced risk of developing AD (10 -12).Abnormal A deposition within the brain is a hallmark of AD neuropat...
The Sir2 enzyme family is responsible for a newly classified chemical reaction, NAD(+)-dependent protein deacetylation. New peptide substrates, the reaction mechanism, and the products of the acetyl transfer to NAD(+) are described for SIR2. The final products of SIR2 reactions are the deacetylated peptide and the 2' and 3' regioisomers of O-acetyl ADP ribose (AADPR), formed through an alpha-1'-acetyl ADP ribose intermediate and intramolecular transesterification reactions (2' --> 3'). The regioisomers, their anomeric forms, the interconversion rates, and the reaction equilibria were characterized by NMR, HPLC, 18O exchange, and MS methods. The mechanism of acetyl transfer to NAD(+) includes (1) ADP ribosylation of the peptide acyl oxygen to form a high-energy O-alkyl amidate intermediate, (2) attack of the 2'-OH group on the amidate to form a 1',2'-acyloxonium species, (3) hydrolysis to 2'-AADPR by the attack of water on the carbonyl carbon, and (4) an SIR2-independent transesterification equilibrating the 2'- and 3'-AADPRs. This mechanism is unprecedented in ADP-ribosyl transferase enzymology. The 2'- and 3'-AADPR products are candidate molecules for SIR2-initiated signaling pathways.
Reactivities and collision-induced dissociation of vanadium oxide cluster cations are investigated using a triple quadrupole mass spectrometer coupled with a laser vaporization source. The dominant peaks in the mass distribution correspond to cluster ions with stoichiometries of (VO 2 ) n (V 2 O 5 ) m (O 2 ) q + . Collision-induced dissociation studies of the vanadium oxide species V 2 O 4-6 + , V 3 O 6-9 + , V 4 O 8-10 + , V 5 O 11-13 + , V 6 O 13-15 + , and V 7 O 16-18 + show that VO 2 , VO 3 , and V 2 O 5 units are the main building blocks for most of these clusters. The reaction pathways observed for these vanadium oxide clusters include molecular association, cracking, dehydration, and oxygenation of the neutral hydrocarbons with the reactivities of specific clusters differing from species to species. For example, V 3 O 7 + is very efficient in the dehydrogenation of 1,3-butadiene and in the cracking of 1-butene. On the other hand, V 3 O 6 + produces only molecular association products with these same reactants. To help explain these differences in reactivity, calculations on the molecular structure of some of these cluster ions were also undertaken, and the findings are presented.
A new method of forming Met-Car−ligand complexes, Ti8C12 +(M) n (M = halogens, π-bonding molecules, and polar molecules, n = 1−8) is reported which involves the direct interaction of titanium with mixtures of methane and selected reactant gases. The results show that the formation of Ti8C12 in the plasma is kinetically and thermodynamically favored over other reaction processes. Through an examination of Met-Car−ligand complexes, various reaction mechanisms of Ti8C12 + are identified and characterized, namely oxidation, complexation, and ion−dipole interaction. Oxidation of Ti8C12 + occurs when Met-Cars react with halogen-containing molecules through valence electron donation from Ti8C12 + to the halogen atoms. When Ti8C12 + interacts with π-bonding molecules, the findings are consistent with the formation of “surface complexes” comprised of the ligand binding across two of the metal atoms in the pentagonal ring of Ti8C12 + through d−π interaction. In these cases, the cluster size distributions in the mass spectra of the reaction products exhibit truncation at Ti8C12 +(M)4. By contrast, ion−dipole interactions lead to the formation of Ti8C12 +(M)1-8 (M denoting polar molecules), which is consistent with previous findings showing that polar molecules bond to each metal site. The product distribution of Ti8C12 + with butanol at various pressures provides new evidence which serves to resolve controversies in the literature regarding observed truncations and their implications concerning the geometric structure of Ti8C12 +; the findings are supportive of the originally proposed Th symmetry. Furthermore, the further reaction of Ti8C12 +(I) with methanol, which gives the product distribution truncation at Ti8C12 +(I)(CH3OH)7, indicates that the titration method is a useful tool to probe the cluster structures in these systems.
Niobium oxide cluster ions are produced by a laser-induced plasma source. The cluster distribution, collision-induced dissociation (CID), and cluster reactivities are studied using a triple-quadrupole mass spectrometer. CID experiments on the cluster ions Nb3O7 - 9 +, Nb4O9 - 11 +, and Nb5O12 + reveal that their building blocks are Nb2O5, NbO2 +, NbO3, Nb3O7 +, O, and O2, whereby the cluster stoichiometry is assigned to have the general form (NbO3) m (NbO2) n (O)0 - 4 +. The trends in the ionization potentials of these species are estimated in terms of the CID fragments produced. Nb3O8 - 9 + and Nb4O11 + cluster ions evidently form via the adsorption of one oxygen atom or molecule onto the cluster surface. Nb3O7 +, Nb4O9 +, and Nb5O12 + have strong reactivities to abstract an oxygen atom from oxygen-containing molecules and adsorb small hydrocarbons at near thermal energies. In particular, the reactivity of the oxygen atom or molecule in the oxide clusters Nb3O8 - 9 + and Nb4O11 + is consistent with our suggestions that it has a radical oxygen character.
To start to understand the role of chromatin structure in regulating transcription in trypanosomes, we analyzed covalent modifications on the four core histones of Trypanosoma brucei. We found unusually few modifications in the N-terminal tails, which are abundantly modified in other organisms and whose sequences, but not composition, are highly divergent in trypanosomes. In contrast, the C-terminal region of H2A appears to be hyper-acetylated. Surprisingly, the N-terminal alanines of H2A, H2B, and H4, were mono-methylated, a modification that has not been described previously for histones. Possible functions and evolutionary explanations for these unusual histone modifications are discussed.
A three electrode thin-layer,¯ow-by electrode cell was coupled on-line with electrospray-mass spectrometry (i.e., ECaES-MS) for the study of biological redox reactions. The cell made use of a commercially available 6.0 mm diameter, offset glassy carbon disk working electrode, a AgaAgCl reference electrode, and a workingacounter electrode spacing gasket (16 mm), along with a home-built PEEK counter electrode block with a Pt foil (7.0 mm wide) counter electrode (cell volume ca. 1.1 mL). Off-line hydrodynamic voltammetry experiments and electrolytic conversion ef®ciency measurements using chronocoulometry were used to characterize the performance of the cell. On-line ECaES-MS conversion ef®ciency was found consistent with the off-line results and the ECaES-MS response time was measured as 5.1 s at a¯ow rate of 30 mLamin and 2.4 s at 62 mLamin. The use of this hybrid system for the study of the products of biologically relevant redox reactions was demonstrated using the oxidation of dopamine in aqueous CH 3 OH (pH 4.0) as a test case. Tandem mass spectrometry experiments provided evidence to conclude that the structure of the two major dopamine oxidation products observed in the ES mass spectra were 5,6-dihydroxyindoline and 5,6-hydroxyindole. Reaction of oxidized dopamine with the surrogate biogenic nucleophile benzene thiol resulted in the formation of mono-, di-, and tri-benzene thiol addition products. These spectra also indicated that the reaction of oxidized dopamine with benzene thiol was signi®cantly faster than the intermolecular cyclization reaction of this intermediate, which normally produces 5,6-dihydroxyindoline.
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