| 1. |
- Crüsemann, Max, et al.
(författare)
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Heterologous Expression, Biosynthetic Studies, and Ecological Function of the Selective Gq-Signaling Inhibitor FR900359
- 2018
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Ingår i: Angewandte Chemie International Edition. - : John Wiley & Sons. - 1433-7851 .- 1521-3773. ; 57:3, s. 836-840
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Tidskriftsartikel (refereegranskat)abstract
- The cyclic depsipeptide FR900359 (FR), isolated from the tropical plant Ardisia crenata, is a strong and selective inhibitor of Gq proteins, making it an indispensable pharmacological tool to study Gq-related processes, as well as a promising drug candidate. Gq inhibition is a novel mode of action for defense chemicals and crucial for the ecological function of FR, as shown by in vivo experiments in mice, its affinity to insect Gq proteins, and insect toxicity studies. The uncultured endosymbiont of A. crenata was sequenced, revealing the FR nonribosomal peptide synthetase (frs) gene cluster. We here provide a detailed model of FR biosynthesis, supported by in vitro enzymatic and bioinformatic studies, and the novel analogue AC-1, which demonstrates the flexibility of the FR starter condensation domains. Finally, expression of the frs genes in E. coli led to heterologous FR production in a cultivable, bacterial host for the first time.
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| 2. |
- Al-Sabri, Mohamed H., et al.
(författare)
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The regulatory role of AP-2 beta in monoaminergic neurotransmitter systems : insights on its signalling pathway, linked disorders and theragnostic potential
- 2022
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Ingår i: Cell & Bioscience. - : BioMed Central (BMC). - 2045-3701. ; 12:1
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Forskningsöversikt (refereegranskat)abstract
- Monoaminergic neurotransmitter systems play a central role in neuronal function and behaviour. Dysregulation of these systems gives rise to neuropsychiatric and neurodegenerative disorders with high prevalence and societal burden, collectively termed monoamine neurotransmitter disorders (MNDs). Despite extensive research, the transcriptional regulation of monoaminergic neurotransmitter systems is not fully explored. Interestingly, certain drugs that act on these systems have been shown to modulate central levels of the transcription factor AP-2 beta (AP-2 beta, gene: TFAP2B). AP-2 beta regulates multiple key genes within these systems and thereby its levels correlate with monoamine neurotransmitters measures; yet, its signalling pathways are not well understood. Moreover, although dysregulation of TFAP2B has been associated with MNDs, the underlying mechanisms for these associations remain elusive. In this context, this review addresses AP-2 beta, considering its basic structural aspects, regulation and signalling pathways in the controlling of monoaminergic neurotransmitter systems, and possible mechanisms underpinning associated MNDS. It also underscores the significance of AP-2 beta as a potential diagnostic biomarker and its potential and limitations as a therapeutic target for specific MNDs as well as possible pharmaceutical interventions for targeting it. In essence, this review emphasizes the role of AP-2 beta as a key regulator of the monoaminergic neurotransmitter systems and its importance for understanding the pathogenesis and improving the management of MNDs.
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| 3. |
- Attwood, Misty M., et al.
(författare)
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Characterization of five transmembrane proteins : With focus on the Tweety, Sidoreflexin, and YIP1 domain families
- 2021
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media S.A.. - 2296-634X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Transmembrane proteins are involved in many essential cell processes such as signal transduction, transport, and protein trafficking, and hence many are implicated in different disease pathways. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e. the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. This analysis investigates the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). More than half of the 58 proteins identified with the 5TM architecture belong to twelve families with two or more members, with ten complete families that do not have any other homologous human proteins identified. Interestingly, more than half the proteins in the dataset function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this family in large contrast with other TM families. The three major 5TM families include the Tweety family, which are pore-forming subunits of the swelling-dependent volume regulated anion channel in astrocytes; the sidoreflexin family that act as mitochondrial amino acid transporters; and the Yip1 domain family engaged in vesicle budding and intra-Golgi transport. About 30% of the 5TM proteins have enhanced expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumour types, indicating further investigation into the function and expression of these proteins is important. This study provides the first comprehensive analysis of proteins with 5TM providing details of the unique characteristics
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| 4. |
- Attwood, Misty M., et al.
(författare)
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Classification of Trispanins : A Diverse Group of Proteins That Function in Membrane Synthesis and Transport Mechanisms
- 2020
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- As the structure and functions of proteins are correlated, investigating groups of proteins with the same gross structure may provide important insights about their functional roles. Trispanins, proteins that contain three alpha-helical transmembrane (3TM) regions, have not been previously studied considering their transmembrane features. Our comprehensive identification and classification using bioinformatic methods describe 152 3TM proteins. These proteins are frequently involved in membrane biosynthesis and lipid biogenesis, protein trafficking, catabolic processes, and in particular signal transduction due to the large ionotropic glutamate receptor family. Proteins that localize to intracellular compartments are overrepresented in the dataset in comparison to the entire human transmembrane proteome, and nearly 45% localize specifically to the endoplasmic reticulum (ER). Furthermore, nearly 20% of the trispanins function in lipid metabolic processes and transport, which are also overrepresented. Nearly one-third of trispanins are identified as being targeted by drugs and/or being associated with diseases. A high number of 3TMs have unknown functions and based on this analysis we speculate on the functional involvement of uncharacterized trispanins in relationship to disease or important cellular activities. This first overall study of trispanins provides a unique analysis of a diverse group of membrane proteins.
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| 5. |
- Attwood, Misty M., et al.
(författare)
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Highly diversified expansions shaped the evolution of membrane bound proteins in metazoans
- 2017
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The dramatic increase in membrane proteome complexity is arguably one of the most pivotal evolutionary events that underpins the origin of multicellular animals. However, the origin of a significant number of membrane families involved in metazoan development has not been clarified. In this study, we have manually curated the membrane proteomes of 22 metazoan and 2 unicellular holozoan species. We identify 123,014 membrane proteins in these 24 eukaryotic species and classify 86% of the dataset. We determine 604 functional clusters that are present from the last holozoan common ancestor (LHCA) through many metazoan species. Intriguingly, we show that more than 70% of the metazoan membrane protein families have a premetazoan origin. The data show that enzymes are more highly represented in the LHCA and expand less than threefold throughout metazoan species; in contrast to receptors that are relatively few in the LHCA but expand nearly eight fold within metazoans. Expansions related to cell adhesion, communication, immune defence, and developmental processes are shown in conjunction with emerging biological systems, such as neuronal development, cytoskeleton organization, and the adaptive immune response. This study defines the possible LHCA membrane proteome and describes the fundamental functional clusters that underlie metazoan diversity and innovation.
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| 6. |
- Attwood, Misty M.
(författare)
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Membrane-bound proteins : Characterization, evolution, and functional analysis
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alpha-helical transmembrane proteins are important components of many essential cell processes including signal transduction, transport of molecules across membranes, protein and membrane trafficking, and structural and adhesion activities, amongst others. Their involvement in critical networks makes them the focus of interest in investigating disease pathways, as candidate drug targets, and in evolutionary analyses to identify homologous protein families and possible functional activities. Transmembrane (TM) proteins can be categorized into major groups based the same gross structure, i.e., the number of transmembrane helices, which are often correlated with specific functional activities, for example as receptors or transporters. The focus of this thesis was to analyze the evolution of the membrane proteome from the last holozoan common ancestor (LHCA) through metazoans to garner insight into the fundamental functional clusters that underlie metazoan diversity and innovation. Twenty-four eukaryotic proteomes were analyzed, with results showing more than 70% of metazoan transmembrane protein families have a pre-metazoan origin. In concert with that, we characterized the previously unstudied groups of human proteins with three, four, and five membrane-spanning regions (3TM, 4TM, and 5TM) and analyzed their functional activities, involvement in disease pathways, and unique characteristics. Combined, we manually curated and classified nearly 11% of the human transmembrane proteome with these three studies. The 3TM data set included 152 proteins, with nearly 45% that localize specifically to the endoplasmic reticulum (ER), and are involved in membrane biosynthesis and lipid biogenesis, proteins trafficking, catabolic processes, and signal transduction due to the large ionotropic glutamate receptor family. The 373 proteins identified in the 4TM data set are predominantly involved in transport activities, as well as cell communication and adhesion, and function as structural elements. The compact 5TM data set includes 58 proteins that engage in localization and transport activities, such as protein targeting, membrane trafficking, and vesicle transport. Notably, ~60% are identified as cancer prognostic markers that are associated with clinical outcomes of different tumour types. This thesis investigates the evolutionary origins of the human transmembrane proteome, characterizes formerly dark areas of the membrane proteome, and extends the fundamental knowledge of transmembrane proteins.
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| 7. |
- Attwood, Misty M., et al.
(författare)
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Orphan Drugs and Their Impact on Pharmaceutical Development
- 2018
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Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 39:6, s. 525-535
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Forskningsöversikt (refereegranskat)abstract
- High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.
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| 8. |
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| 9. |
- Attwood, Misty M., et al.
(författare)
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Soluble ligands as drug targets
- 2020
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Ingår i: Nature reviews. Drug discovery. - : NATURE RESEARCH. - 1474-1776 .- 1474-1784. ; 19:10, s. 695-710
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Forskningsöversikt (refereegranskat)abstract
- Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases. With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.
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| 10. |
- Attwood, Misty M., et al.
(författare)
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Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome
- 2016
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Membrane proteins are key components in a large spectrum of diverse functions and thus account for the major proportion of the drug-targeted portion of the genome. From a structural perspective, the a-helical transmembrane proteins can be categorized into major groups based on the number of transmembrane helices and these groups are often associated with specific functions. When compared to the well-characterized seven-transmembrane containing proteins (7TM), other TM groups are less explored and in particular the 4TM group. In this study, we identify the complete 4TM complement from the latest release of the human genome and assess the 4TM structure group as a whole. We functionally characterize this dataset and evaluate the resulting groups and ubiquitous functions, and furthermore describe disease and drug target involvement.Results: We classified 373 proteins, which represents similar to 7 % of the human membrane proteome, and includes 69 more proteins than our previous estimate. We have characterized the 4TM dataset based on functional, structural, and/or evolutionary similarities. Proteins that are involved in transport activity constitute 37 % of the dataset, 23 % are receptor-related, and 13 % have enzymatic functions. Intriguingly, proteins involved in transport are more than double the 15 % of transporters in the entire human membrane proteome, which might suggest that the 4TM topological architecture is more favored for transporting molecules over other functions. Moreover, we found an interesting exception to the ubiquitous intracellular N- and C-termini localization that is found throughout the entire membrane proteome and 4TM dataset in the neurotransmitter gated ion channel families. Overall, we estimate that 58 % of the dataset has a known association to disease conditions with 19 % of the genes possibly involved in different types of cancer.Conclusions: We provide here the most robust and updated classification of the 4TM complement of the human genome as a platform to further understand the characteristics of 4TM functions and to explore pharmacological opportunities.
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