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Merlino A Howes BD Prisco Gd Verde C Smulevich G Mazzarella L Vergara A 《IUBMB life》2011,63(5):295-303
Spectroscopic and crystallographic evidence of endogenous (His) ligation at the sixth coordination site of the heme iron has been reported for monomeric, dimeric, and tetrameric hemoglobins (Hbs) in both ferrous (hemochrome) and ferric (hemichrome) oxidation states. In particular, the ferric bis- histidyl adduct represents a common accessible ordered state for the β chains of all tetrameric Hbs isolated from Antarctic and sub-Antarctic fish. Indeed, the crystal structures of known tetrameric Hbs in the bis-His state are characterized by a different binding state of the α and β chains. An overall analysis of the bis-histidyl adduct of globin structures deposited in the Protein Data Bank reveals a marked difference between hemichromes in tetrameric Hbs compared to monomeric/dimeric Hbs. Herein, we review the structural, spectroscopic and stability features of hemichromes in tetrameric Antarctic fish Hbs. The role of bis-histidyl adducts is also addressed in a more evolutionary context alongside the concept of its potential physiological role. 相似文献
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Andrea Renzetti Antonello Di Crescenzo Feilin Nie Andrew D. Bond Stéphane Gérard Janos Sapi Antonella Fontana Claudio Villani 《Chirality》2015,27(11):779-783
The three‐component reaction of indole, isobutyraldehyde, and methyl acetoacetate affords methyl 2‐(acetyl)‐3‐(1H‐indol‐3‐yl)‐4‐methylpentanoate as a single diastereomer. To investigate the origin of the observed diastereoselectivity, the thermodynamics and kinetics of interconversion of diastereomers 1 and 2 in solution were studied by a combination of 1H nuclear magnetic resonance (NMR) spectroscopy, high‐performance liquid chromatography (HPLC), mass spectrometry, and deuteration experiments. The results indicate that interconversion is both acid‐ and base‐catalyzed, and that the alpha carbon is the only stereolabile center in the molecule. The evidence points to an enolization mechanism for the interconversion process. The selective precipitation of 1 in the presence of the equilibrium 1 ? 2 eventually results in the exclusive formation of 1 (crystallization‐induced asymmetric transformation). Chirality 27:779–783, 2015. © 2015 Wiley Periodicals, Inc. 相似文献
76.
Stefano Mazzoleni Fabrizio Cartenì Giuliano Bonanomi Guido Incerti Maria Luisa Chiusano Pasquale Termolino Antonello Migliozzi Mauro Senatore Francesco Giannino Max Rietkerk Antonio Risitano Virginia Lanzotti 《Phytochemistry Reviews》2014,13(4):937-946
The research for new products against pathogens, parasites and infesting species, in both agriculture and medicine, implies huge and increasing scientific, industrial and economic efforts. Traditional approaches are based on random screening procedures searching for bioactive compounds. However, the success of such methodologies in most cases has been strongly limited by side-effects of the potential new drugs, especially toxicity and pharmacological resistance. The use of nucleic acids in drug development has been introduced searching for target-specific effect. In addition, a recent discovery revealed that randomly fragmented extracellular self-DNA may act as highly species-specific inhibitory product for different species, suggesting an unprecedented use of DNA for biological control. On this base, a new scenario of pharmacological applications is discussed. 相似文献
77.
Antonello Merlino Irene Russo Krauss Immacolata Castellano Maria Rosaria Ruocco Alessandra Capasso Emmanuele De Vendittis Bianca Rossi Filomena Sica 《Biochimica et Biophysica Acta - Proteins and Proteomics》2014,1844(3):632-640
A peculiar feature of the psychrophilic iron superoxide dismutase from Pseudoalteromonas haloplanktis (PhSOD) is the presence in its amino acid sequence of a reactive cysteine (Cys57). To define the role of this residue, a structural characterization of the effect of two PhSOD mutations, C57S and C57R, was performed. Thermal and denaturant-induced unfolding of wild type and mutant PhSOD followed by circular dichroism and fluorescence studies revealed that C→R substitution alters the thermal stability and the resistance against denaturants of the enzyme, whereas C57S only alters the stability of the protein against urea. The crystallographic data on the C57R mutation suggest an involvement of the Arg side chain in the formation of salt bridges on protein surface. These findings support the hypothesis that the thermal resistance of PhSOD relies on optimization of charge–charge interactions on its surface. Our study contributes to a deeper understanding of the denaturation mechanism of superoxide dismutases, suggesting the presence of a structural dimeric intermediate between the native state and the unfolded state. This hypothesis is supported by the crystalline and solution data on the reduced form of the enzyme. 相似文献
78.
Bovine pancreatic ribonuclease (RNase A) forms two 3-dimensional domain-swapped dimers with different quaternary structures. One dimer is characterized by the swapping of the C-terminal region (C-Dimer) and presents a rather loose structure. The other dimer (N-Dimer) exhibits a very compact structure with exchange of the N-terminal helix. Here we report the results of a molecular dynamics/essential dynamics (MD/ED) study carried out on the N-Dimer. This investigation, which represents the first MD/ED analysis on a three-dimensional domain-swapped enzyme, provides information on the dynamic properties of the active site residues as well as on the global motions of the dimer subunits. In particular, the analysis of the flexibility of the active site residues agrees well with recent crystallographic and site-directed mutagenesis studies on monomeric RNase A, thus indicating that domain swapping does not affect the dynamics of the active sites. A slight but significant rearrangement of N-Dimer quaternary structure, favored by the formation of additional hydrogen bonds at subunit interface, has been observed during the MD simulation. The analysis of collective movements reveals that each subunit of the dimer retains the functional breathing motion observed for RNase A. Interestingly, the breathing motion of the two subunits is dynamically coupled, as they open and close in phase. These correlated motions indicate the presence of active site intercommunications in this dimer. On these bases, we propose a speculative mechanism that may explain negative cooperativity in systems preserving structural symmetry during the allosteric transitions. 相似文献
79.
Pellegrini S Censini S Guidotti S Iacopetti P Rocchi M Bianchi M Covacci A Gabrielli F 《Biochimica et biophysica acta》2002,1574(3):215-222
We have previously described the cloning of Hep27, a short-chain dehydrogenase/reductase, which is synthesized in human hepatoblastoma HepG2 cells following growth arrest induced by butyrate treatment. The present report describes the cloning, the structure and the physical and cytogenetic mapping of the gene coding for Hep27. We also show that Hep27 is synthesized in a limited number of human normal tissues and that it is localized in the nuclei and cytoplasm of HepG2 cells. 相似文献
80.
Ingallinella P Fattori D Altamura S Steinkühler C Koch U Cicero D Bazzo R Cortese R Bianchi E Pessi A 《Biochemistry》2002,41(17):5483-5492
Serine proteases are the most studied class of proteolytic enzymes and a primary target for drug discovery. Despite the large number of inhibitors developed so far, very few make contact with the prime site of the enzyme, which constitutes an almost untapped opportunity for drug design. In the course of our studies on the serine protease NS3/4A of hepatitis C virus (HCV), we found that this enzyme is an excellent example of both the opportunities and the challenges of such design. We had previously reported on two classes of peptide inhibitors of the enzyme: (a) product inhibitors, which include the P(6)-P(1) region of the substrate and derive much of their binding energy from binding of their C-terminal carboxylate in the active site, and (b) decapeptide inhibitors, which span the S(6)-S(4)' subsites of the enzyme, whose P(2)'-P(4)' tripeptide fragment crucially contributes to potency. Here we report on further work, which combined the key binding elements of the two series and led to the development of inhibitors binding exclusively to the prime site of NS3/4A. We prepared a small combinatorial library of tripeptides, capped with a variety of constrained and unconstrained diacids. The SAR was derived from multiple analogues of the initial micromolar lead. Binding of the inhibitor(s) to the enzyme was further characterized by circular dichroism, site-directed mutagenesis, a probe displacement assay, and NMR to unequivocally prove that, according to our design, the bound inhibitor(s) occupies (occupy) the S' subsite and the active site of the protease. In addition, on the basis of the information collected, the tripeptide series was evolved toward reduced peptide character, reduced molecular weight, and higher potency. Beyond their interest as HCV antivirals, these compounds represent the first example of prime site inhibitors of a serine protease. We further suggest that the design of an inhibitor with an analogous binding mode may be possible for other serine proteases. 相似文献