38 research outputs found
Four of a Kind: A Complete Collection of ADP-Ribosylated Histidine Isosteres Using Cu(I)- and Ru(II)-Catalyzed Click Chemistry
This is the final version. Available from American Chemical Society via the DOI in this record.âŻThe data underlying this study are available in the published article and its online Supporting Material. The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c00827.Adenosine diphosphate ribosylation (ADP-ribosylation) is a crucial post-translational modification involved in important regulatory mechanisms of numerous cellular pathways including histone maintenance and DNA damage repair. To study this modification, well-defined ADP-ribosylated peptides, proteins, and close analogues thereof have been invaluable tools. Recently, proteomics studies have revealed histidine residues to be ADP-ribosylated. We describe here the synthesis of a complete set of triazole-isosteres of ADP-ribosylated histidine to serve as probes for ADP-ribosylating biomachinery. By exploiting Cu(I)- and Ru(II)-catalyzed click chemistry between a propargylglycine building block and an α- or ÎČ-configured azidoribose, we have successfully assembled the α- and ÎČ-configured 1,4- and 1,5-triazoles, mimicking N(Ï)- and N(Ï)-ADP-ribosylated histidine, respectively. The ribosylated building blocks could be incorporated into a peptide sequence using standard solid-phase peptide synthesis and transformed on resin into the ADP-ribosylated fragments to provide a total of four ADP-ribosyl triazole conjugates, which were evaluated for their chemical and enzymatic stability. The 1,5-triazole analogues mimicking the N(Ï)-substituted histidines proved susceptible to base-induced epimerization and the ADP-ribosyl α-1,5-triazole linkage could be cleaved by the (ADP-ribosyl)hydrolase ARH3.Biotechnology and Biological Sciences Research Council (BBSRC)Wellcome TrustWellcome TrustOvarian Cancer Research Allianc
The Formation and Evolution of the First Massive Black Holes
The first massive astrophysical black holes likely formed at high redshifts
(z>10) at the centers of low mass (~10^6 Msun) dark matter concentrations.
These black holes grow by mergers and gas accretion, evolve into the population
of bright quasars observed at lower redshifts, and eventually leave the
supermassive black hole remnants that are ubiquitous at the centers of galaxies
in the nearby universe. The astrophysical processes responsible for the
formation of the earliest seed black holes are poorly understood. The purpose
of this review is threefold: (1) to describe theoretical expectations for the
formation and growth of the earliest black holes within the general paradigm of
hierarchical cold dark matter cosmologies, (2) to summarize several relevant
recent observations that have implications for the formation of the earliest
black holes, and (3) to look into the future and assess the power of
forthcoming observations to probe the physics of the first active galactic
nuclei.Comment: 39 pages, review for "Supermassive Black Holes in the Distant
Universe", Ed. A. J. Barger, Kluwer Academic Publisher
The Formation of the First Massive Black Holes
Supermassive black holes (SMBHs) are common in local galactic nuclei, and
SMBHs as massive as several billion solar masses already exist at redshift z=6.
These earliest SMBHs may grow by the combination of radiation-pressure-limited
accretion and mergers of stellar-mass seed BHs, left behind by the first
generation of metal-free stars, or may be formed by more rapid direct collapse
of gas in rare special environments where dense gas can accumulate without
first fragmenting into stars. This chapter offers a review of these two
competing scenarios, as well as some more exotic alternative ideas. It also
briefly discusses how the different models may be distinguished in the future
by observations with JWST, (e)LISA and other instruments.Comment: 47 pages with 306 references; this review is a chapter in "The First
Galaxies - Theoretical Predictions and Observational Clues", Springer
Astrophysics and Space Science Library, Eds. T. Wiklind, V. Bromm & B.
Mobasher, in pres
Dark Matter in the Milky Way's Dwarf Spheroidal Satellites
The Milky Way's dwarf spheroidal satellites include the nearest, smallest and
least luminous galaxies known. They also exhibit the largest discrepancies
between dynamical and luminous masses. This article reviews the development of
empirical constraints on the structure and kinematics of dSph stellar
populations and discusses how this phenomenology translates into constraints on
the amount and distribution of dark matter within dSphs. Some implications for
cosmology and the particle nature of dark matter are discussed, and some
topics/questions for future study are identified.Comment: A version with full-resolution figures is available at
http://www.cfa.harvard.edu/~mwalker/mwdsph_review.pdf; 70 pages, 22 figures;
invited review article to be published in Vol. 5 of the book "Planets, Stars,
and Stellar Systems", published by Springe
Relativistic Dynamics and Extreme Mass Ratio Inspirals
It is now well-established that a dark, compact object (DCO), very likely a
massive black hole (MBH) of around four million solar masses is lurking at the
centre of the Milky Way. While a consensus is emerging about the origin and
growth of supermassive black holes (with masses larger than a billion solar
masses), MBHs with smaller masses, such as the one in our galactic centre,
remain understudied and enigmatic. The key to understanding these holes - how
some of them grow by orders of magnitude in mass - lies in understanding the
dynamics of the stars in the galactic neighbourhood. Stars interact with the
central MBH primarily through their gradual inspiral due to the emission of
gravitational radiation. Also stars produce gases which will subsequently be
accreted by the MBH through collisions and disruptions brought about by the
strong central tidal field. Such processes can contribute significantly to the
mass of the MBH and progress in understanding them requires theoretical work in
preparation for future gravitational radiation millihertz missions and X-ray
observatories. In particular, a unique probe of these regions is the
gravitational radiation that is emitted by some compact stars very close to the
black holes and which could be surveyed by a millihertz gravitational wave
interferometer scrutinizing the range of masses fundamental to understanding
the origin and growth of supermassive black holes. By extracting the
information carried by the gravitational radiation, we can determine the mass
and spin of the central MBH with unprecedented precision and we can determine
how the holes "eat" stars that happen to be near them.Comment: Update from the first version, 151 pages, accepted for publication @
Living Reviews in Relativit
Relativistic Binaries in Globular Clusters
Galactic globular clusters are old, dense star systems typically containing
10\super{4}--10\super{7} stars. As an old population of stars, globular
clusters contain many collapsed and degenerate objects. As a dense population
of stars, globular clusters are the scene of many interesting close dynamical
interactions between stars. These dynamical interactions can alter the
evolution of individual stars and can produce tight binary systems containing
one or two compact objects. In this review, we discuss theoretical models of
globular cluster evolution and binary evolution, techniques for simulating this
evolution that leads to relativistic binaries, and current and possible future
observational evidence for this population. Our discussion of globular cluster
evolution will focus on the processes that boost the production of hard binary
systems and the subsequent interaction of these binaries that can alter the
properties of both bodies and can lead to exotic objects. Direct {\it N}-body
integrations and Fokker--Planck simulations of the evolution of globular
clusters that incorporate tidal interactions and lead to predictions of
relativistic binary populations are also discussed. We discuss the current
observational evidence for cataclysmic variables, millisecond pulsars, and
low-mass X-ray binaries as well as possible future detection of relativistic
binaries with gravitational radiation.Comment: 88 pages, 13 figures. Submitted update of Living Reviews articl
Probing the proteasome cavity in three steps: bio-orthogonal photo-reactive suicide substrates.
Tri-functional activity-based protein probes that encompass an electrophilic trap, a photo-reactive group and a bio-orthogonal ligation handle are described. With these, and in a three-step chemical proteomics approach, proteasomal catalytic sites are covalently and irreversibly modified, followed by photocrosslinking of these to flanking subunits and Staudinger-Bertozzi ligation for visualization and identification of the resulting conjugates
SolidâPhase Synthesis and Biological Evaluation of Peptides ADPâribosylated at Histidine
This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordThe transfer of an adenosine diphosphate (ADP) ribose moiety to a nucleophilic side chain by consumption of nicotinamide adenine dinucleotide is referred to as ADP-ribosylation, which allows for the spatiotemporal regulation of vital processes such as apoptosis and DNA repair. Recent mass-spectrometry based analyses of the âADP-ribosylomeâ have identified histidine as ADP-ribose acceptor site. In order to study this modification, a fully synthetic strategy towards α-configured N(Ï)- and N(Ï)-ADP-ribosylated histidine-containing peptides has been developed. Ribofuranosylated histidine building blocks were obtained via Mukaiyama-type glycosylation and the building blocks were integrated into an ADP-ribosylome derived peptide sequence using fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase peptide synthesis. On-resin installation of the ADP moiety was achieved using phosphoramidite chemistry, and global deprotection provided the desired ADP-ribosylated oligopeptides. The stability under various chemical conditions and resistance against (ADP-ribosyl) hydrolase-mediated degradation has been investigated to reveal that the constructs are stable under various chemical conditions and non-degradable by any of the known ADP-ribosylhydrolases.Medical Research Council (MRC)National Institute for Health and Care Research (NIHR)Wellcome TrustBiotechnology and Biological Sciences Research Council (BBSRC)Cancer Research UKOvarian Cancer Research Allianc