0
selected
-
1.
[Sitosterolemia (phytosterolemia)].
Lütjohann, D
Der Internist. 2019;(8):871-877
Abstract
Sitosterolemia or phytosterolemia is a rare autosomal recessive hereditary lipid storage disorder. It is caused by homozygous or compound heterozygous mutations in one of the two ABCG5 and ABCG8 genes encoding the intestinal and hepatic heterodimer ABCG5 (sterolin 1)/ABCG8 (sterolin 2) efflux transporters. These mutations lead to intestinal hyperabsorption and reduced hepatic secretion of cholesterol and plant sterols with subsequent accumulation of phytosterols and cholesterol in plasma and deposition in tissue (xanthoma). Phytosterols are found mainly in vegetable oils, margarine, nuts, grains, soybeans and avocados. Patients with sitosterolemia show extreme phenotypic heterogeneity from almost asymptomatic individuals to those with combined severe hypercholesterolemia at a young age, leading to increased atherosclerosis and premature cardiac death. Early abnormalities include hemolytic anemia with stomatocytosis, macrothrombocytopenia and splenomegaly. In addition to strict avoidance of phytosterol-containing foods, the use of the sterol absorption inhibitor ezetimibe, possibly in combination with the bile acid-binding resin cholestyramine, is the most effective treatment option.
-
2.
The oligopeptide ABC-importers are essential communication channels in Gram-positive bacteria.
Slamti, L, Lereclus, D
Research in microbiology. 2019;(8):338-344
Abstract
The transport of peptides in microorganisms plays an important role in their physiology and behavior, both as a nutrient source and as a proxy to sense their environment. This latter function is evidenced in Gram-positive bacteria where cell-cell communication is mediated by small peptides. Here, we highlight the importance of the oligopeptide permease (Opp) systems in the various major processes controlled by signaling peptides, such as sporulation, virulence and conjugation. We underline that the functioning of these communication systems is tightly linked to the developmental status of the bacteria via the regulation of opp gene expression by transition phase regulators.
-
3.
Exploring the Genetic Landscape of Retinal Diseases in North-Western Pakistan Reveals a High Degree of Autozygosity and a Prevalent Founder Mutation in ABCA4.
Rehman, AU, Peter, VG, Quinodoz, M, Rashid, A, Khan, SA, Superti-Furga, A, Rivolta, C
Genes. 2019;(1)
Abstract
Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity). We leveraged on the high degree of consanguinity by applying genome-wide high-density single-nucleotide polymorphism (SNP) genotyping followed by targeted Sanger sequencing of candidate gene(s) lying inside autozygous intervals. In addition, we performed whole-exome sequencing (WES) on at least one proband per family. We identified 7 known and 4 novel variants in a total of 10 genes (ABCA4, BBS2, CNGA1, CNGA3, CNGB3, MKKS, NMNAT1, PDE6B, RPE65, and TULP1) previously known to cause inherited retinal diseases. In spite of all families being consanguineous, compound heterozygosity was detected in one family. All homozygous pathogenic variants resided in autozygous intervals ≥2.0 Mb in size. Putative founder variants were observed in the ABCA4 (NM_000350.2:c.214G>A; p.Gly72Arg; ten families) and NMNAT1 genes (NM_022787.3:c.25G>A; p.Val9Met; two families). We conclude that geographic isolation and sociocultural tradition of intrafamilial mating in North-Western Pakistan favor both the clinical manifestation of rare "generic" variants and the prevalence of founder mutations.
-
4.
The SUF system: an ABC ATPase-dependent protein complex with a role in Fe-S cluster biogenesis.
Garcia, PS, Gribaldo, S, Py, B, Barras, F
Research in microbiology. 2019;(8):426-434
Abstract
Iron-sulfur (Fe-S) clusters are considered one of the most ancient and versatile inorganic cofactors present in the three domains of life. Fe-S clusters can act as redox sensors or catalysts and are found to be used by a large number of functional and structurally diverse proteins. Here, we cover current knowledge of the SUF multiprotein machinery that synthesizes and inserts Fe-S clusters into proteins. Specific focus is put on the ABC ATPase SufC, which contributes to building Fe-S clusters, and appeared early on during evolution.
-
5.
Holding-Oriented versus Gating-Oriented Live-Cell Distinction: Highlighting the Role of Transporters in Cell Imaging Probe Development.
Choi, YK, Kim, JJ, Chang, YT
Accounts of chemical research. 2019;(11):3097-3107
Abstract
Small molecule imaging probes are powerful tools to understand complex biological systems. The mainstreams of imaging probe developments have been focused on the target holding of the probes; the holding targets are often cell-type-specific biomarkers. This type of the probe mechanism can be designated as holding-oriented live-cell distinction (HOLD). Our group has worked on the development of cell-type-selective probes using a diversity-oriented fluorescence library approach (DOFLA), where unbiased phenotypic screening is employed using fluorescent library compounds. Through the conventional target identification methods such as an affinity-based analysis, we elucidated that some of the probe mechanisms are HOLD. However, we also realized that sometimes there is no specific holding target for probes or the holding targets are ubiquitous. The observation led us to test an alternative mechanism of cell-type-specific probes as gating-oriented live-cell distinction (GOLD). We started to examine the gating mechanism of probes, which is mainly based on transporters but which does not necessarily require probe holding to cellular targets. Transporters can control the in and out movement of various nutrients and chemicals. Different expression levels of transporters in various cell types could provide the molecular mechanism of differential staining of cells by regulating the intracellular accumulation of a certain specific probe. A number of GOLD probes have been developed by modifying or mimicking endogenous substrates of transporters such as inorganic ions, glucose, amino acids, or neurotransmitters, utilizing broad substrate specificity of transporters. The radiolabeled or fluorophore-conjugated substrate mimetics have been widely used for live cell distinction and various applications such as disease-related cell or tissue imaging. In humans, there are about 400 solute carrier (SLC) transporters and 50 ATP-binding cassette (ABC) transporters. Since some transporters have broad substrate specificity, they can transport not only derivatives of endogenous natural substrates but also totally synthetic diverse imaging probes, such as DOFLA probes. Without preconsidering the structure of endogenous substrates, we recently demonstrated a series of live-cell imaging probes and elucidated their molecular mechanism as a gating one, either by SLC or ABC transporters. Transporter inhibitor panel and CRISPR-based transporter libraries could provide a systematic gating target elucidation platform. Considering the generality of DOFLA and the CRISPR-based genomic tool for transporter systems (>450 in humans), the GOLD approach will offer new insight and promise for unprecedented levels of novel cell imaging probe development.
-
6.
The Abc of Phosphonate Breakdown: A Mechanism for Bacterial Survival.
Manav, MC, Sofos, N, Hove-Jensen, B, Brodersen, DE
BioEssays : news and reviews in molecular, cellular and developmental biology. 2018;(11):e1800091
Abstract
Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi ) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon-phosphorus (C-P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the challenges involved in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C-P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C-P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP-binding cassette (ABC) proteins.
-
7.
Functions of ABC transporters in plant growth and development.
Do, THT, Martinoia, E, Lee, Y
Current opinion in plant biology. 2018;:32-38
Abstract
ABC transporters are essential for plant development, playing roles in processes such as gametogenesis, seed development, seed germination, organ formation, and secondary growth. ABC transporters are directly energized by ATP and can transport complex organic materials against concentration gradients; thus, they are uniquely suited to provide the complex building blocks required for the development of specialized plant cells. We review recent progress in our understanding of the contribution ABC transporters make to the growth and development of plants, including their roles in protective layer formation and in transporting phytohormones.
-
8.
Exploring the biological roles of Dothideomycetes ABC proteins: Leads from their phylogenetic relationships with functionally-characterized Ascomycetes homologs.
Dube, G, Kadoo, N, Prashant, R
PloS one. 2018;(8):e0197447
Abstract
BACKGROUND The ATP-binding cassette (ABC) superfamily is one of the largest, ubiquitous and diverse protein families in nature. Categorized into nine subfamilies, its members are important to most organisms including fungi, where they play varied roles in fundamental cellular processes, plant pathogenesis or fungicide tolerance. However, these proteins are not yet well-understood in the class Dothideomycetes, which includes several phytopathogens that infect a wide range of food crops including wheat, barley and maize and cause major economic losses. RESULTS We analyzed the genomes of 14 Dothideomycetes fungi (Test set) and seven well-known Ascomycetes fungi (Model set- that possessed gene expression/ functional analysis data about the ABC genes) and predicted 578 and 338 ABC proteins from each set respectively. These proteins were classified into subfamilies A to I, which revealed the distribution of the subfamily members across the Dothideomycetes and Ascomycetes genomes. Phylogenetic analysis of Dothideomycetes ABC proteins indicated evolutionary relationships among the subfamilies within this class. Further, phylogenetic relationships among the ABC proteins from the Model and the Test fungi within each subfamily were analyzed, which aided in classifying these proteins into subgroups. We compiled and curated functional and gene expression information from the previous literature for 118 ABC genes and mapped them on the phylogenetic trees, which suggested possible roles in pathogenesis and/or fungicide tolerance for the newly identified Dothideomycetes ABC proteins. CONCLUSIONS The present analysis is one of the firsts to extensively analyze ABC proteins from Dothideomycetes fungi. Their phylogenetic analysis and annotating the clades with functional information indicated a subset of Dothideomycetes ABC genes that could be considered for experimental validation for their roles in plant pathogenesis and/or fungicide tolerance.
-
9.
ATR-101 inhibits cholesterol efflux and cortisol secretion by ATP-binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells.
Burns, VE, Kerppola, TK
British journal of pharmacology. 2017;(19):3315-3332
-
-
Free full text
-
Abstract
BACKGROUND AND PURPOSE To further the development of new agents for the treatment of adrenocortical carcinoma (ACC), we characterized the molecular and cellular mechanisms of cytotoxicity by the adrenalytic compound ATR-101 (PD132301-02). EXPERIMENTAL APPROACH We compared the effects of ATR-101, PD129337, and ABC transporter inhibitors on cholesterol accumulation and efflux, on cortisol secretion, on ATP levels, and on caspase activation in ACC-derived cell lines. We examined the effects of these compounds in combination with methyl-β-cyclodextrin or exogenous cholesterol to determine the roles of altered cholesterol levels in the effects of these compounds. KEY RESULTS ATR-101 caused cholesterol accumulation, ATP depletion, and caspase activation within 30 minutes after addition to ACC-derived cells, whereas PD129337 did not. Suppression of cholesterol accumulation by methyl-β-cyclodextrin or exogenous cholesterol, prevented ATP depletion and caspase activation by ATR-101. ATR-101 blocked cholesterol efflux and cortisol secretion, suggesting that it inhibited ABCA1, ABCG1, and MDR1 transporters. Combinations of ABCA1, ABCG1, and MDR1 inhibitors were also cytotoxic. Combinations of ATR-101 with inhibitors of ABCG1, MDR1, or mitochondrial functions had increased cytotoxicity. Inhibitors of steroidogenesis reduced ATP depletion by ATR-101, whereas U18666A enhanced cholesterol accumulation and ATP depletion together with ATR-101. ATR-101 repressed ABCA1, ABCG1, and IDOL transcription by mechanisms that were distinct from the mechanisms that caused cholesterol accumulation. CONCLUSIONS AND IMPLICATIONS Inhibition of multiple ABC transporters and the consequent accumulation of cholesterol mediated the cytotoxicity of ATR-101. Compounds that replicate these effects in tumours are likely to be useful in the treatment of ACC.
-
10.
Effect of Oxidative Stress on ABC Transporters: Contribution to Epilepsy Pharmacoresistance.
Grewal, GK, Kukal, S, Kanojia, N, Saso, L, Kukreti, S, Kukreti, R
Molecules (Basel, Switzerland). 2017;(3)
Abstract
Epilepsy is a neurological disorder affecting around 1%-2% of population worldwide and its treatment includes use of antiepileptic drugs to control seizures. Failure to respond to antiepileptic drug therapy is a major clinical problem and over expression of ATP-binding cassette transporters is considered one of the major reasons for pharmacoresistance. In this review, we have summarized the regulation of ABC transporters in response to oxidative stress due to disease and antiepileptic drugs. Further, ketogenic diet and antioxidants were examined for their role in pharmacoresistance. The understanding of signalling pathways and mechanism involved may help in identifying potential therapeutic targets and improving drug response.