Catalytic RNAs – molecular fossils of the RNA world

Katalitičke RNA se ubrajaju u skupinu bioloških katalizatora, u koju spadaju i mnogo rašireniji, efikasniji i mlađi proteinski enzimi. Okosnica molekule RNA je gusto negativno nabijena s vrlo fleksibilnim vezama, a funkcionalne skupine za katalizu su malobrojne i monotone. Ipak, RNA katalizira nekoliko centralnih staničnih reakcija koristeći najviše katalizu metalnim ionima i kiselinsko-baznu katalizu, ali i doprinos vezne energije, elektrostatsku katalizu, kovalentnu, te ponekad čak i organske kofaktore i sam supstrat kao pomoć u katalizi. Mali ribozimi (hammerhead, hairpin i HDV) cijepaju sami sebe koristeći kao nukleofil 2'-OH riboze na čijem se 3' kraju nalazi veza koja podliježe cijepanju. Veliki ribozimi (introni grupe I i II) koriste hidroksilnu skupinu riboze udaljenog ili vanjskog nukleotida kao nukleofil, a sudjeluju u procesu izrezivanja introna iz pre-RNA i ligaciji eksona. U stanici postoji i nekoliko ribonukleoproteinskih kompleksa gdje RNA ima katalitičku ulogu, među kojima je najbitniji ribosom. Činjenica da RNA može sadržavati genetički zapis i omogućavati njegov kontinuitet, s jedne strane, te katalizirati kemijske reakcije, s druge, ide u prilog hipotezi o RNA-svijetu prema kojoj je ova molekula, u počecima života na Zemlji, objedinila rani metabolizam i prijenos informacije.Catalytic RNAs are biological catalysts, a group of molecules which also comprises a much bigger number of younger and more effective catalysts – the enzymes. The RNA backbone is highly negatively charged with very flexible bonds, and the functional groups are few and monotonous. However, RNA catalyzes a few biochemical reactions that are of central importance for cells, using mostly metal ion catalysis and acid-base catalysis, as well as the contribution of binding energy, electrostatic and covalent catalysis, and even sometimes using organic cofactors and the supstrate itself as a contributing factor in catalysis. Small ribozymes (the hammerhead, hairpin and HDV) are self-cleaving; they activate the 2'-OH group of the ribose adjacent to the scissile phosphate for nucleophilic attack. In large ribozymes (group I and II introns) the nucleophile is the –OH group of the ribose of a distant or even exogenous nucleotide; they catalyze intron splicing. There are also a few ribonucleoprotein complexes in the cell in which RNA is the catalytical entity. The most important is the ribosome. The fact that RNA is a molecule that can contain genetic information and allow genetic continuity, on one hand, and can catalyze chemical reactions, on the other, is supportive of the hypothesis of an RNA world in which, during the beginnings of life on Earth, RNA combined early metabolism and information transfer

Catalytic RNAs – molecular fossils of the RNA world

Katalitičke RNA se ubrajaju u skupinu bioloških katalizatora, u koju spadaju i mnogo rašireniji, efikasniji i mlađi proteinski enzimi. Okosnica molekule RNA je gusto negativno nabijena s vrlo fleksibilnim vezama, a funkcionalne skupine za katalizu su malobrojne i monotone. Ipak, RNA katalizira nekoliko centralnih staničnih reakcija koristeći najviše katalizu metalnim ionima i kiselinsko-baznu katalizu, ali i doprinos vezne energije, elektrostatsku katalizu, kovalentnu, te ponekad čak i organske kofaktore i sam supstrat kao pomoć u katalizi. Mali ribozimi (hammerhead, hairpin i HDV) cijepaju sami sebe koristeći kao nukleofil 2'-OH riboze na čijem se 3' kraju nalazi veza koja podliježe cijepanju. Veliki ribozimi (introni grupe I i II) koriste hidroksilnu skupinu riboze udaljenog ili vanjskog nukleotida kao nukleofil, a sudjeluju u procesu izrezivanja introna iz pre-RNA i ligaciji eksona. U stanici postoji i nekoliko ribonukleoproteinskih kompleksa gdje RNA ima katalitičku ulogu, među kojima je najbitniji ribosom. Činjenica da RNA može sadržavati genetički zapis i omogućavati njegov kontinuitet, s jedne strane, te katalizirati kemijske reakcije, s druge, ide u prilog hipotezi o RNA-svijetu prema kojoj je ova molekula, u počecima života na Zemlji, objedinila rani metabolizam i prijenos informacije.Catalytic RNAs are biological catalysts, a group of molecules which also comprises a much bigger number of younger and more effective catalysts – the enzymes. The RNA backbone is highly negatively charged with very flexible bonds, and the functional groups are few and monotonous. However, RNA catalyzes a few biochemical reactions that are of central importance for cells, using mostly metal ion catalysis and acid-base catalysis, as well as the contribution of binding energy, electrostatic and covalent catalysis, and even sometimes using organic cofactors and the supstrate itself as a contributing factor in catalysis. Small ribozymes (the hammerhead, hairpin and HDV) are self-cleaving; they activate the 2'-OH group of the ribose adjacent to the scissile phosphate for nucleophilic attack. In large ribozymes (group I and II introns) the nucleophile is the –OH group of the ribose of a distant or even exogenous nucleotide; they catalyze intron splicing. There are also a few ribonucleoprotein complexes in the cell in which RNA is the catalytical entity. The most important is the ribosome. The fact that RNA is a molecule that can contain genetic information and allow genetic continuity, on one hand, and can catalyze chemical reactions, on the other, is supportive of the hypothesis of an RNA world in which, during the beginnings of life on Earth, RNA combined early metabolism and information transfer

Molecular dynamics study of functionally relevant interdomain and active site interactions in the autotransporter esterase EstA from Pseudomonas aeruginosa

Enzim EstA je funkcionalno GDSL esteraza. Putuje kroz vanjsku membranu bakterije Pseudomonas aeruginosa mehanizmom Va ili autotransporterskim mehanizmom kod kojeg se katalitička domena prenosi u izvanstanični prostor uz pomoć β bačve (autotransporterske domene). U slučaju EstA β bačva i na nju vezana katalitička domena ostaje učvršćena u membrani. Biološki supstrat EstA je nepoznat, ali je poznato da je aktivnost ovog enzima povezana s pokretljivošću bakterijske stanice, stvaranjem biofilmova i produkcijom ramnogalakturonana. Kao u ostalih GDSL hidrolaza, i u aktivnom mjestu EstA se nalazi katalitička trijada i oksioanionska šupljina. U ovom radu su identificirane funkcionalno važne aminokiseline i mreža vodikovih veza u aktivnom mjestu. Uz to, opisane su hidrofobne interakcije i vodikove veze između domena. U odcijepljenoj katalitičkoj domeni je zamijećeno otvaranje aktivnog mjesta kako bi se omogućilo pristajanje tetraedarskog intermedijera, dok je u cjelovitom enzimu EstA s vezanim intermedijerom zamijećena promjena u strukturi heliksa 6 u aktivnom mjestu. Svi rezultati su temeljeni na 100 ns dugim simulacijama molekulske dinamike odcijepljene katalitičke domene i cjelovitog enzima EstA, u oba slučaja sa i bez vezanog tetraedarskog intermedijera.The enzyme EstA is functionally a GDSL esterase. It is transferred through the outer membrane of Pseudomonas aeruginosa by the type Va or autotransporter mechanism, where the transfer of the catalytic domain (the passenger) to the cell exterior is aided by the β barrel domain (the autotransporter). In EstA the barrel remains membrane embedded with the passenger bound to it. The physiological substrate of EstA is unknown, although its activity is known to be related to bacterial cell motility, biofilm formation and rhamnogalacturonan production. As a GDSL hydrolase, the active site of EstA contains a catalytic triad and oxyanion hole. Relevant active site residues, including an active site hydrogen bond network, are described in this work. In addition, interdomain hydrogen bonds and hydrophobic interactions are characterised. Active site opening to fit the tetrahedral intermediate was observed in the isolated passenger domain, while a structural perturbation of the active site helix 6 was noticed when the tetrahedral intermediate was bound in full-length EstA. All results are based on 100 ns long molecular dynamics simulations of the passenger domain of EstA and full-length membrane embedded EstA, both with and without a bound tetrahedral intermediate

Catalytic RNAs – molecular fossils of the RNA world

Katalitičke RNA se ubrajaju u skupinu bioloških katalizatora, u koju spadaju i mnogo rašireniji, efikasniji i mlađi proteinski enzimi. Okosnica molekule RNA je gusto negativno nabijena s vrlo fleksibilnim vezama, a funkcionalne skupine za katalizu su malobrojne i monotone. Ipak, RNA katalizira nekoliko centralnih staničnih reakcija koristeći najviše katalizu metalnim ionima i kiselinsko-baznu katalizu, ali i doprinos vezne energije, elektrostatsku katalizu, kovalentnu, te ponekad čak i organske kofaktore i sam supstrat kao pomoć u katalizi. Mali ribozimi (hammerhead, hairpin i HDV) cijepaju sami sebe koristeći kao nukleofil 2'-OH riboze na čijem se 3' kraju nalazi veza koja podliježe cijepanju. Veliki ribozimi (introni grupe I i II) koriste hidroksilnu skupinu riboze udaljenog ili vanjskog nukleotida kao nukleofil, a sudjeluju u procesu izrezivanja introna iz pre-RNA i ligaciji eksona. U stanici postoji i nekoliko ribonukleoproteinskih kompleksa gdje RNA ima katalitičku ulogu, među kojima je najbitniji ribosom. Činjenica da RNA može sadržavati genetički zapis i omogućavati njegov kontinuitet, s jedne strane, te katalizirati kemijske reakcije, s druge, ide u prilog hipotezi o RNA-svijetu prema kojoj je ova molekula, u počecima života na Zemlji, objedinila rani metabolizam i prijenos informacije.Catalytic RNAs are biological catalysts, a group of molecules which also comprises a much bigger number of younger and more effective catalysts – the enzymes. The RNA backbone is highly negatively charged with very flexible bonds, and the functional groups are few and monotonous. However, RNA catalyzes a few biochemical reactions that are of central importance for cells, using mostly metal ion catalysis and acid-base catalysis, as well as the contribution of binding energy, electrostatic and covalent catalysis, and even sometimes using organic cofactors and the supstrate itself as a contributing factor in catalysis. Small ribozymes (the hammerhead, hairpin and HDV) are self-cleaving; they activate the 2'-OH group of the ribose adjacent to the scissile phosphate for nucleophilic attack. In large ribozymes (group I and II introns) the nucleophile is the –OH group of the ribose of a distant or even exogenous nucleotide; they catalyze intron splicing. There are also a few ribonucleoprotein complexes in the cell in which RNA is the catalytical entity. The most important is the ribosome. The fact that RNA is a molecule that can contain genetic information and allow genetic continuity, on one hand, and can catalyze chemical reactions, on the other, is supportive of the hypothesis of an RNA world in which, during the beginnings of life on Earth, RNA combined early metabolism and information transfer

In the quest for new targets for pathogen eradication: the adenylosuccinate synthetase from the bacterium Helicobacter pylori

Adenylosuccinate synthetase (AdSS) is an enzyme at regulatory point of purine metabolism. In pathogenic organisms which utilise only the purine salvage pathway, AdSS asserts itself as a promising drug target. One of these organisms is Helicobacter pylori, a wide-spread human pathogen involved in the development of many diseases. The rate of H. pylori antibiotic resistance is on the increase, making the quest for new drugs against this pathogen more important than ever. In this context, we describe here the properties of H. pylori AdSS. This enzyme exists in a dimeric active form independently of the presence of its ligands. Its narrow stability range and pH-neutral optimal working conditions reflect the bacterium’s high level of adaptation to its living environment. Efficient inhibition of H. pylori AdSS with hadacidin and adenylosuccinate gives hope of finding novel drugs that aim at eradicating this dangerous pathogen

Multiplicity dependence of light (anti-)nuclei production in p–Pb collisions at sNN=5.02 TeV

The measurement of the deuteron and anti-deuteron production in the rapidity range −1 < y < 0 as a function of transverse momentum and event multiplicity in p–Pb collisions at √sNN = 5.02 TeV is presented. (Anti-)deuterons are identified via their specific energy loss dE/dx and via their time-of- flight. Their production in p–Pb collisions is compared to pp and Pb–Pb collisions and is discussed within the context of thermal and coalescence models. The ratio of integrated yields of deuterons to protons (d/p) shows a significant increase as a function of the charged-particle multiplicity of the event starting from values similar to those observed in pp collisions at low multiplicities and approaching those observed in Pb–Pb collisions at high multiplicities. The mean transverse particle momenta are extracted from the deuteron spectra and the values are similar to those obtained for p and particles. Thus, deuteron spectra do not follow mass ordering. This behaviour is in contrast to the trend observed for non-composite particles in p–Pb collisions. In addition, the production of the rare 3He and 3He nuclei has been studied. The spectrum corresponding to all non-single diffractive p-Pb collisions is obtained in the rapidity window −1 < y < 0 and the pT-integrated yield dN/dy is extracted. It is found that the yields of protons, deuterons, and 3He, normalised by the spin degeneracy factor, follow an exponential decrease with mass number

Measurements of the groomed and ungroomed jet angularities in pp collisions at s \sqrt{s} = 5.02 TeV

International audienceThe jet angularities are a class of jet substructure observables which characterize the angular and momentum distribution of particles within jets. These observables are sensitive to momentum scales ranging from perturbative hard scatterings to nonperturbative fragmentation into final-state hadrons. We report measurements of several groomed and ungroomed jet angularities in pp collisions at $\sqrt{s}$ = 5.02 TeV with the ALICE detector. Jets are reconstructed using charged particle tracks at midrapidity (|η| < 0.9). The anti-k$_{T}$ algorithm is used with jet resolution parameters R = 0.2 and R = 0.4 for several transverse momentum {p}_{\mathrm{T}}^{\mathrm{ch}} ^{jet} intervals in the 20–100 GeV/c range. Using the jet grooming algorithm Soft Drop, the sensitivity to softer, wide-angle processes, as well as the underlying event, can be reduced in a way which is well-controlled in theoretical calculations. We report the ungroomed jet angularities, λ$_{α}$, and groomed jet angularities, λ$_{α,g}$, to investigate the interplay between perturbative and nonperturbative effects at low jet momenta. Various angular exponent parameters α = 1, 1.5, 2, and 3 are used to systematically vary the sensitivity of the observable to collinear and soft radiation. Results are compared to analytical predictions at next-to-leading-logarithmic accuracy, which provide a generally good description of the data in the perturbative regime but exhibit discrepancies in the nonperturbative regime. Moreover, these measurements serve as a baseline for future ones in heavy-ion collisions by providing new insight into the interplay between perturbative and nonperturbative effects in the angular and momentum substructure of jets. They supply crucial guidance on the selection of jet resolution parameter, jet transverse momentum, and angular scaling variable for jet quenching studies.[graphic not available: see fulltext

Inclusive quarkonium production in pp collisions at s=5.02\sqrt{s} = 5.02 TeV

This article reports on the inclusive production cross section of several quarkonium states, $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, $\Upsilon\rm(2S)$, and $\Upsilon\rm(3S)$, measured with the ALICE detector at the LHC, in \pp collisions at $\sqrt{s} = 5.02$ TeV. The analysis is performed in the dimuon decay channel at forward rapidity ($2.5 < y < 4$). The measured cross sections, assuming unpolarized quarkonia, are: $\sigma_{\mathrm{J}/\psi} = 5.88 \pm 0.03 \pm 0.34\ \mu$b, $\sigma_{\psi {\rm (2S)}} = 0.87 \pm 0.06 \pm 0.10\ \mu$b, $\sigma_{\Upsilon\rm(1S)} = 45.5 \pm 3.9 \pm 3.5$ nb, $\sigma_{\Upsilon\rm(2S)} = 22.4 \pm 3.2 \pm 2.7$ nb, and $\sigma_{\Upsilon\rm(3S)} = 4.9 \pm 2.2 \pm 1.0$ nb, where the first (second) uncertainty is the statistical (systematic) one. The transverse-momentum ($p_{\rm T}$) and rapidity ($y$) differential cross sections for $\mathrm{J}/\psi$, $\psi {\rm (2S)}$, $\Upsilon\rm(1S)$, and the $\psi {\rm (2S)}$-to-$\mathrm{J}/\psi$ cross section ratios are presented. For the first time, the cross sections of the three $\Upsilon$ states, as well as the $\psi {\rm (2S)}$ one as a function of $p_{\rm T}$ and $y$, are measured at $\sqrt{s} = 5.02$ TeV at forward rapidity. These measurements also significantly extend the $\mathrm{J}/\psi$$p_{\rm T}$ reach with respect to previously published results. A comparison with ALICE measurements in pp collisions at $\sqrt{s} = 2.76$, 7, 8, and 13 TeV is presented and the energy dependence of quarkonium production cross sections is discussed. Finally, the results are compared with the predictions from several production models

Forward rapidity J/ψ production as a function of charged-particle multiplicity in pp collisions at s \sqrt{s} = 5.02 and 13 TeV

International audienceThe production of J/ψ is measured as a function of charged-particle multiplicity at forward rapidity in proton-proton (pp) collisions at center-of-mass energies $\sqrt{s}$ = 5.02 and 13 TeV. The J/ψ mesons are reconstructed via their decay into dimuons in the rapidity interval (2.5 < y < 4.0), whereas the charged-particle multiplicity density (dN$_{ch}$/dη) is measured at midrapidity (|η| < 1). The production rate as a function of multiplicity is reported as the ratio of the yield in a given multiplicity interval to the multiplicity-integrated one. This observable shows a linear increase with charged-particle multiplicity normalized to the corresponding average value for inelastic events (dN$_{ch}$/dη/〈dN$_{ch}$/dη〉), at both the colliding energies. Measurements are compared with available ALICE results at midrapidity and theoretical model calculations. First measurement of the mean transverse momentum (〈p$_{T}$〉) of J/ψ in pp collisions exhibits an increasing trend as a function of dN$_{ch}$/dη/〈dN$_{ch}$/dη〉 showing a saturation towards high charged-particle multiplicities.[graphic not available: see fulltext