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61.
Identification of a mutation cluster in mevalonate kinase deficiency, including a new mutation in a patient of Mennonite ancestry.
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D D Hinson R M Ross S Krisans J L Shaw V Kozich M O Rolland P Divry J Mancini G F Hoffmann K M Gibson 《American journal of human genetics》1999,65(2):327-335
Mevalonate kinase (MKase) deficiency (MKD) is a rare autosomal recessive disorder in the pathway of cholesterol and nonsterol isoprenoid biosynthesis. Thus far, two disease-causing missense alleles have been identified, N301T and A334T. We report four additional mutations associated with MKD: L264F, T243I, L265P, and I268T, the last found in a patient of Mennonite ancestry. Electrophoretic analysis of bacterially expressed wild-type and mutant MKase indicated that I268T and T243I mutants produced normal or somewhat reduced amounts of MKase protein; conversely, L264F and L265P mutations resulted in considerably decreased, or absent, MKase protein. Immunoblot analysis of MKase from all patients suggested that the MKase polypeptide was grossly intact and produced in amounts comparable to control levels. Three mutations resulted in significantly diminished MKase enzyme activity (<2%), whereas the I268T allele yielded approximately 20% residual enzyme activity. Our results should allow more-accurate identification of carriers and indicate a mutation "cluster" within amino acids 240-270 of the mature MKase polypeptide. 相似文献
62.
Human red and green visual pigment genes are X-linked duplicate genes. To
study their evolutionary history, introns 2 and 4 (1,987 and 1,552 bp,
respectively) of human red and green pigment genes were sequenced.
Surprisingly, we found that intron 4 sequences of these two genes are
identical and that the intron 2 sequences differ by only 0.3%. The low
divergences are unexpected because the duplication event producing the two
genes is believed to have occurred before the separation of the human and
Old World monkey (OWM) lineages. Indeed, the divergences in the two introns
are significantly lower than both the synonymous divergence (3.2% +/- 1.1%)
and the nonsynonymous divergence (2.0% +/- 0.5%) in the coding sequences
(exons 1-6). A comparison of partial sequences of exons 4 and 5 of human
and OWM red and green pigment genes supports the hypothesis that the gene
duplication occurred before the human-OWM split. In conclusion, the high
similarities in the two intron sequences might be due to very recent gene
conversion, probably during evolution of the human lineage.
相似文献
63.
Yvonne A Kwaffo Mabel Sarpong-Duah Kwabena Owusu-Boateng Winfred SK Gbewonyo Jonathan P Adjimani Lydia Mosi 《Experimental biology and medicine (Maywood, N.J.)》2021,246(17):1884
Mycobacterium ulcerans produces a macrolide exotoxin, mycolactone which suppresses immune cells activity, is toxic to most cells and the key virulence factor in the pathogenesis of Buruli ulcer disease. Mycolactone is reported to mediate the production of reactive oxygen species in keratinocytes; cells that play critical role in wound healing. Increased levels of reactive oxygen species have been shown to disrupt the well-ordered process of wound repair; hence, the function of wound-healing cells such as macrophages, keratinocytes, and fibroblast could be impaired in the presence of the reactive oxygen species mediator, mycolactone. To ensure regeneration of tissues in chronic ulcers, with proper and timely healing of the wounds, natural antioxidants that can combat the effects of induced reactive oxygen species in wound-healing cells ought to be investigated. Reactive oxygen species activity was determined in mycolactone-treated RAW 264.7 macrophages and the scavenging ability of the antioxidants (ascorbic acid, gallic acid, and green tea kombucha) against mycolactone-induced reactive oxygen species (superoxide anions) was assessed using fluorescein probe (DCF-DA) and nitroblue tetrazolium dye. Cytotoxicity of the antioxidants, mycolactone, and the protective effect of the antioxidants on the cells upon treatment with mycolactone were determined using the Alamar blue assay. The expression levels of endogenous antioxidant enzyme genes (superoxide dismutase, catalase, and glutathione peroxidase) in response to mycolactone-mediated reactive oxygen species were determined using RT-qPCR. Mycolactone induced the production of reactive oxygen species in RAW 264.7 macrophages, and the resulting superoxide anions were scavenged by some of the antioxidants. The selected endogenous antioxidant enzyme genes in the macrophages were upregulated in the presence of the antioxidants and mycolactone. The exogenously supplied ascorbic acid and green tea kombucha offered moderate protection to the macrophages against the toxicity of mycolactone. We conclude that the results provide insights into alternate and adjunct therapeutic approaches in Buruli ulcer treatment, which could significantly attenuate the toxicity of the pathogenic factor; mycolactone. 相似文献
64.
Central role of peroxisomes in isoprenoid biosynthesis 总被引:7,自引:0,他引:7
Peroxisomes contain enzymes catalyzing a number of indispensable metabolic functions mainly related to lipid metabolism. The importance of peroxisomes in man is stressed by the existence of genetic disorders in which the biogenesis of the organelle is defective, leading to complex developmental and metabolic phenotypes. The purpose of this review is to emphasize some of the recent findings related to the localization of cholesterol biosynthetic enzymes in peroxisomes and to discuss the impairment of cholesterol biosynthesis in peroxisomal deficiency diseases. 相似文献
65.
66.
A.?GraffEmail author D.?Tropel SK.?Raman G.?Machaidze U.?Aebi P.?BurkhardEmail author 《NanoBioTechnology》2005,1(3):293-294
A challenging topic in cancer research is to create drug delivery system that can bring in a specific and noncytotoxic manner
a therapeutic compound. Usually, tumor targeting requires very specific compounds. Currently, peptide analogues like somatostatin,
neurotensin, or bombesin are used to target G-coupled receptors, which are overexpressed on tumor cells. However, many of
those analogues are rapidly degraded in the plasma and are cytotoxic [1–2]. Due to the limited efficiency and high toxicity
of conventional chemotherapy different strategies have been developed for non-cytotoxic cancer treatment and cancer localization
[3–5].
The recent development in bio-nanotechnology offers new avenues for cancer therapy. A lot of studies have been devoted to
nanoparticulate delivery systems (10–100nm) like lipid or polymer particles [6–8]. Due to the nanometer sized of such cargos,
the transportation of therapeutic compounds in the blood stream is increased in terms of time circulation. But their surface
functionalization to improve drug-targeting properties is usually complicated and rather uneffective.
We have recently designed a novel type of functional nanoparticles with regular icosahedral symmetry, mimicking small, rigid
viral capsids (Fig. 1 (A)) and a diameter of about 17 nm (Fig. 1 (C)) which self-assemble from single polypeptide chains (Fig.
1 (B)). 相似文献
67.
Kovacs WJ Tape KN Shackelford JE Duan X Kasumov T Kelleher JK Brunengraber H Krisans SK 《Histochemistry and cell biology》2007,127(3):273-290
Previous studies have indicated that the early steps in the isoprenoid/cholesterol biosynthetic pathway occur in peroxisomes.
However, the role of peroxisomes in cholesterol biosynthesis has recently been questioned in several reports concluding that
three of the peroxisomal cholesterol biosynthetic enzymes, namely mevalonate kinase, phosphomevalonate kinase, and mevalonate
diphosphate decarboxylase, do not localize to peroxisomes in human cells even though they contain consensus peroxisomal targeting
signals. We re-investigated the subcellular localization of the cholesterol biosynthetic enzymes of the pre-squalene segment
in human cells by using new stable isotopic techniques and data computations with isotopomer spectral analysis, in combination
with immunofluorescence and cell permeabilization techniques. Our present findings clearly show and confirm previous studies
that the pre-squalene segment of the cholesterol biosynthetic pathway is localized to peroxisomes. In addition, our data are
consistent with the hypothesis that acetyl-CoA derived from peroxisomal β-oxidation of very long-chain fatty acids and medium-chain
dicarboxylic acids is preferentially channeled to cholesterol synthesis inside the peroxisomes without mixing with the cytosolic
acetyl-CoA pool. 相似文献
68.
Human C-reactive protein (CRP) is a clinically important classical acute phase protein. Although CRP has been reported to
bind with many nucleated cells, the direct binding of CRP to erythrocytes in diseases remains largely unexplored. The main
focus of the present study was to investigate the binding of disease-specific CRP to erythrocytes of same patients. Distinct
molecular variant of disease-specific CRP was affinity purified from sera of malaria patients (CRPMal). This CRP showed strong binding with malaria erythrocytes (RBCMal) as confirmed by flow cytometric analysis (FACS), enzyme-linked immunosorbent assays (ELISA), and radio binding assays. Calcium
and phosphoryl choline (PC) were found to be essential for this interaction. A 2.3-fold increased binding of induced CRP to
RBCMal as compared to normal erythrocytes (RBCN) confirmed disease-specificity. Preincubation of RBCMal with unconjugated CRP showed 3–5 fold inhibition. The association constant of CRP and RBCMal was 4.7 × 106 cpm/μg with the corresponding number of receptors/cell being 4.3 × 105. The effector function of CRPMal has been demonstrated by its potency to activate the complement pathway. An optimal dose of 10 μg/ml of CRP induced three-fold
higher hemolysis of patient erythrocytes as compared to RBCN. These studies provide direct evidence for an important phagocytic functional interaction of this acute-phase protein by
triggering the CRP-complement pathway after the binding of CRPMal with RBCMal. Hemolysis as triggered by this pathway may be one of the causative factors of anemia, a common clinical manifestation of
this disease. 相似文献
69.
70.
Synthesis of a mixture of the 25(R) and 25(S) isomers of 5 beta-cholestane-3 alpha,7 alpha,12 alpha, 26(27)-tetrol from cholic acid in four steps, including a Wittig reaction, is described. 相似文献