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Frontiers in Bioengineering and... 2023Metabolic engineering strategies for terpenoid production have mainly focused on bottlenecks in the supply of precursor molecules and cytotoxicity to terpenoids. In... (Review)
Review
Metabolic engineering strategies for terpenoid production have mainly focused on bottlenecks in the supply of precursor molecules and cytotoxicity to terpenoids. In recent years, the strategies involving compartmentalization in eukaryotic cells has rapidly developed and have provided several advantages in the supply of precursors, cofactors and a suitable physiochemical environment for product storage. In this review, we provide a comprehensive analysis of organelle compartmentalization for terpenoid production, which can guide the rewiring of subcellular metabolism to make full use of precursors, reduce metabolite toxicity, as well as provide suitable storage capacity and environment. Additionally, the strategies that can enhance the efficiency of a relocated pathway by increasing the number and size of organelles, expanding the cell membrane and targeting metabolic pathways in several organelles are also discussed. Finally, the challenges and future perspectives of this approach for the terpenoid biosynthesis are also discussed.
PubMed: 36911190
DOI: 10.3389/fbioe.2023.1132244 -
International Journal of Molecular... Nov 2017Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely... (Review)
Review
Benzylisoquinoline alkaloids (BIAs) are among the most important plant secondary metabolites, in that they include a number of biologically active substances widely employed as pharmaceuticals. Isolation of BIAs from their natural sources is an expensive and time-consuming procedure as they accumulate in very low levels in plant. Moreover, total synthesis is challenging due to the presence of stereogenic centers. In view of these considerations, green and scalable methods for BIA synthesis using fully enzymatic approaches are getting more and more attention. The aim of this paper is to review fully enzymatic strategies for producing the benzylisoquinoline central precursor, ()-norcoclaurine and its derivatives. Specifically, we will detail the current status of synthesis of BIAs in microbial hosts as well as using isolated and recombinant enzymes.
Topics: Alkaloids; Bacteria; Benzylisoquinolines; Bioreactors; Escherichia coli; Plants; Recombinant Proteins; Saccharomyces cerevisiae; Tetrahydroisoquinolines
PubMed: 29156609
DOI: 10.3390/ijms18112464 -
Nature Reviews. Rheumatology Mar 2015Osteoclasts are cells of haematopoietic origin that are uniquely specialized to degrade bone. Under physiological conditions, the osteoclastogenesis pathway depends on... (Review)
Review
Osteoclasts are cells of haematopoietic origin that are uniquely specialized to degrade bone. Under physiological conditions, the osteoclastogenesis pathway depends on macrophage colony-stimulating factor 1 (CSF-1, also known as M-CSF) and receptor activator of nuclear factor κB ligand (RANKL). However, an emerging hypothesis is that alternative pathways of osteoclast generation might be active during inflammatory arthritis. In this Perspectives article, we summarize the physiological pathway of osteoclastogenesis and then focus on experimental findings that support the hypothesis that infiltrating inflammatory cells and the cytokine milieu provide multiple routes to bone destruction. The precise identity of osteoclast precursor(s) is not yet known. We propose that myeloid cell differentiation during inflammation could be an important contributor to the differentiation of osteoclast populations and their associated pathologies. Understanding the dynamics of osteoclast differentiation in inflammatory arthritis is crucial for the development of therapeutic strategies for inflammatory joint disease in children and adults.
Topics: Animals; Arthritis; Bone Resorption; Humans; Inflammation; Osteoclasts
PubMed: 25422000
DOI: 10.1038/nrrheum.2014.198 -
The Journal of Nutrition Sep 2020A gluconeogenic precursor is a biochemical compound acted on by a gluconeogenic pathway enabling the net synthesis of glucose. Recognized gluconeogenic precursors in...
A gluconeogenic precursor is a biochemical compound acted on by a gluconeogenic pathway enabling the net synthesis of glucose. Recognized gluconeogenic precursors in fasting placental mammals include glycerol, lactate/pyruvate, certain amino acids, and odd-chain length fatty acids. Each of these precursors is capable of contributing net amounts of carbon to glucose synthesis via the tricarboxylic acid cycle (TCA cycle) because they are anaplerotic, that is, they are able to increase the pools of TCA cycle intermediates by the contribution of more carbon than is lost via carbon dioxide. The net synthesis of glucose from even-chain length fatty acids (ECFAs) in fasting placental mammals, via the TCA cycle alone, is not possible because equal amounts of carbon are lost via carbon dioxide as is contributed from fatty acid oxidation via acetyl-CoA. Therefore, ECFAs do not meet the criteria to be recognized as a gluconeogenic precursor via the TCA cycle alone. ECFAs are gluconeogenic precursors in organisms with a functioning glyoxylate cycle, which enables the net contribution of carbon to the intermediates of the TCA cycle from ECFAs and the net synthesis of glucose. The net conversion of ECFAs to glucose in fasting placental mammals via C3 metabolism of acetone may be a competent though inefficient metabolic path by which ECFA could be considered a gluconeogenic precursor. Defining a substrate as a gluconeogenic precursor requires careful articulation of the definition, organism, and physiologic conditions under consideration.
Topics: Acetyl Coenzyme A; Carbon; Citric Acid Cycle; Fatty Acids; Gluconeogenesis; Glucose; Glyoxylates; Humans; Oxidation-Reduction
PubMed: 32652033
DOI: 10.1093/jn/nxaa166 -
The Journal of Biological Chemistry Jan 2024Developing quantitative models of substrate specificity for RNA processing enzymes is a key step toward understanding their biology and guiding applications in... (Review)
Review
Developing quantitative models of substrate specificity for RNA processing enzymes is a key step toward understanding their biology and guiding applications in biotechnology and biomedicine. Optimally, models to predict relative rate constants for alternative substrates should integrate an understanding of structures of the enzyme bound to "fast" and "slow" substrates, large datasets of rate constants for alternative substrates, and transcriptomic data identifying in vivo processing sites. Such data are either available or emerging for bacterial ribonucleoprotein RNase P a widespread and essential tRNA 5' processing endonuclease, thus making it a valuable model system for investigating principles of biological specificity. Indeed, the well-established structure and kinetics of bacterial RNase P enabled the development of high throughput measurements of rate constants for tRNA variants and provided the necessary framework for quantitative specificity modeling. Several studies document the importance of conformational changes in the precursor tRNA substrate as well as the RNA and protein subunits of bacterial RNase P during binding, although the functional roles and dynamics are still being resolved. Recently, results from cryo-EM studies of E. coli RNase P with alternative precursor tRNAs are revealing prospective mechanistic relationships between conformational changes and substrate specificity. Yet, extensive uncharted territory remains, including leveraging these advances for drug discovery, achieving a complete accounting of RNase P substrates, and understanding how the cellular context contributes to RNA processing specificity in vivo.
Topics: Escherichia coli; Nucleic Acid Conformation; Ribonuclease P; RNA Precursors; RNA, Bacterial; RNA, Transfer; Substrate Specificity; Bacterial Proteins; Protein Binding
PubMed: 38013087
DOI: 10.1016/j.jbc.2023.105498 -
Journal of Neurochemistry May 2017Most growth factors and hormones are synthesized as pre-pro-proteins which are processed to the biologically active mature protein. The pre- and prodomains are cleaved... (Review)
Review
Most growth factors and hormones are synthesized as pre-pro-proteins which are processed to the biologically active mature protein. The pre- and prodomains are cleaved from the precursor protein in the secretory pathway or, in some cases, extracellularly. The canonical functions of these prodomains are to assist in folding and stabilization of the mature domain, to direct intra and extracellular localization, to facilitate storage, and to regulate bioavailability of their mature counterpart. Recently, exciting evidence has revealed that prodomains of certain growth factors, after cleaved from the precursor pro-protein, can act as independent active signaling molecules. In this review, we discuss the various classical functions of prodomains, and the biological consequences of these pro-peptides acting as ligands. We will focus our attention on the brain-derived neurotrophic factor prodomain (pBDNF), which has been recently described as a novel secreted ligand influencing neuronal morphology and physiology.
Topics: Animals; Brain-Derived Neurotrophic Factor; Hormones; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Protein Precursors
PubMed: 28218971
DOI: 10.1111/jnc.13993 -
Biochemical Society Transactions Nov 2021Many growth factors and cytokines are produced as larger precursors, containing pro-domains, that require proteolytic processing to release the bioactive ligand. These... (Review)
Review
Many growth factors and cytokines are produced as larger precursors, containing pro-domains, that require proteolytic processing to release the bioactive ligand. These pro-domains can be significantly larger than the mature domains and can play an active role in the regulation of the ligands. Mining the UniProt database, we identified almost one hundred human growth factors and cytokines with pro-domains. These are spread across several unrelated protein families and vary in both their size and composition. The precise role of each pro-domain varies significantly between the protein families. Typically they are critical for controlling bioactivity and protein localisation, and they facilitate diverse mechanisms of activation. Significant gaps in our understanding remain for pro-domain function - particularly their fate once the bioactive ligand has been released. Here we provide an overview of pro-domain roles in human growth factors and cytokines, their processing, regulation and activation, localisation as well as therapeutic potential.
Topics: Animals; Biomarkers; Cytokines; Drug Discovery; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Protein Domains; Protein Precursors; Proteolysis; Signal Transduction
PubMed: 34495310
DOI: 10.1042/BST20200663 -
Seminars in Cell & Developmental Biology Aug 2014Secreted cytokines of the TGFβ family are found in all multicellular organisms and implicated in regulating fundamental cell behaviors such as proliferation,... (Review)
Review
Secreted cytokines of the TGFβ family are found in all multicellular organisms and implicated in regulating fundamental cell behaviors such as proliferation, differentiation, migration and survival. Signal transduction involves complexes of specific type I and II receptor kinases that induce the nuclear translocation of Smad transcription factors to regulate target genes. Ligands of the BMP and Nodal subgroups act at a distance to specify distinct cell fates in a concentration-dependent manner. These signaling gradients are shaped by multiple factors, including proteases of the proprotein convertase (PC) family that hydrolyze one or several peptide bonds between an N-terminal prodomain and the C-terminal domain that forms the mature ligand. This review summarizes information on the proteolytic processing of TGFβ and related precursors, and its spatiotemporal regulation by PCs during development and various diseases, including cancer. Available evidence suggests that the unmasking of receptor binding epitopes of TGFβ is only one (and in some cases a non-essential) function of precursor processing. Future studies should consider the impact of proteolytic maturation on protein localization, trafficking and turnover in cells and in the extracellular space.
Topics: Animals; Humans; Latent TGF-beta Binding Proteins; Models, Molecular; Proprotein Convertases; Protein Binding; Protein Precursors; Protein Structure, Tertiary; Signal Transduction; Transforming Growth Factor beta
PubMed: 24508081
DOI: 10.1016/j.semcdb.2014.01.008 -
National Science Review Jul 2023Precursor liquid is a nanoscale liquid creeping ahead of the macroscopic edge of spreading liquids, whose behaviors tightly correlate with the three-phase reaction...
Precursor liquid is a nanoscale liquid creeping ahead of the macroscopic edge of spreading liquids, whose behaviors tightly correlate with the three-phase reaction efficiency and patterning accuracy. However, the important spatial-temporal characteristic of the precursor liquid still remains obscure because its real-time spreading process has not been directly observed. Here, we report that the spreading ionic liquid precursors in a silicon corner can be directly captured on video using scanning electron microscopy. spreading videos show that the precursor liquid spreads linearly over time ([Formula: see text]) rather than obeying the classic Lucas-Washburn law ([Formula: see text]) and possesses a characteristic width of ∼250-310 nm. Theoretical analyses and molecular dynamics simulations demonstrate that the unique behaviors of precursor liquids originate from the competing effect of van der Waals force and surface energy. These findings provide avenues for directly observing liquid/solid interfacial phenomena on a microscopic level.
PubMed: 37266559
DOI: 10.1093/nsr/nwad119 -
The New Phytologist Jan 2021The gaseous plant hormone ethylene is produced by a fairly simple two-step biosynthesis route. Despite this pathway's simplicity, recent molecular and genetic studies... (Review)
Review
The gaseous plant hormone ethylene is produced by a fairly simple two-step biosynthesis route. Despite this pathway's simplicity, recent molecular and genetic studies have revealed that the regulation of ethylene biosynthesis is far more complex and occurs at different layers. Ethylene production is intimately linked with the homeostasis of its general precursor S-adenosyl-l-methionine (SAM), which experiences transcriptional and posttranslational control of its synthesising enzymes (SAM synthetase), as well as the metabolic flux through the adjacent Yang cycle. Ethylene biosynthesis continues from SAM by two dedicated enzymes: 1-aminocyclopropane-1-carboxylic (ACC) synthase (ACS) and ACC oxidase (ACO). Although the transcriptional dynamics of ACS and ACO have been well documented, the first transcription factors that control ACS and ACO expression have only recently been discovered. Both ACS and ACO display a type-specific posttranslational regulation that controls protein stability and activity. The nonproteinogenic amino acid ACC also shows a tight level of control through conjugation and translocation. Different players in ACC conjugation and transport have been identified over the years, however their molecular regulation and biological significance is unclear, yet relevant, as ACC can also signal independently of ethylene. In this review, we bring together historical reports and the latest findings on the complex regulation of the ethylene biosynthesis pathway in plants.
Topics: Amino Acid Oxidoreductases; Ethylenes; Gene Expression Regulation, Plant; Lyases; Plants
PubMed: 32790878
DOI: 10.1111/nph.16873