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1.
M. V. Nogués M. Moussaoui E. Boix M. Vilanova M. Ribó C. M. Cuchillo 《Cellular and molecular life sciences : CMLS》1998,54(8):766-774
The enzymatic catalysis of polymeric substrates such as proteins, polysaccharides or nucleic acids requires precise alignment
between the enzyme and the substrate regions flanking the region occupying the active site. In the case of ribonucleases,
enzyme-substrate binding may be directed by electrostatic interactions between the phosphate groups of the RNA molecule and
basic amino acid residues on the enzyme. Specific interactions between the nitrogenated bases and particular amino acids in
the active site or adjacent positions may also take place. The substrate-binding subsites of ribonuclease A have been characterized
by structural and kinetic studies. In addition to the active site (p1 ), the role of other noncatalytic phosphate-binding subsites in the correct alignment of the polymeric substrate has been
proposed. p2 and p0 have been described as phosphate-binding subsites that bind the phosphate group adjacent to the 3′ side and 5′ side, respectively,
of the phosphate in the active site. In both cases, basic amino acids (Lys-7 and Arg-10 in p2 , and Lys-66 in p0 ) are involved in binding. However, these binding sites play different roles in the catalytic process of ribonuclease A.
The electrostatic interactions in p2 are important both in catalysis and in the endonuclease activity of the enzyme, whilst the p0 electrostatic interaction contributes only to binding of the RNA. 相似文献
2.
γ-Secretase is a promiscuous protease that cleaves bitopic membrane proteins within the lipid bilayer. Elucidating both the
mechanistic basis of γ-secretase proteolysis and the precise factors regulating substrate identification is important because
modulation of this biochemical degradative process can have important consequences in a physiological and pathophysiological
context. Here, we briefly review such information for all major classes of intramembranously cleaving proteases (I-CLiPs),
with an emphasis on γ-secretase, an I-CLiP closely linked to the etiology of Alzheimer’s disease. A large body of emerging
data allows us to survey the substrates of γ-secretase to ascertain the conformational features that predispose a peptide
to cleavage by this enigmatic protease. Because substrate specificity in vivo is closely linked to the relative subcellular compartmentalization of γ-secretase and its substrates, we also survey the
voluminous body of literature concerning the traffic of γ-secretase and its most prominent substrate, the amyloid precursor
protein.
Received 4 October 2007; received after revision 1 December 2007; accepted 7 December 2007 相似文献
3.
Hurtaud C Gelly C Bouillaud F Lévi-Meyrueis C 《Cellular and molecular life sciences : CMLS》2006,63(15):1780-1789
Uncoupling protein 2 (UCP2) belongs to a family of transporters of the mitochondrial inner membrane. In vivo low expression of UCP2 contrasts with a high UCP2 mRNA level, and induction of UCP2 expression occurs without change in mRNA
level, demonstrating a translational control. The UCP2 mRNA is characterized by a long 5′ untranslated region (5′UTR), in
which an upstream open reading frame (uORF) codes for a 36-amino-acid sequence. The 5′UTR and uORF have an inhibitory role
in the translation of UCP2. The present study demonstrates that the 3′ region of the uORF is a major determinant for this
inhibitory role. In this 3′ region, a single-base substitution that kept the codon sense unchanged significantly modified
UCP2 translation, whereas some important amino acid changes had no effect. We discuss our results within the framework of
the existing models explaining initiation of translation downstream of a uORF.
Received 22 March 2006; received after revision 19 May 2006; accepted 8 June 2006
C. Hurtaud and C. Gelly contributed equally to this work. 相似文献
4.
Polyphenolic phytochemicals are ubiquitous in plants, in which they function in various protective roles. A ‘recommended’
human diet contains significant quantities of polyphenolics, as they have long been assumed to be ‘antioxidants’ that scavenge
excessive, damaging, free radicals arising from normal metabolic processes. There is recent evidence that polyphenolics also
have ‘indirect’ antioxidant effects through induction of endogenous protective enzymes. There is also increasing evidence
for many potential benefits through polyphenolic-mediated regulation of cellular processes such as inflammation. Inductive
or signalling effects may occur at concentrations much lower than required for effective radical scavenging. Over the last
2 – 3 years, there have been many exciting new developments in the elucidation of the in vivo mechanisms of the health benefits of polyphenolics. We summarise the current knowledge of the intake, bio-availability and
metabolism of polyphenolics, their antioxidant effects, regulatory effects on signalling pathways, neuro-protective effects
and regulatory effects on energy metabolism and gut health.
Received 14 May 2007; received after revision 27 June 2007; accepted 24 July 2007 相似文献
5.
6.
Hippocrates’ assertion that ‘what the lance does not heal, fire will’ underscores the fact that for thousands of years heat
has been used to treat a variety of diseases, including cancer. Indeed, spontaneous tumor remission has been observed in patients
following feverish infection [1], and expression of activated oncogenes, such as Ras, can render tumor cells sensitive to
heat compared with normal cells [2, 3]. In the past, a primary drawback to the use of heat as a clinical therapy was the inability
to selectively focus heat to tumors in situ. Of late, however, several approaches have been devised to deliver heat more precisely, including the use of heated nanoparticles,
making hyperthermia a more clinically tractable treatment option [4, 5]. Despite these practical advances, the mechanisms
responsible for heat shock-induced cell death remain controversial and ill-defined. In this Visions and Reflections we discuss recent findings surrounding the initiation of heat shock-induced apoptosis, and propose future areas of research.
Received 17 March 2007; received after revision 25 April 2007; accepted 22 May 2007 相似文献
7.
Golgi-endomannosidase provides an alternate glucosidase-independent pathway of glucose trimming. Activity for endomannosidase
is detectable in various tissues and cell lines but not in CHO cells. Cloning of CHO cell endomannosidase revealed that the
highly conserved Trp188 and Arg177 of vertebrate endomannosidase were both substituted by Cys. The Trp188Cys substitution
was functionally important since it alone resulted in endoplasmic reticulum (ER) mislocalization of endomannosidase and caused
the greatly reduced in vivo activity. These effects could be reversed in cells with a back-engineered Cys188Trp CHO cell endomannosidase, in particular
N-glycans of α1-antitrypsin became fully processed. The intramolecular disulfide bridge of CHO cell endomannosidase formed
with the additional Cys188 was not solely responsible for the reduced enzyme activity since endomannosidase with engineered
Cys188Ala or Ser substitutions did not restore enzyme activity and was ER mislocalized. Thus, the conserved Trp188 residue
in endomannosidases is of critical importance for correct subcellular localization and in vivo activity of the enzyme.
Received 7 May 2007; received after revision 31 May 2007; accepted 11 June 2007 相似文献
8.
The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen 总被引:1,自引:1,他引:0
The life of aerobes is dependent on iron and oxygen for efficient bioenergetics. Due to potential risks associated with iron/oxygen
chemistry, iron acquisition, concentration, storage, utilization, and efflux are tightly regulated in the cell. A central
role in regulating iron/oxygen chemistry in animals is played by mRNA translation or turnover via the iron responsive element
(IRE)/iron regulatory protein (IRP) system. The IRE family is composed of three-dimensional RNA structures located in 3′ or
5′ untranslated regions of mRNA. To date, there are 11 different IRE mRNAs in the family, regulated through translation initiation
or mRNA stability. Iron or oxidant stimuli induce a set of graded responses related to mRNA-specific IRE substructures, indicated
by differential responses to iron in vivo and binding IRPs in vitro. Molecular effects of phosphorylation, iron and oxygen remain to be added to the structural information of the IRE-RNA and
IRP repressor in the regulatory complex.
Received 21 April 2007; received after revision 13 July 2007; accepted 2 August 2007 相似文献
9.
Bhavani S. Sahu Parshuram J. Sonawane Nitish R. Mahapatra 《Cellular and molecular life sciences : CMLS》2010,67(6):861-874
Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues.
Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states
including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive
peptides such as vasostatin-I (human CHGA1–76) and catestatin (human CHGA352–372) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but catestatin is diminished in EH. Moreover,
genetic variants in the promoter, catestatin, and 3′-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe
arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes
CHGA as a novel susceptibility gene for EH. 相似文献
10.
Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development 总被引:12,自引:0,他引:12
Kageyama T 《Cellular and molecular life sciences : CMLS》2002,59(2):288-306
Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and
prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined
to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin,
and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly
bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function
as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds
autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly,
and a stepwise pathway through a pseudopepsin(s). The active-site cleft is large enough to accommodate at least seven residues
of a substrate, thus forming S4 through S3′ subsites. Hydrophobic and aromatic amino acids are preferred at the P1 and P1′ positions. Interactions at additional subsites are important in some cases, for example with cleavage of κ-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate
in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression
from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors,
including steroid hormones.
Received 25 May 2001; received after revision 27 August 2001; accepted 30 August 2001 相似文献
11.
T. Yamada K. Kageyama Y. Joh J. Konishi K. Ienaga 《Cellular and molecular life sciences : CMLS》1998,54(2):125-128
2′-O-Methylinosine (1) has been isolated for the first time and shown to be an intrinsic hypotensive principle. Its probable in vivo precursor,
2′-O-methyladenosine (3), showed stronger and even orally potent hypotensive activity. Resistance of the methyladenosine (3) against adenosine deaminase is thought to contribute to its long-lasting activity. The effect of both nucleosides (1 and 3) was not accompanied with any significant change in heart rate, which is often observed with adenosine.
Received 2 October 1997; accepted 28 October 1997 相似文献
12.
Hellgren M Strömberg P Gallego O Martras S Farrés J Persson B Parés X Höög JO 《Cellular and molecular life sciences : CMLS》2007,64(4):498-505
The metabolism of all-trans- and 9-cis-retinol/ retinaldehyde has been investigated with focus on the activities of human, mouse and rat alcohol dehydrogenase 2
(ADH2), an intriguing enzyme with apparently different functions in human and rodents. Kinetic constants were determined with
an HPLC method and a structural approach was implemented by in silico substrate dockings. For human ADH2, the determined Km values ranged from 0.05 to 0.3 μM and kcat values from 2.3 to 17.6 min−1, while the catalytic efficiency for 9-cis-retinol showed the highest value for any substrate. In contrast, poor activities
were detected for the rodent enzymes. A mouse ADH2 mutant (ADH2Pro47His) was studied that resembles the human ADH2 setup.
This mutation increased the retinoid activity up to 100-fold. The Km values of human ADH2 are the lowest among all known human retinol dehydrogenases, which clearly support a role in hepatic
retinol oxidation at physiological concentrations.
Received 12 October 2006; received after revision 6 December 2006; accepted 8 January 2007 相似文献
13.
In the hepatitis delta virus, ribozymes are encoded in both the genomic strand RNA and its complement, the antigenomic strand.
The two ribozymes are similar in sequence and structure, are most active in the presence of divalent cation and catalyze RNA
cleavage reactions which generate a 5′-hydroxyl group and a 2′,3′-cyclic phosphate group. Recent progress has been made in
understanding the catalytic mechanism. One key was a crystal structure of the genomic ribozyme that revealed a specific cytosine
positioned to act as a general acid-base catalyst. The folding of the ribozyme in the context of the longer viral RNA is another
area of interest. The biology requires that each ribozyme act only once, and mechanisms proposed for regulation of ribozyme
activity sometimes invoke alternative RNA structures. Likewise, interference of ribozyme function by polyadenylation of the
antigenomic RNA strand could be controlled through alternative structures, and a model for such control is proposed.
Received 21 June 2001; received after revision 18 July 2001; accepted 20 July 2001 相似文献
14.
Roglio I Bianchi R Giatti S Cavaletti G Caruso D Scurati S Crippa D Garcia-Segura LM Camozzi F Lauria G Melcangi RC 《Cellular and molecular life sciences : CMLS》2007,64(9):1158-1168
In this study we have assessed the effect of testosterone (T), dihydrotestosterone (DHT) and 5αandrostan-3α, 17β-diol (3α-diol)
therapies on diabetic neuropathy. Diabetes was induced in adult male rats by the injection of streptozotocin and resulted
in decreased T and increased 3α-diol levels in plasma and in decreased levels of pregnenolone and DHT in the sciatic nerve.
Moreover, a reduced expression of the enzyme converting Tinto DHT (i.e., the 5α-reductase) also occurs at the level of sciatic nerve, suggesting that the decrease of DHT levels could be due to
an impairment of this enzyme. Chronic treatment for 1 month with DHT or 3α-diol increased tail nerve conduction velocity and
partially counteracted the increase of thermal threshold induced by diabetes. Treatment with DHT increased tibial Na+,K+-ATPase activity and the expression of myelin protein P0 in the sciatic nerve.DHT, 3α-diol and T reversed the reduction of
intra-epidermal nerve fiber density induced by diabetes. These observations indicate that T metabolites can reverse behavioral,
neurophysiological, morphological and biochemical alterations induced by peripheral diabetic neuropathy.
I. Roglio, R. Bianchi: These authors contributed equally to this study.
Received 4 January 2007; received after revision 13 February 2007; accepted 27 March 2007 相似文献
15.
The polypyrimidine tract binding protein (PTB) is a 58-kDa RNA binding protein involved in multiple aspects of mRNA metabolism
including splicing regulation, polyadenylation, 3′end formation, internal ribosomal entry site-mediated translation, RNA localization
and stability. PTB contains four RNA recognition motifs (RRMs) separated by three linkers. In this review we summarize structural
information on PTB in solution that has been gathered during the past 7 years using NMR spectroscopy and small-angle X-ray
scattering. The structures of all RRMs of PTB in their free state and in complex with short pyrimidine tracts, as well as
a structural model of PTB RRM2 in complex with a peptide, revealed unusual structural features that provided new insights
into the mechanisms of action of PTB in the different processes of RNA metabolism and in particular splicing regulation.
Received 16 August 2007; received after revision 18 September 2007; accepted 2 October 2007 相似文献
16.
Heike Betat Christiane Rammelt Mario Mörl 《Cellular and molecular life sciences : CMLS》2010,67(9):1447-1463
RNA polymerases are important enzymes involved in the realization of the genetic information encoded in the genome. Thereby,
DNA sequences are used as templates to synthesize all types of RNA. Besides these classical polymerases, there exists another
group of RNA polymerizing enzymes that do not depend on nucleic acid templates. Among those, tRNA nucleotidyltransferases
show remarkable and unique features. These enzymes add the nucleotide triplet C–C–A to the 3′-end of tRNAs at an astonishing
fidelity and are described as “CCA-adding enzymes”. During this incorporation of exactly three nucleotides, the enzymes have
to switch from CTP to ATP specificity. How these tasks are fulfilled by rather simple and small enzymes without the help of
a nucleic acid template is a fascinating research area. Surprising results of biochemical and structural studies allow scientists
to understand at least some of the mechanistic principles of the unique polymerization mode of these highly unusual enzymes. 相似文献
17.
Evidence for essential catalytic determinants for human erythrocyte pyrimidine 5′-nucleotidase 总被引:1,自引:0,他引:1
Amici A Ciccioli K Naponelli V Raffaelli N Magni G 《Cellular and molecular life sciences : CMLS》2005,62(14):1613-1620
Human erythrocyte pyrimidine 5′-nucleotidase, PN-I, catalyzes the dephosphorylation of pyrimidine nucleoside monophosphates. The enzyme also possesses phosphotransferase activity, transferring phosphate groups between pyrimidine nucleoside monophosphates and various pyrimidine nucleosides. Deficiency of the enzyme activity is associated with a hemolytic anemia. PN-I cDNA has been expressed in Escherichia coli, yielding a fully active recombinant enzyme, which was purified to homogeneity and extensively characterized. Multiple sequence alignment of PN-I and homologues proteins revealed the existence of conserved regions, whose importance in catalysis was examined by performing experiments designed to intercept covalent intermediates as strongly suggested by our previous kinetic studies. Furthermore, a functional analysis of the enzyme was carried out through site-directed mutagenesis designed on the basis of the sequence of the identified conserved regions as well as mutations observed in PN-I-deficient patients.Received 25 March 2005; received after revision 3 May 2005; accepted 13 May 2005 相似文献
18.
A role for <Emphasis Type="Italic">N</Emphasis>-acetylglucosamine as a nutrient sensor and mediator of insulin resistance 总被引:4,自引:0,他引:4
The ability to regulate energy balance at both the cellular and whole body level is an essential process of life. As western
society has shifted to a higher caloric diet and more sedentary lifestyle, the incidence of type 2 diabetes (non-insulin-dependent
diabetes mellitus) has increased to epidemic proportions. Thus, type 2 diabetes has been described as a disease of 'chronic
overnutrition'. There are abundant data to support the relationship between nutrient availability and insulin action. However,
there have been multiple hypotheses and debates as to the mechanism by which nutrient availability modulates insulin signaling
and how excess nutrients lead to insulin resistance. One well-established pathway for nutrient sensing is the hexosamine biosynthetic
pathway (HSP), which produces the acetylated aminosugar nucleotide uridine 5′-diphospho-N-acetylglucosamine (UDP-GlcNAc) as its end product. Since UDP-GlcNAc is the donor substrate for modification of nucleocytoplasmic
proteins at serine and threonine residues with N-acetylglucosamine (O-GlcNAc), the possibility of this posttranslational modification serving as the nutrient sensor has been proposed. We have
recently directly tested this model in adipocytes by examining the effect of elevated levels of O-GlcNAc on insulin-stimulated glucose uptake. In this review, we summarize the existing work that implicates the HSP and O-GlcNAc modification as nutrient sensors and regulators of insulin signaling.
RID="*"
ID="*"Corresponding author. 相似文献
19.
20.
A microorganism has to adapt to changing environmental conditions in order to survive. Cells could follow one of two basic
strategies to address such environmental fluctuations. On the one hand, cells could anticipate a fluctuating environment by
spontaneously generating a phenotypically diverse population of cells, with each subpopulation exhibiting different capacities
to flourish in the different conditions. Alternatively, cells could sense changes in the surrounding conditions – such as
temperature, nutritional availability or the presence of other individuals – and modify their behavior to provide an appropriate
response to that information. As we describe, examples of both strategies abound among different microorganisms. Moreover,
successful application of either strategy requires a level of memory and information processing that has not been normally
associated with single cells, suggesting that such organisms do in fact have the capacity to ‘think’.
Received 3 January 2007; accepted 4 April 2007 相似文献