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1.
Pandi-Perumal SR Srinivasan V Maestroni GJ Cardinali DP Poeggeler B Hardeland R 《The FEBS journal》2006,273(13):2813-2838
Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions. 相似文献
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The nuclear pore complex: a jack of all trades? 总被引:16,自引:0,他引:16
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57Fe-Mössbauer spectroscopy is a method that probes transitions between the nuclear ground state (I = 1/2) and the first nuclear excited state (I = 3/2). This technique provides detailed information about the chemical environment and electronic structure of iron. Therefore, it has played an important role in studies of the numerous iron-containing proteins and enzymes. In conjunction with the freeze-quench method, 57Fe-Mössbauer spectroscopy allows for monitoring changes of the iron site(s) during a biochemical reaction. This approach is particularly powerful for detection and characterization of reactive intermediates. Comparison of experimentally determined Mössbauer parameters to those predicted by density functional theory for hypothetical model structures can then provide detailed insight into the structures of reactive intermediates. We have recently used this methodology to study the reactions of various mononuclear non-heme-iron enzymes by trapping and characterizing several Fe(IV)-oxo reaction intermediates. In this article, we summarize these findings and demonstrate the potential of the method. 相似文献
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Peters JM 《The EMBO journal》2012,31(9):2061-2063
EMBO J
31
9, 2076–2089
March132012EMBO J
31
9, 2090–2102
March132012It is well known that somatic and germ cells use different cohesin complexes to
mediate sister chromatid cohesion, but why different isoforms of cohesin also
co-exist within somatic vertebrate cells has remained a mystery. Two papers in this
issue of The EMBO Journal have begun to address this question by analysing
mouse cells lacking SA1, an isoform of a specific cohesin subunit.When one cell divides into two, many things have to go right for the two daughter cells
to receive identical copies of their mother cell''s genome. It has long been
recognized that sister chromatid cohesion, the physical connection established during
DNA replication between newly synthesized sister DNA molecules, is one of these
essential prerequisites for proper chromosome segregation. It is this cohesion that
enables the bi-orientation of chromosomes on the mitotic or meiotic spindle, and thus
makes their symmetrical segregation possible. Cohesion is mediated by cohesin, a
multi-subunit protein complex, which is thought to connect sister DNA molecules by
embracing them as a ring (Figure 1; reviewed in Peters et al, 2008). It is well established that cohesin complexes
differ between somatic and germ cells, where they are needed for the proper separation
of sister chromatids and of homologous chromosomes, respectively. What has been largely
ignored, however, is that even within somatic vertebrate cells there are different forms
of cohesin, containing mutually exclusive variable subunits: either SA1 or the closely
related SA2 protein (also known as STAG1 and STAG2, respectively), and either Pds5A or
the related Pds5B subunit (Peters et al, 2008). Why
is that? Two papers from the Losada lab (Remeseiro et al,
2012a, 2012b) have begun to address this
question by generating mouse cells lacking the SA1 gene, revealing unexpected
insights into the functions of SA1 subunit-containing cohesin complexes
(cohesin-SA1).Open in a separate windowFigure 1Schematic drawing illustrating how the SA1 and SA2 proteins interact in a
mutually exclusive manner with three core subunits of cohesin (Smc1, Smc3,
Rad21) that form a ring-like structure. It has been proposed that these
complexes mediate cohesion by trapping the two sister DNA molecules inside
the cohesin ring (above), and that cohesin rings might affect chromatin
structure by forming or stabilizing intra-chromatid loops (below). Cohesin
is thought to influence gene regulation at least in part by mediating
chromatin looping.Although cohesin is best known for its role in sister chromatid cohesion, it is clearly
also needed for homologous recombination-mediated DNA repair and for gene regulation.
Much of what we know about these functions comes from studies in yeast and fruit flies,
organisms with only a single SA1/SA2-related mitotic subunit (Scc3 in budding yeast),
and only a single Pds5 subunit. It is therefore plausible that, like many other genes
during vertebrate evolution, SA1/SA2 and Pds5A/Pds5B have arisen by gene duplication to
constitute paralogs, with functional differences between them assumed to be subtle.
Consistently, absence of either Pds5A or Pds5B causes only mild, if any, defects in
sister chromatid cohesion, and mice lacking either protein can develop to term, although
they die shortly after birth owing to multiple organ defects (Zhang
et al, 2007, 2009). First
indications that the situation may be different for the Scc3-related subunits came from
Canudas and Smith (2009), who reported that RNAi
depletion of SA1 and SA2 from HeLa cells caused defects in telomere and centromere
cohesion, respectively. The generation of mice lacking either one or both alleles of the
SA1 gene has now allowed a more systematic and thorough analysis of SA1
function (Remeseiro et al, 2012a, 2012b).One of the most striking results obtained in these studies is that most mice lacking SA1
die around day 12 of embryonic development, clearly showing that the function of SA1
cannot be fulfilled by SA2, despite the fact that SA2 is substantially more abundant in
somatic cells than SA1 (Holzmann et al, 2010). What
could this SA1-specific function be? Losada and colleagues report observations, which
imply that SA1 does not have just one, but possibly several important functions in
different processes. First, the authors confirm the previous observation that SA1 is
required for cohesion specifically at telomeres, while likely collaborating with SA2 in
chromosome arms or centromeric regions. Furthermore, telomeres have an unusual
morphology in mitotic chromosomes lacking SA1 (Remeseiro et al,
2012a), reminiscent of a fragile-site phenotype previously reported in
telomeres with DNA replication defects (Sfeir et al,
2009), and SA1 is indeed required for efficient telomere duplication.
Depletion of sororin, a protein that is required for cohesin''s ability to mediate
sister chromatid cohesion, also causes a fragile-site phenotype at telomeres. These
findings imply that SA1''s role in telomere cohesion is important for efficient
telomere replication, perhaps, as the authors speculate, because telomere cohesion may
help to stabilize or re-start stalled replication forks, or because cohesion-dependent
homologous recombination might be involved in repair of DNA double strand breaks created
by collapsed replication forks. Interestingly, cells lacking SA1 frequently show
chromosome bridges in anaphase, often fail to divide, and either die or become
bi-nucleated. The exact origin of chromosome bridges is difficult to determine, but
previous studies have found such bridges often associated with fragile sites on
chromosomes; treatment with low doses of DNA replication inhibitors was shown to
increase the frequency of such bridges (Chan et al,
2009), and similar observations were indeed made by Remeseiro et al (2012a) in mouse embryonic fibroblasts. It is
therefore plausible that the telomere cohesion defect observed in SA1-lacking cells
leads to incomplete telomere replication, which in turn results in the formation of
anaphase chromosome bridges and subsequent cytokinesis defects. Losada and colleagues
further speculate that these chromosome segregation defects could underlie the increased
frequency of spontaneous development of various tumours in mice containing just one
instead of two SA1 alleles (Remeseiro et al, 2012a).
This is an attractive interpretation since tetraploidy and aneuploidy are thought to
contribute to the rate with which tumour cells can evolve; however, Losada and
colleagues report SA1 deficiency to cause defects also in other cohesin functions, which
may therefore as well contribute to tumour formation.To further understand why SA1 cannot be fulfilled by SA2, Losada and colleagues also
analysed the distribution of these proteins in the non-repetitive parts of the mouse
genome by chromatin immunoprecipitation coupled to deep sequencing (ChIP-seq). The
results of these experiments, published in the second of the two papers (Remeseiro et al, 2012b), raise the interesting possibility
that cohesin-SA1 associates more frequently with gene promoters than cohesin-SA2.
However, the fact that different antibodies have to be used for any ChIP-based
comparison of the distribution of two proteins makes it difficult to know to what degree
observed differences might be due to different antibody efficiency. Obviously, such
limitations do not exist if the distribution of one and the same protein is analysed
under different conditions, and in such an experimental setting, Remeseiro et al
indeed make some striking observations. When SA1 is absent, SA2 does not detectably
change in abundance, but its distribution in the genome does, in that more than half of
all SA2-binding sites in SA1-deficient cells differ from those bound in wild-type cells.
Most SA2-binding sites in SA1-deficient cells are in intergenic regions, and CTCF, a
zinc finger protein often co-localizing with cohesin and implicated in its gene
regulation function (Peters et al, 2008), appears to
be absent at many of these sites. It presently remains a mystery why cohesin-SA2 changes
its distribution so dramatically in the absence of SA1, but the observation that gene
promoters are more frequently occupied by cohesin in the presence of SA1 than in its
absence raises the possibility that cohesin-SA1 may have a specific role in gene
regulation. This possibility is particularly interesting in light of a recent study that
found hardly any change in gene expression upon re-expression of SA2 in SA2-deficient
human glioblastoma cells (Solomon et al, 2011),
despite the fact that cohesin is thought to regulate numerous genes. With this in mind,
Remeseiro et al analysed gene expression in mouse cells and indeed found 549
genes to be mis-regulated in the absence of SA1, in striking contrast to the
above-mentioned comparison of human SA2-deficient or proficient cells that found only 19
genes to change in expression levels (Solomon et al,
2011). Obviously direct comparisons will be essential to analyse further
the specific roles of SA1 and SA2 in gene regulation, but the current evidence raises
the interesting possibility that SA1 may have a particularly important role in gene
regulation, whereas cohesin-SA2 is dedicated to creating arm and centromeric cohesive
structures for chromosome segregation.That is not to say that cohesin-SA1 cannot mediate sister chromatid cohesion. It almost
certainly can, as it is essential for cohesion at telomeres (Canudas
and Smith, 2009; Remeseiro et al,
2012a). Likewise, it would be wrong to assume that we now fully understand why
SA1 and SA2 co-exist in somatic vertebrate cells, and what their precise functions is.
There are many things we do not understand. For example, if SA2 has little or no role in
gene regulation, as the Solomon et al (2011) study
implies, why does SA2 nevertheless interact directly with CTCF (Xiao
et al, 2011), its gene regulation collaborator? How do
cohesin-SA1 and cohesin-SA2 complexes further differ in their genomic distributions and
their functions depending on whether they contain either Pds5A or Pds5B, constituting
really not just two but four distinct cohesin complexes? The work by Losada and
colleagues represents an important step towards understanding these questions, but there
is still a long and presumably exciting way to go to understand how different cohesin
complexes control the mammalian genome. 相似文献
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In two landmark articles, Hanahan and Weinberg synthesized into one conceptual framework 'the hallmarks of cancer', a massive amount of information describing the characteristics of a cancer cell. Although this is neither the intention nor the belief of the authors, hallmarks are often interpreted as applying to a canonic cancer cell, or equally to all cells within a cancer. In this article, we clarify the separate concepts of causes, oncogenic events, signal transduction programs, and hallmarks to show that there is no unimodal relation between these concepts but a complex network of interrelations that vary in different cells, between cells, and at different times in any given cell. We consider cancer as an evolving, dynamic, and heterogeneous system, explaining, at least in part, the difficulty of treating cancer and supporting the use of simultaneous, multitarget therapies. 相似文献
10.
The IKK complex: an integrator of all signals that activate NF-kappaB? 总被引:17,自引:0,他引:17
Israël A 《Trends in cell biology》2000,10(4):129-133
11.
Amr Ali Ahmed Ali Attia Daniela Cioloboc Alexandru Lupan Radu Silaghi-Dumitrescu 《Journal of biological inorganic chemistry》2013,18(1):95-101
It is generally accepted that the catalytic cycles of superoxide reductases (SORs) and cytochromes P450 involve a ferric hydroperoxo intermediate at a mononuclear iron center with a coordination sphere consisting of four equatorial nitrogen ligands and one axial cysteine thiolate trans to the hydroperoxide. However, although SORs and P450s have similar intermediates, SORs selectively cleave the Fe–O bond and liberate peroxide, whereas P450s cleave the O–O bond to yield a high-valent iron center. This difference has attracted the interest of researchers, and is further explored here. Meta hybrid DFT (M06-2X) results for the reactivity of the putative peroxo/hydroperoxo reaction intermediates in the catalytic cycle of SORs were found to indicate a high-spin preference in all cases. An exploration of the energy profiles for Fe–O and O–O bond cleavage in all spin states in both ferric and ferrous models revealed that Fe–O bond cleavage always occurs more easily than O–O bond cleavage. While O–O bond cleavage appears to be thermodynamically and kinetically unfeasible in ferric hydrogen peroxide complexes, it could occur as a minor (significantly disfavored) side reaction in the interaction of ferrous SOR with hydrogen peroxide. 相似文献
12.
The β-propeller is a highly symmetrical structure with 4-10 repeats of a four-stranded antiparallel β-sheet motif. Although β-propeller proteins with different blade numbers all adopt disc-like shapes, they are involved in a diverse set of functions, and defects in this family of proteins have been associated with human diseases. However, it has remained ambiguous how variations in blade number could alter the function of β-propellers. In addition to the regularly arranged β-propeller topology, a recently discovered β-pinwheel propeller has been found. Here, we review the structural and functional diversity of β-propeller proteins, including β-pinwheels, as well as recent advances in the typical and atypical propeller structures. 相似文献
13.
Kinetic competence of enzymic intermediates: fact or fiction? 总被引:2,自引:0,他引:2
W W Cleland 《Biochemistry》1990,29(13):3194-3197
A number of enzymatic reactions involve intermediates that are not normally released during the reaction. Whether such an intermediate when added to the enzyme reacts as fast or faster than the normal substrates, and thus is "kinetically competent", depends on the degree to which the equilibrium constant for forming the intermediate from the substrates is different on the enzyme surface and in solution, as well as on the relative affinities of the enzyme for substrate and intermediate. Similar values for these equilibrium constants require that the intermediate react slowly, while a far more favorable value for intermediate formation on the enzyme allows the intermediate to react at up to the diffusion-limiting rate. When one intermediate is formed from two substrates, it may react much more rapidly than when two intermediates are formed from two substrates, or one from one. Comparison of the kinetics of the putative intermediate(s) and the substrate(s) can reveal a great deal about the mechanism of the catalytic reaction and the kinetic barrier that normally keeps the intermediate(s) on the enzyme. 相似文献
14.
Summary. The paper describes the synthesis of α-aminosuberic acid derivatives suitable for the synthesis of peptides. These include Z-, Boc- and Fmoc-protection on the α-amino group, benzyl ester, Boc-hydrazide and Z-hydrazide as well as the free carboxylic function in the side chain, and methyl
ester, benzyl ester or free α-carboxylic group. Their use is demonstrated on the synthesis of the respective derivatives of Asu-Val-Leu. The enzyme catalyzed
reaction was succesfully used both as a route to L-Asu from the D,L-compound as well as for the direct synthesis of the optically
active tripeptide derivative from the Z-D,L-Asu-OH.
Received February 5, 1999 相似文献
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Jonathan C. K. Wells 《Disease models & mechanisms》2012,5(5):595-607
Because obesity is associated with diverse chronic diseases, little attention has been directed to the multiple beneficial functions of adipose tissue. Adipose tissue not only provides energy for growth, reproduction and immune function, but also secretes and receives diverse signaling molecules that coordinate energy allocation between these functions in response to ecological conditions. Importantly, many relevant ecological cues act on growth and physique, with adiposity responding as a counterbalancing risk management strategy. The large number of individual alleles associated with adipose tissue illustrates its integration with diverse metabolic pathways. However, phenotypic variation in age, sex, ethnicity and social status is further associated with different strategies for storing and using energy. Adiposity therefore represents a key means of phenotypic flexibility within and across generations, enabling a coherent life-history strategy in the face of ecological stochasticity. The sensitivity of numerous metabolic pathways to ecological cues makes our species vulnerable to manipulative globalized economic forces. The aim of this article is to understand how human adipose tissue biology interacts with modern environmental pressures to generate excess weight gain and obesity. The disease component of obesity might lie not in adipose tissue itself, but in its perturbation by our modern industrialized niche. Efforts to combat obesity could be more effective if they prioritized ‘external’ environmental change rather than attempting to manipulate ‘internal’ biology through pharmaceutical or behavioral means. 相似文献
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A key step for the success of meiosis is programmed homologous recombination, during which crossovers, or exchange of chromosome arms, take place. Crossovers increase genetic diversity but their main function is to ensure accurate chromosome segregation. Defects in crossover number and position produce aneuploidies that represent the main cause of miscarriages and chromosomal abnormalities such as Down's syndrome. Recombination is initiated by the formation of programmed double strand breaks (DSBs), which occur preferentially at places called DSB hotspots. Among all DSBs generated, only a small fraction is repaired by crossover, the other being repaired by other homologous recombination pathways. Crossover maps have been generated in a number of organisms, defining crossover hotspots. With the availability of genome-wide maps of DSBs as well as the ability to measure genetically the repair outcome at several hotspots, it is becoming more and more clear that not all DSB hotspots behave the same for crossover formation, suggesting that chromosomal features distinguish different types of hotspots. 相似文献
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Where does all the carbon go? The missing sink 总被引:1,自引:1,他引:0
Elise Pendall 《The New phytologist》2002,153(2):207-210