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Mahmood M Hussain - One of the best experts on this subject based on the ideXlab platform.
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atp binding Cassette Family a protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma
Journal of Lipid Research, 2018Co-Authors: Jahangir Iqbal, Meghan T Walsh, Samar M Hammad, Marina Cuchel, Daniel J Rader, Mahmood M HussainAbstract:Sphingolipids, including ceramide, SM, and hexosylceramide (HxCer), are carried in the plasma by lipoproteins. They are possible markers of metabolic diseases, but little is known about their control. We previously showed that microsomal triglyceride transfer protein (MTP) is critical to determine plasma ceramide and SM, but not HxCer, levels. In human plasma and mouse models, we examined possible HxCer-modulating pathways, including the role of ABCA1 in determining sphingolipid plasma concentrations. Compared with control samples, plasma from patients with Tangier disease (deficient in ABCA1) had significantly lower HxCer (−69%) and SM (−40%) levels. Similarly, mice deficient in hepatic and intestinal ABCA1 had significantly reduced HxCer (−79%) and SM (−85%) levels. Tissue-specific ablation studies revealed that hepatic ABCA1 determines plasma HxCer and SM levels; that ablation of MTP and ABCA1 in the liver and intestine reduces plasma HxCer, SM, and ceramide levels; and that hepatic and intestinal MTP contribute to plasma ceramide levels, whereas only hepatic MTP modulates plasma SM levels. These results identify the contribution of ABCA1 to plasma SM and HxCer levels and suggest that MTP and ABCA1 are critical determinants of plasma sphingolipid levels.
Lawrence M Nogee - One of the best experts on this subject based on the ideXlab platform.
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fatal familial lung disease caused by abca3 deficiency without identified abca3 mutations
The Journal of Pediatrics, 2010Co-Authors: Adam W Gower, Jeffrey A Whitsett, Susan E Wert, Jennifer S Ginsberg, Agneta Golan, Lawrence M NogeeAbstract:Objective To test the hypothesis that some functionally significant variants in the gene encoding member A3 of the ATP Binding Cassette Family (ABCA3) are not detected using exon-based sequencing approaches. Study design The first of 2 female siblings who died from neonatal respiratory failure was examined for mutations with sequence analysis of all ABCA3 exons and known regulatory elements within the 5' untranslated region. Lung tissue from both siblings was immunostained for ABCA3 and examined with electron microscopy. Segregation of ABCA3 alleles was determined with analysis of polymorphisms in the parents and all children. Results No mutations were identified with ABCA3 sequence analysis in the first affected infant. Affected siblings were concordant for their ABCA3 alleles, but discordant from those of their unaffected siblings. ABCA3 protein was not detectable with immunostaining in lung tissue samples from both affected infants. Electron microscopy demonstrated small, dense lamellar bodies, characteristically seen with ABCA3 mutations. Conclusions The segregation of ABCA3 alleles, absence of ABCA3 immunostaining, lung pathology, and ultrastructural findings support genetic ABCA3 deficiency as the cause of lung disease in these 2 infants, despite the lack of an identified genetic variant.
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abca3 mutations associated with pediatric interstitial lung disease
American Journal of Respiratory and Critical Care Medicine, 2005Co-Authors: Janine E Bullard, Susan E Wert, Jeffrey A Whitsett, Michael Dean, Lawrence M NogeeAbstract:Rationale: ABCA3 is a member of the ATP-binding Cassette Family of proteins that mediate the translocation of a wide variety of substrates, including lipids, across cellular membranes. Mutations in the gene encoding ABCA3 were recently identified in full-term neonates with fatal surfactant deficiency. Objective: To test the hypothesis that ABCA3 mutations are not always associated with fatal neonatal lung disease but are a cause of pediatric interstitial lung disease. Methods: DNA samples were obtained from 195 children with chronic lung disease of unknown etiology. The 30 coding exons of the ABCA3 gene were sequenced in four unrelated children with a referring diagnosis of desquamative interstitial pneumonitis and who were older than 10 years at the time of enrollment. Results: Three of four patients (ages 16, 23, and 11 years) with desquamative interstitial pneumonitis had ABCA3 mutations identified on both alleles. All three had the same missense mutation (E292V) and a second unique mutation. The E292V mutation was not found on 200 control alleles from adults without lung disease, but seven additional patients of the remaining study patients had the E292V mutation on one allele. Immunohistochemical analysis of surfactant protein expression in three patients revealed a specific staining pattern for surfactant protein-B, which was the same pattern observed in several infants with fatal lung disease due to ABCA3 mutations. Conclusion: ABCA3 mutations cause some types of interstitial lung disease in pediatric patients.
Howard A Shuman - One of the best experts on this subject based on the ideXlab platform.
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maltose maltodextrin system of escherichia coli transport metabolism and regulation
Microbiology and Molecular Biology Reviews, 1998Co-Authors: Winfried Boos, Howard A ShumanAbstract:The maltose system of Escherichia coli offers an unusually rich set of enzymes, transporters, and regulators as objects of study. This system is responsible for the uptake and metabolism of glucose polymers (maltodextrins), which must be a preferred class of nutrients for E. coli in both mammalian hosts and in the environment. Because the metabolism of glucose polymers must be coordinated with both the anabolic and catabolic uses of glucose and glycogen, an intricate set of regulatory mechanisms controls the expression of mal genes, the activity of the maltose transporter, and the activities of the maltose/maltodextrin catabolic enzymes. The ease of isolating many of the mal gene products has contributed greatly to the understanding of the structures and functions of several classes of proteins. Not only was the outer membrane maltoporin, LamB, or the phage lambda receptor, the first virus receptor to be isolated, but also its three-dimensional structure, together with extensive knowledge of functional sites for ligand binding as well as for phage λ binding, has led to a relatively complete description of this sugar-specific aqueous channel. The periplasmic maltose binding protein (MBP) has been studied with respect to its role in both maltose transport and maltose taxis. Again, the combination of structural and functional information has led to a significant understanding of how this soluble receptor participates in signaling the presence of sugar to the chemosensory apparatus as well as how it participates in sugar transport. The maltose transporter belongs to the ATP binding Cassette Family, and although its structure is not yet known at atomic resolution, there is some insight into the structures of several functional sites, including those that are involved in interactions with MBP and recognition of substrates and ATP. A particularly astonishing discovery is the direct participation of the transporter in transcriptional control of the mal regulon. The MalT protein activates transcription at all mal promoters. A subset also requires the cyclic AMP receptor protein for transcription. The MalT protein requires maltotriose and ATP as ligands for binding to a dodecanucleotide MalT box that appears in multiple copies upstream of all mal promoters. Recent data indicate that the ATP binding Cassette transporter subunit MalK can directly inhibit MalT when the transporter is inactive due to the absence of substrate. Despite this wealth of knowledge, there are still basic issues that require clarification concerning the mechanism of MalT-mediated activation, repression by the transporter, biosynthesis and assembly of the outer membrane and inner membrane transporter proteins, and interrelationships between the mal enzymes and those of glucose and glycogen metabolism.
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characterization of the structural requirements for assembly and nucleotide binding of an atp binding Cassette transporter the maltose transport system of escherichia coli
Journal of Biological Chemistry, 1993Co-Authors: Cynthia H Panagiotidis, Moraima Reyes, A Sievertsen, Winfried Boos, Howard A ShumanAbstract:Abstract The periplasmic maltose-binding protein-dependent, maltose transport system of Escherichia coli is a well studied member of the ATP-binding Cassette Family of transport ATPases. In addition to the water-soluble maltose-binding protein, the system comprises three membrane proteins, MalF, MalG, and MalK, which form a heterotetrameric complex (FGK2) in the cytoplasmic membrane. The purified complex exhibits transport-associated ATPase activity. To characterize the requirements for nucleotide binding and hydrolysis by the FGK2 complex, we used plasmids to express different combinations of the individual subunits as well as mutant forms of the MalK subunit. Prior to measuring nucleotide binding, we examined membrane preparations for the presence of each subunit from strains that contained all possible permutations of the three structural genes, malF, malG, and malK. We found that when all three genes were present or when malF and malK were present together, the corresponding antigens were detected easily on Western immunoblots and were soluble in the non-ionic detergent, Triton X-100. In contrast, all other permutations resulted in decreased amounts of antigen or antigen that was Triton X-100-insoluble. We relied on photocross-linking with 8-azido-[32P]ATP and ATP hydrolysis as indicators of the ability of the transport complex to interact with purine nucleotides. 8-Azido-[32P]ATP was photocross-linked to the MalK subunit. Photolabeling of MalK was inhibited by ATP, ADP, and GTP and not by other nucleotides. Photolabeling of MalK required the presence of MalF but not MalG. Mutations in malK that affect amino acid residues thought to be directly involved in nucleotide binding did indeed abolish labeling and resulted in loss of transport activity without affecting protein stability. In general, ATP hydrolysis correlated with the photocross-linking. A notable exception is the MalK941 mutant protein which retained the ability to be labeled by 8-azido-[32P]ATP but was unable to catalyze detectable levels of ATP hydrolysis. Some, but not all, of the malK mutations were dominant to wild type. To study the mechanism of dominance we devised a means of measuring the ability of different wild-type and mutant MalK proteins to interact with the MalF and MalG subunits. This assay relies on the fact that, when a bifunctional MalK-LacZ hybrid protein is associated with the MalF and MalG subunits, it is membrane-bound. Excess MalK competed with the MalK-LacZ hybrid protein for sites in the membrane and resulted in the hybrid fractionating as a soluble protein.(ABSTRACT TRUNCATED AT 400 WORDS)
Jahangir Iqbal - One of the best experts on this subject based on the ideXlab platform.
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atp binding Cassette Family a protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma
Journal of Lipid Research, 2018Co-Authors: Jahangir Iqbal, Meghan T Walsh, Samar M Hammad, Marina Cuchel, Daniel J Rader, Mahmood M HussainAbstract:Sphingolipids, including ceramide, SM, and hexosylceramide (HxCer), are carried in the plasma by lipoproteins. They are possible markers of metabolic diseases, but little is known about their control. We previously showed that microsomal triglyceride transfer protein (MTP) is critical to determine plasma ceramide and SM, but not HxCer, levels. In human plasma and mouse models, we examined possible HxCer-modulating pathways, including the role of ABCA1 in determining sphingolipid plasma concentrations. Compared with control samples, plasma from patients with Tangier disease (deficient in ABCA1) had significantly lower HxCer (−69%) and SM (−40%) levels. Similarly, mice deficient in hepatic and intestinal ABCA1 had significantly reduced HxCer (−79%) and SM (−85%) levels. Tissue-specific ablation studies revealed that hepatic ABCA1 determines plasma HxCer and SM levels; that ablation of MTP and ABCA1 in the liver and intestine reduces plasma HxCer, SM, and ceramide levels; and that hepatic and intestinal MTP contribute to plasma ceramide levels, whereas only hepatic MTP modulates plasma SM levels. These results identify the contribution of ABCA1 to plasma SM and HxCer levels and suggest that MTP and ABCA1 are critical determinants of plasma sphingolipid levels.
Mei Hong - One of the best experts on this subject based on the ideXlab platform.
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biochemical studies on the structure function relationship of major drug transporters in the atp binding Cassette Family and solute carrier Family
Advanced Drug Delivery Reviews, 2017Co-Authors: Mei HongAbstract:Human drug transporters often play key roles in determining drug accumulation within cells. Their activities are often directly related to therapeutic efficacy, drug toxicity as well as drug-drug interactions. However, the progress for interpretation of their crystal structures is relatively slow. Hence, conventional biochemical studies together with computer modeling became useful manners to reveal essential structures of these membrane proteins. Over the years, quite a few structure-function relationship information had been obtained for members of the two major transporter families: the ATP-binding Cassette Family and the solute carrier Family. Critical structural features of drug transporters include transmembrane domains, post-translational modification sites and domains for cell surface assembly and protein-protein interactions. Alterations at these important sites may affect protein stability, trafficking to the plasma membrane and/or ability of transporters to interact with substrates.