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Cytochromes P450 and metabolism of xenobiotics 总被引:17,自引:0,他引:17
Cytochromes P450 (henceforth P450s) are involved in a variety of metabolic and biosynthetic processes. The number of known
P450 enzymes exceeds 1000, while the endogenous substrates of most of them remain unknown. All P450 enzymes exhibit similarity
in their structure and general mechanism of action; however, there are significant differences in the detailed function of
individual enzymes as well as in the structures and properties of their active sites. This review discusses the properties
of the most important P450 enzymes taking part in drug metabolism in humans. P450 3A4 is of paramount importance, because
it is the most abundant P450 in the human liver and is known to metabolize the majority of drugs whose biotransformation is
known. Genetically dependent variabilities of individual P450 activities and levels are described, documenting the importance
of pharmacogenetics aimed at explaining differences in the response of the organism to various drugs.
Received 7 November 2000; received after revision 9 January 2001; accepted 10 January 2001 相似文献
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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
5.
L.A. Pile F.W.-H. Lee D.A. Wassarman 《Cellular and molecular life sciences : CMLS》2001,58(11):1715-1718
We examined the consequences of the deacetylase inhibitor trichostatin A (TSA) on the development of Drosophila melanogaster. When fed to flies, TSA caused lethality and delayed development at concentrations as low as 5 μM, had stronger effects on
males than females, and acted synergistically with mutations in the gene encoding the RPD3 deacetylase to cause notched wings,
but did not appear to affect a SINA signaling pathway that is normally repressed by the SIN3 corepressor. These findings suggest
that deacetylated histones play an important role in normal developmental progression and establish parameters for genetic
screens to dissect the role of deacetylases in this process.
Received 14 June 2001; received after revision 31 July 2001; accepted 21 August 2001 相似文献
6.
Arginase expression in peritoneal macrophages and increase in circulating polyamine levels in mice infected with Schistosoma mansoni 总被引:5,自引:0,他引:5
Abdallahi OM Bensalem H Augier R Diagana M De Reggi M Gharib B 《Cellular and molecular life sciences : CMLS》2001,58(9):1350-1357
We investigated the nitric oxide (NO) synthase and arginase pathways in resident peritoneal macrophages of mice infected
with the tropical parasite Schistosoma mansoni. The two enzymes may have opposite effects, insofar as NO may be involved in the killing of the parasite whereas arginase
may stimulate parasite growth via polyamine synthesis. We determined the effects of the infection on the expression and activity
of the two enzymes in macrophages, before and after cytokine activation. Cells from infected mice expressed the hepatic type
I arginase, whereas in control cells, the enzyme was expressed only after cytokine activation, as were NO synthase II and
type II arginase in both groups of cells. Moreover, we found that in infected mice, arginase expression in macrophages was
associated with a ten fold increase in the concentration of circulating ornithine-derived polyamines. This may be of pathological
importance, since parasitic helminths are though to be dependent on their hosts for the uptake and interconversion of polyamines.
Received 13 March 2001; received after revision 4 May 2001; accepted 7 June 2001 相似文献
7.
Schwarz G 《Cellular and molecular life sciences : CMLS》2005,62(23):2792-2810
The molybdenum cofactor (Moco) forms the active site of all molybdenum (Mo) enzymes, except nitrogenase. Mo enzymes catalyze
important redox reactions in global metabolic cycles. Moco consists of Mo covalently bound to one or two dithiolates attached
to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by an ancient and conserved
biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclic
pyranopterin monophosphate), MPT and adenylated MPT. In a fifth step modifications such as attachment of nucleotides, sulfuration
or bond formation between Mo and the protein result in different catalytic Mo centers. A defect in any of the steps of Moco
biosynthesis results in the pleiotropic loss of all Mo enzyme activities. Human Moco deficiency is a hereditary metabolic
disorder characterized by severe neurodegeneration resulting in early childhood death. Recently, a first substitution therapy
was established.
Received 17 June 2005; received after revision 18 August 2005; accepted 1 September 2005 相似文献
8.
The trans-Golgi network (TGN) is a major secretory pathway sorting station that directs newly synthesized proteins to different
subcellular destinations. The TGN also receives extracellular materials and recycled molecules from endocytic compartments.
In this review, we summarize recent progress on understanding TGN structure and the dynamics of trafficking to and from this
compartment. Protein sorting into different transport vesicles requires specific interactions between sorting motifs on the
cargo molecules and vesicle coat components that recognize these motifs. Current understanding of the various targeting signals
and vesicle coat components that are involved in TGN sorting are discussed, as well as the molecules that participate in retrieval
to this compartment in both yeast and mammalian cells. Besides proteins, lipids and lipid-modifying enzymes also participate
actively in the formation of secretory vesicles. The possible mechanisms of action of these lipid hydrolases and lipid kinases
are discussed. Finally, we summarize the fundamentally different apical and basolateral cell surface delivery mechanisms and
the current facts and hypotheses on protein sorting from the TGN into the regulated secretory pathway in neuroendocrine cells.
Received 2 November 2000; received after revision 19 February 2001; accepted 19 February 2001 相似文献
9.
Identification of proteins in human prostate tumor material by two-dimensional gel electrophoresis and mass spectrometry 总被引:4,自引:0,他引:4
Alaiya AA Oppermann M Langridge J Roblick U Egevad L Brindstedt S Hellström M Linder S Bergman T Jörnvall H Auer G 《Cellular and molecular life sciences : CMLS》2001,58(2):307-311
Protein patterns in cells collected from benign prostatic tissues and prostate carcinomas were analyzed using two-dimensional
polyacrylamide gel electrophoresis and mass spectrometry. Polypeptide expression was evaluated by computer-assisted image
analysis (PDQUEST). Proteins expressed by prostate tumors were identified via in-gel digestion and subsequent matrix-assisted
laser desorption/ionization mass spectrometry. In addition to cytoskeletal and mitochondrial proteins, a 40-kDa protein was
identified as prostatic acid phosphatase (PAP). PAP expression decreased approximately twofold between benign and malignant
tissue. Increased expression of heat shock protein 70 and decreased expression of tropomyosin 1 were also observed in the
malignant tissue. The analysis of prostate material by two-dimensional gel electrophoresis and mass spectrometry shows that
particular proteins are of interest as markers of disease.
Received 18 December 2000; accepted 4 January 2001 相似文献
10.
Significance and molecular targets of protein kinase A during cAMP-mediated protection of cold stored liver grafts 总被引:6,自引:0,他引:6
The use of marginal donor livers is followed by a higher frequency of primary dys- or nonfunction after transplantation.
The present study was designed to test the hypothesis that stimulation of the cAMP second-messenger signal pathway might protect
the liver from ischemic injury, laying emphasis on the role of protein kinase A-mediated signal transduction.?Rat livers were
harvested after 45 min of cardiac arrest and preserved in HTK solution for 24 h. Hepatic integrity was assessed thereafter
using a blood-free reperfusion model.?Supplementation of the preservation solution with dibutyryl-cAMP (db-cAMP) promoted
phosphorylation of BAD at Ser 112 and concomitantly mitigated mitochondrial release of cytochrome c into the cytosol. Apoptotic
cell transformation was evident in reperfused livers by positive TUNEL-staining of sinusoidal lining cells and the detection
of cleaved poly(ADP-ribose) polymerase (PARP) in tissue homogenates by western analysis. Treatment with db-cAMP was effective
in minimizing both TUNEL staining and PARP cleavage and significantly reduced postischemic enzyme leakage of alanine aminotransferase
to one half, while hepatic bile production was enhanced by approximately 60% when compared to untreated livers. This functional
improvement was accompanied by a net amelioration of portal vascular conductivity. Inhibition of A kinase-anchoring protein
with HT31 completely reversed any of the observed effects obtained by db-cAMP.?We conclude that enhancement of cellular cAMP
signal maintains hepatic integrity during and after ischemic preservation which may be attributed to protein kinase A dependent
phosphorylation of BAD in line with subsequent inhibition of mitochondria-initiated apoptosis of sinusoidal lining cells.
Received 12 July 2001; received after revision 14 August 2001; accepted 14 August 2001 相似文献
11.
The correct repair of double-strand breaks (DSBs) is essential for the genomic integrity of a cell, as inappropriate repair
can lead to chromosomal rearrangements such as translocations. In many hematologic cancers and sarcomas, translocations are
the etiological factor in tumorigenesis, resulting in either the deregulation of a proto-oncogene or the expression of a fusion
protein with transforming properties. Mammalian cells are able to repair DSBs by pathways involving homologous recombination
and nonhomologous end-joining. The analysis of translocation breakpoints in a number of cancers and the development of model
translocation systems are beginning to shed light on specific DSB repair pathway(s) responsible for the improper repair of
broken chromosomes.
Received 19 June 2001; received after revision 6 September 2001; accepted 11 September 2001 相似文献
12.
G. M. Rossolini S. Schippa M. L. Riccio F. Berlutti L. E. Macaskie M. C. Thaller 《Cellular and molecular life sciences : CMLS》1998,54(8):833-850
Bacterial nonspecific acid phosphohydrolases (NSAPs) are secreted enzymes, produced as soluble periplasmic proteins or as
membrane-bound lipoproteins, that are usually able to dephosphorylate a broad array of structurally unrelated substrates and
exhibit optimal catalytic activity at acidic to neutral pH values. Bacterial NSAPs are monomeric or oligomeric proteins containing
polypeptide components with an M
r of 25 – 30 kDa. On the basis of amino acid sequence relatedness, three different molecular families of NSAPs can be distinguished,
indicated as molecular class A, B and C, respectively. Members of each class share some common biophysical and functional
features, but may also exhibit functional differences. NSAPs have been detected in several microbial taxa, and enzymes of
different classes can be produced by the same bacterial species. Structural and phyletic relationships exist among the various
bacterial NSAPs and some other bacterial and eucaryotic phosphohydrolases. Current knowledge on bacterial NSAPs is reviewed,
together with analytical tools that may be useful for their characterization. An overview is also presented concerning the
use of bacterial NSAPs in biotechnology.
Received 21 November 1997; received after revision 10 March 1998; accepted 10 March 1998 相似文献
13.
Malaria results in up to 2.5 million deaths annually, with young children and pregnant women at greatest risk. The great
majority of severe disease is caused by Plasmodium falciparum. A characteristic feature of infection with P. falciparum is the accumulation or sequestration of parasite-infected red blood cells (RBCs) in various organs, such as the brain, lung
and placenta, and together with other factors is important in the pathogenesis of severe forms of malaria. Sequestration results
from adhesive interactions between parasite-derived proteins expressed on the surface of infected RBCs and a number of host
molecules on the surface of endothelial cells, placental cells and uninfected RBCs. Some receptors for parasite adhesion have
been implicated in particular malaria syndromes, such as intercellular adhesion molecule 1 in cerebral malaria and chondroitin
sulfate A and hyaluronic acid in placental infection. The principal parasite ligand and antigen on the RBC surface, P. falciparum erythrocyte membrane protein 1 encoded by a multigene family termed var, is clonally variant, enabling evasion of specific immune responses. An understanding of these host-parasite interactions
in the context of clinical disease and immunity may reveal potential targets to prevent or treat severe forms of malaria.
Received 25 June 2001; received after revision 22 August 2001; accepted 24 August 2001 相似文献
14.
Apaf1 has been described as the core of the apoptosome. Deficiency in murine Apaf1 leads to embryonic lethality with a phenotype affecting many aspects of developmental apoptosis. In the developing brain,
Apaf1 is a death regulator of the neuronal founder cells. Combined intercrosses of mouse lines mutant for members of the mitochondrial
death pathway are providing us with some clues about the relative regulation existing among neuronal cell populations. Apaf1-deficient embryos display an interesting phenotype in the inner ear and in limb development, which involves different caspase-dependent
and -independent pathways. Moreover, APAF1 is mutated in human melanomas, and its depletion contributes to malignant transformation in a mouse model of cancer. This
review has a double aim: the analysis of the alternatives taken by the embryo to bring into the suicidal program different
cells at different stages, and the relevance of APAF1 in the onset and progression of cancer.
Received 5 March 2001; received after revision 19 April 2001; accepted 4 May 2001 相似文献
15.
Regulation of insulin receptor function 总被引:1,自引:0,他引:1
Youngren JF 《Cellular and molecular life sciences : CMLS》2007,64(7-8):873-891
Resistance to the biological actions of insulin contributes to the development of type 2 diabetes and risk of cardiovascular
disease. A reduced biological response to insulin by tissues results from an impairment in the cascade of phosphorylation
events within cells that regulate the activity of enzymes comprising the insulin signaling pathway. In most models of insulin
resistance, there is evidence that this decrement in insulin signaling begins with either the activation or substrate kinase
activity of the insulin receptor (IR), which is the only component of the pathway that is unique to insulin action. Activation
of the IR can be impaired by post-translational modifications of the protein involving serine phosphorylation, or by binding
to inhibiting proteins such as PC-1 or members of the SOCS or Grb protein families. The impact of these processes on the conformational
changes and phosphorylation events required for full signaling activity, as well as the role of these mechanisms in human
disease, is reviewed in this article.
Received 3 August 2006; received after revision 1 December 2006; accepted 8 January 2007 相似文献
16.
Starch-binding domains in the post-genome era 总被引:1,自引:1,他引:0
Starch belongs to the most abundant biopolymers on Earth. As a source of energy, starch is degraded by a large number of various
amylolytic enzymes. However, only about 10% of them are capable of binding and degrading raw starch. These enzymes usually
possess a distinct sequence-structural module, the so-called starchbinding domain (SBD). In general, all carbohydrate-binding
modules (CBMs) have been classified into the CBM families. In this sequence-based classification the individual types of SBDs
have been placed into seven CBM families: CBM20, CBM21, CBM25, CBM26, CBM34, CBM41 and CBM45. The family CBM20, known also
as a classical C-terminal SBD of microbial amylases, is the most thoroughly studied. The three-dimensional structures have
already been determined by X-ray crystallography or nuclear magnetic resonance for SBDs from five CBM families (20, 25, 26,
34 and 41), and the structure of the CBM21 has been modelled. Despite differences among the amino acid sequences, the fold
of a distorted β-barrel seems to be conserved together with a similar way of substrate binding (mainly stacking interactions
between aromatic residues and glucose rings). SBDs have recently been discovered in many non-amylolytic proteins. These may,
for example, have regulatory functions in starch metabolism in plants or glycogen metabolism in mammals. SBDs have also found
practical uses.
Received 25 May 2006; received after revision 26 June 2006; accepted 3 August 2006 相似文献
17.
The prolyl oligopeptidase family 总被引:6,自引:0,他引:6
Polgár L 《Cellular and molecular life sciences : CMLS》2002,59(2):349-362
A group of serine peptidases, the prolyl oligopeptidase family, cannot hydrolyze peptides containing more than about 30 residues.
This group is unrelated to the classical trypsin and subtilisin families, and includes dipeptidyl peptidase IV, acylaminoacyl
peptidase and oligopeptidase B, in addition to the prototype prolyl oligopeptidase. The recent crystal structure determination
of prolyl oligopeptidase (80 kDa) has shown that the enzyme contains a peptidase domain with an α/β hydrolase fold, and its catalytic triad is covered by the central tunnel of an unusual seven-bladed β-propeller. This domain operates as a gating filter, excluding large, structured peptides from the active site. The binding
mode of substrates and the catalytic mechanism differ from that of the classical serine peptidases in several features. The
members of the family are important targets of drug design. Prolyl oligopeptidase is involved in amnesia, depression and blood
pressure control, dipeptidyl peptidase IV in type 2 diabetes and oligopeptidase B in trypanosomiasis.
Received 8 August 2001; received after revision 19 September 2001; accepted 21 September 2001 相似文献
18.
Bromelain: biochemistry, pharmacology and medical use 总被引:10,自引:0,他引:10
Maurer HR 《Cellular and molecular life sciences : CMLS》2001,58(9):1234-1245
Bromelain is a crude extract from the pineapple that contains, among other components, various closely related proteinases,
demonstrating, in vitro and in vivo, antiedematous, antiinflammatory, antithrombotic and fibrinolytic activities. The active
factors involved are biochemically characterized only in part. Due to its efficacy after oral administration, its safety and
lack of undesired side effects, bromelain has earned growing acceptance and compliance among patients as a phytotherapeutical
drug. A wide range of therapeutic benefits has been claimed for bromelain, such as reversible inhibition of platelet aggregation,
angina pectoris, bronchitis, sinusitis, surgical traumas, thrombophlebitis, pyelonephritis and enhanced absorption of drugs,
particularly of antibiotics. Biochemical experiments indicate that these pharmacological properties depend on the proteolytic
activity only partly, suggesting the presence of nonprotein factors in bromelain. Recent results from preclinical and pharmacological
studies recommend bromelain as an orally given drug for complementary tumor therapy: bromelain acts as an immunomodulator
by raising the impaired immunocytotoxicity of monocytes against tumor cells from patients and by inducing the production of
distinct cytokines such as tumor necrosis factor-α, interleukin (Il)-1β, Il-6, and Il-8. In a recent clinical study with mammary tumor patients, these findings could be partially confirmed. Especially
promising are reports on animal experiments claiming an antimetastatic efficacy and inhibition of metastasis-associated platelet
aggregation as well as inhibition of growth and invasiveness of tumor cells. Apparently, the antiinvasive activity does not
depend on the proteolytic activity. This is also true for bromelain effects on the modulation of immune functions, its potential
to eliminate burn debris and to accelerate wound healing. Whether bromelain will gain wide acceptance as a drug that inhibits
platelet aggregation, is antimetastatic and facilitates skin debridement, among other indications, will be determined by further
clinical trials. The claim that bromelain cannot be effective after oral administration is definitely refuted at this time.
Received 25 August 2000; received after revision 29 March 2001; accepted 30 March 2001 相似文献
19.
Prosperi-Meys C Wouters J Galleni M Lamotte-Brasseur J 《Cellular and molecular life sciences : CMLS》2001,58(14):2136-2143
Increased resistance to β-lactam antibiotics is mainly due to β-lactamases whose production by pathogenic bacteria makes their broad activity spectrum
especially frightening. X-ray structures of several zinc β-lactamases have revealed the coordination of the two metal ions, but their mode of action remains unclear. Geometry optimisation
of stable complexes along the reaction pathway of benzylpenicillin hydrolysis highlighted a proton shuttle occurring from
D120 of the Bacillus cereus β-lactamase to the β-lactam nitrogen via Zn2 which is central to the network. First, the Zn1 ion has a structural role maintaining Zn-bound waters,
WAT1 and WAT2, either directly or through the Zn1 tetrahedrally coordinated histidine ligands. The Zn2 ion has a more catalytic
role, stabilising the tetrahedral intermediate, accepting the β-lactam nitrogen atom as a ligand. The role of Zn2 and the flexibility in the coordination geometry of both Zn ions is of
crucial importance for catalysis.
Received 14 August 2001; received after revision 19 October 2001; accepted 30 October 2001 相似文献
20.
Axonal transport of neurofilaments in normal and disease states 总被引:5,自引:0,他引:5
Miller CC Ackerley S Brownlees J Grierson AJ Jacobsen NJ Thornhill P 《Cellular and molecular life sciences : CMLS》2002,59(2):323-330
Neurofilaments are among the most abundant organelles in neurones. They are synthesised in cell bodies and then transported
into and through axons by a process termed 'slow axonal transport' at a rate that is distinct from that driven by conventional
fast motors. Several recent studies have now demonstrated that this slow rate of transport is actually the consequence of
conventional fast rates of movement that are interrupted by extended pausing. At any one time, most neurofilaments are thus
stationary. Accumulations of neurofilaments are a pathological feature of several human neurodegenerative diseases suggesting
that neurofilament transport is disrupted in disease states. Here, we review recent advances in our understanding of neurofilament
transport in both normal and disease states. Increasing evidence suggests that phosphorylation of neurofilaments is a mechanism
for regulating their transport properties, possibly by promoting their detachment from the motor(s). In some neurodegenerative
diseases, signal transduction mechanisms involving neurofilament kinases and phosphatases may be perturbed leading to disruption
of transport.
Received 11 July 2001; received after revision 30 August 2001; accepted 31 August 2001 相似文献