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1.
Int J Mol Sci ; 23(13)2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1934132

ABSTRACT

Boesenbergia rotunda (Zingiberaceae), is a high-value culinary and ethno-medicinal plant of Southeast Asia. The rhizomes of this herb have a high flavanone and chalcone content. Here we report the genome analysis of B. rotunda together with a complete genome sequence as a hybrid assembly. B. rotunda has an estimated genome size of 2.4 Gb which is assembled as 27,491 contigs with an N50 size of 12.386 Mb. The highly heterozygous genome encodes 71,072 protein-coding genes and has a 72% repeat content, with class I TEs occupying ~67% of the assembled genome. Fluorescence in situ hybridization of the 18 chromosome pairs at the metaphase showed six sites of 45S rDNA and two sites of 5S rDNA. An SSR analysis identified 238,441 gSSRs and 4604 EST-SSRs with 49 SSR markers common among related species. Genome-wide methylation percentages ranged from 73% CpG, 36% CHG and 34% CHH in the leaf to 53% CpG, 18% CHG and 25% CHH in the embryogenic callus. Panduratin A biosynthetic unigenes were most highly expressed in the watery callus. B rotunda has a relatively large genome with a high heterozygosity and TE content. This assembly and data (PRJNA71294) comprise a source for further research on the functional genomics of B. rotunda, the evolution of the ginger plant family and the potential genetic selection or improvement of gingers.


Subject(s)
Ginger , Zingiberaceae , Biosynthetic Pathways , DNA, Ribosomal , Flavonoids , Ginger/genetics , In Situ Hybridization, Fluorescence , Microsatellite Repeats/genetics , Zingiberaceae/genetics
2.
Nat Prod Rep ; 38(7): 1251-1281, 2021 07 01.
Article in English | MEDLINE | ID: covidwho-1324434

ABSTRACT

Covering: July 2012 to December 2019Over the last seven years, expanding research efforts focused on sesterterpenoids has led to the isolation, identification, and characterization of numerous structurally novel and biologically active sesterterpenoids. These newly reported sesterterpenoids provide diverse structures that often incorporate unprecedented ring systems and new carbon skeletons, as well as unusual functional group arrays. Biological activities of potential biomedical importance including suppression of cancer cell growth, inhibition of enzymatic activity, and modulation of receptor signaling, as well as ecologically important functions such as antimicrobial effects and deterrence of herbivorous insects have been associated with a variety of sesterterpenoids. There has also been a rapid growth in our knowledge of the genomics, enzymology, and specific pathways associated with sesterterpene biosynthesis. This has opened up new opportunities for future sesterterpene discovery and diversification through the expression of new cryptic metabolites and the engineered manipulation of associated biosynthetic machinery and processes. In this paper we reviewed 498 new sesterterpenoids, including their structures, source organisms, country of origin, relevant bioactivities, and biosynthesis.


Subject(s)
Sesterterpenes , Bacteria , Biological Products/chemistry , Biological Products/pharmacology , Biosynthetic Pathways , Fungi , Molecular Structure , Plants , Sesterterpenes/chemistry , Sesterterpenes/pharmacology
3.
Plant J ; 107(5): 1299-1319, 2021 09.
Article in English | MEDLINE | ID: covidwho-1282039

ABSTRACT

Caffeoylquinic acids (CQAs) are specialized plant metabolites we encounter in our daily life. Humans consume CQAs in mg-to-gram quantities through dietary consumption of plant products. CQAs are considered beneficial for human health, mainly due to their anti-inflammatory and antioxidant properties. Recently, new biosynthetic pathways via a peroxidase-type p-coumaric acid 3-hydroxylase enzyme were discovered. More recently, a new GDSL lipase-like enzyme able to transform monoCQAs into diCQA was identified in Ipomoea batatas. CQAs were recently linked to memory improvement; they seem to be strong indirect antioxidants via Nrf2 activation. However, there is a prevalent confusion in the designation and nomenclature of different CQA isomers. Such inconsistencies are critical and complicate bioactivity assessment since different isomers differ in bioactivity and potency. A detailed explanation regarding the origin of such confusion is provided, and a recommendation to unify nomenclature is suggested. Furthermore, for studies on CQA bioactivity, plant-based laboratory animal diets contain CQAs, which makes it difficult to include proper control groups for comparison. Therefore, a synthetic diet free of CQAs is advised to avoid interferences since some CQAs may produce bioactivity even at nanomolar levels. Biotransformation of CQAs by gut microbiota, the discovery of new enzymatic biosynthetic and metabolic pathways, dietary assessment, and assessment of biological properties with potential for drug development are areas of active, ongoing research. This review is focused on the chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity recently reported for mono-, di-, tri-, and tetraCQAs.


Subject(s)
Anti-Inflammatory Agents/chemistry , Antioxidants/chemistry , Cognitive Dysfunction/prevention & control , Neuroprotective Agents/chemistry , Phytochemicals/chemistry , Plants, Medicinal/chemistry , Quinic Acid/analogs & derivatives , Acyltransferases/genetics , Acyltransferases/metabolism , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , Biosynthetic Pathways , Brachypodium/enzymology , Dietary Supplements , Humans , Ipomoea batatas/enzymology , Mixed Function Oxygenases/genetics , Mixed Function Oxygenases/metabolism , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Phytochemicals/metabolism , Phytochemicals/pharmacology , Plant Proteins/genetics , Plant Proteins/metabolism , Quinic Acid/chemistry , Quinic Acid/metabolism , Quinic Acid/pharmacology , Terminology as Topic
4.
Life Sci ; 277: 119508, 2021 Jul 15.
Article in English | MEDLINE | ID: covidwho-1185152

ABSTRACT

Antiviral strategies for viruses that utilize proteoglycan core proteins (syndecans and glypicans) as receptors should focus on heparan sulfate (HS) biosynthesis rather than on inhibition of these sugar chains. Here, we show that heparin and certain xylosides, which exhibit in vitro viral entry inhibitory properties against HSV-1, HSV-2, HPV-16, HPV-31, HVB, HVC, HIV-1, HTLV-1, SARS-CoV-2, HCMV, DENV-1, and DENV-2, stimulated HS biosynthesis at the cell surface 2- to 3-fold for heparin and up to 10-fold for such xylosides. This is consistent with the hypothesis from a previous study that for core protein attachment, viruses are glycosylated at HS attachment sites (i.e., serine residues intended to receive the D-xylose molecule for initiating HS chains). Heparanase overexpression, endocytic entry, and syndecan shedding enhancement, all of which are observed during viral infection, lead to glycocalyx deregulation and appear to be direct consequences of this hypothesis. In addition to the appearance of type 2 diabetes and the degradation of HS observed during viral infection, we linked this hypothesis to that proposed in a previous publication.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Biosynthetic Pathways/drug effects , Heparitin Sulfate/metabolism , Virus Internalization/drug effects , Animals , Drug Discovery , Glycosides/chemistry , Glycosides/pharmacology , Heparin/chemistry , Heparin/pharmacology , Humans , Virus Diseases/drug therapy
5.
Cell ; 184(1): 106-119.e14, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064913

ABSTRACT

The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.


Subject(s)
COVID-19/genetics , Coronavirus Infections/genetics , Coronavirus/physiology , Genome-Wide Association Study , Host-Pathogen Interactions , SARS-CoV-2/physiology , A549 Cells , Animals , Biosynthetic Pathways/drug effects , COVID-19/virology , Cell Line , Chlorocebus aethiops , Cholesterol/biosynthesis , Cholesterol/metabolism , Cluster Analysis , Clustered Regularly Interspaced Short Palindromic Repeats , Common Cold/genetics , Common Cold/virology , Coronavirus/classification , Coronavirus Infections/virology , Gene Knockout Techniques , Host-Pathogen Interactions/drug effects , Humans , Mice , Phosphatidylinositols/biosynthesis , Vero Cells , Virus Internalization/drug effects , Virus Replication
6.
Cell ; 184(1): 92-105.e16, 2021 01 07.
Article in English | MEDLINE | ID: covidwho-1064907

ABSTRACT

To better understand host-virus genetic dependencies and find potential therapeutic targets for COVID-19, we performed a genome-scale CRISPR loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection of human alveolar epithelial cells. Top-ranked genes cluster into distinct pathways, including the vacuolar ATPase proton pump, Retromer, and Commander complexes. We validate these gene targets using several orthogonal methods such as CRISPR knockout, RNA interference knockdown, and small-molecule inhibitors. Using single-cell RNA-sequencing, we identify shared transcriptional changes in cholesterol biosynthesis upon loss of top-ranked genes. In addition, given the key role of the ACE2 receptor in the early stages of viral entry, we show that loss of RAB7A reduces viral entry by sequestering the ACE2 receptor inside cells. Overall, this work provides a genome-scale, quantitative resource of the impact of the loss of each host gene on fitness/response to viral infection.


Subject(s)
COVID-19/genetics , COVID-19/virology , Host-Pathogen Interactions , SARS-CoV-2/physiology , A549 Cells , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , Angiotensin-Converting Enzyme 2/metabolism , Biosynthetic Pathways , COVID-19/metabolism , Cholesterol/biosynthesis , Clustered Regularly Interspaced Short Palindromic Repeats , Endosomes/metabolism , Gene Expression Profiling , Gene Knockdown Techniques , Gene Knockout Techniques/methods , Genome-Wide Association Study , Host-Pathogen Interactions/drug effects , Humans , RNA Interference , SARS-CoV-2/growth & development , Single-Cell Analysis , Viral Load/drug effects , rab GTP-Binding Proteins/genetics
7.
J Phys Chem B ; 124(50): 11406-11418, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-960265

ABSTRACT

Chronic inflammation is now widely recognized to play important roles in many commonly occurring diseases, including COVID-19. The resolution response to this chronic inflammation is an active process governed by specialized pro-resolving mediators (SPMs) like the lipid mediators known as lipoxins. The biosynthesis of lipoxins is catalyzed by several lipoxygenases (LOXs) from arachidonic acid. However, the molecular details of the mechanisms involved are not well known yet. In this paper, we have combined molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations to analyze how reticulocyte 15-LOX-1 catalyzes the production of lipoxins from 5(S),15(S)-diHpETE. Our results indicate that the dehydration mechanism from 5(S),15(S)-diHpETE, via the formation of an epoxide, presents huge energy barriers even though it was one of the two a priori synthetic proposals. This result is compatible with the fact that no epoxide has been directly detected as an intermediate in the catalytic formation of lipoxins from 5(S),15(S)-diHpETE. Conversely, the oxygenation of 5(S),15(S)-diHpETE at C14 is feasible because there is an open channel connecting the protein surface with this carbon atom, and the energy barrier for oxygen addition through this channel is small. The analysis of the following steps of this mechanism, leading to the corresponding hydroperoxide at the 15-LOX-1 active site, indicates that the oxygenation mechanism will lead to the formation of lipoxinB4 after the final action of a reductase. In contrast, our calculations are in agreement with experiments that lipoxinA4 cannot derive from 5(S),15(S)-diHpETE by either of the two proposed mechanisms and that 5(S),15(S)-diHETE is not an intermediate of lipoxin biosynthesis catalyzed by 15-LOX-1.


Subject(s)
Arachidonate 15-Lipoxygenase/metabolism , Leukotrienes/biosynthesis , Lipid Peroxides/biosynthesis , Lipoxins/biosynthesis , Reticulocytes/enzymology , Biosynthetic Pathways , COVID-19/complications , Catalysis , Humans , Inflammation/etiology , Inflammation/metabolism , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Oxygen/chemistry , Quantum Theory
8.
Int J Mol Sci ; 21(10)2020 May 17.
Article in English | MEDLINE | ID: covidwho-277083

ABSTRACT

The current Coronavirus disease 2019 or COVID-19 pandemic has infected over two million people and resulted in the death of over one hundred thousand people at the time of writing this review. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Even though multiple vaccines and treatments are under development so far, the disease is only slowing down under extreme social distancing measures that are difficult to maintain. SARS-COV-2 is an enveloped virus that is surrounded by a lipid bilayer. Lipids are fundamental cell components that play various biological roles ranging from being a structural building block to a signaling molecule as well as a central energy store. The role lipids play in viral infection involves the fusion of the viral membrane to the host cell, viral replication, and viral endocytosis and exocytosis. Since lipids play a crucial function in the viral life cycle, we asked whether drugs targeting lipid metabolism, such as statins, can be utilized against SARS-CoV-2 and other viruses. In this review, we discuss the role of lipid metabolism in viral infection as well as the possibility of targeting lipid metabolism to interfere with the viral life cycle.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/metabolism , Lipid Metabolism , Pneumonia, Viral/metabolism , Animals , Biosynthetic Pathways , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Endocytosis/drug effects , Humans , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , SARS-CoV-2 , Virus Internalization/drug effects
9.
Rev Med Virol ; 30(3): e2109, 2020 05.
Article in English | MEDLINE | ID: covidwho-95194

ABSTRACT

There is a growing appreciation that the regulation of the melatonergic pathways, both pineal and systemic, may be an important aspect in how viruses drive the cellular changes that underpin their control of cellular function. We review the melatonergic pathway role in viral infections, emphasizing influenza and covid-19 infections. Viral, or preexistent, suppression of pineal melatonin disinhibits neutrophil attraction, thereby contributing to an initial "cytokine storm", as well as the regulation of other immune cells. Melatonin induces the circadian gene, Bmal1, which disinhibits the pyruvate dehydrogenase complex (PDC), countering viral inhibition of Bmal1/PDC. PDC drives mitochondrial conversion of pyruvate to acetyl-coenzyme A (acetyl-CoA), thereby increasing the tricarboxylic acid cycle, oxidative phosphorylation, and ATP production. Pineal melatonin suppression attenuates this, preventing the circadian "resetting" of mitochondrial metabolism. This is especially relevant in immune cells, where shifting metabolism from glycolytic to oxidative phosphorylation, switches cells from reactive to quiescent phenotypes. Acetyl-CoA is a necessary cosubstrate for arylalkylamine N-acetyltransferase, providing an acetyl group to serotonin, and thereby initiating the melatonergic pathway. Consequently, pineal melatonin regulates mitochondrial melatonin and immune cell phenotype. Virus- and cytokine-storm-driven control of the pineal and mitochondrial melatonergic pathway therefore regulates immune responses. Virus-and cytokine storm-driven changes also increase gut permeability and dysbiosis, thereby suppressing levels of the short-chain fatty acid, butyrate, and increasing circulating lipopolysaccharide (LPS). The alterations in butyrate and LPS can promote viral replication and host symptom severity via impacts on the melatonergic pathway. Focussing on immune regulators has treatment implications for covid-19 and other viral infections.


Subject(s)
Coronavirus Infections/physiopathology , Influenza, Human/metabolism , Melatonin/metabolism , Pneumonia, Viral/physiopathology , Animals , Betacoronavirus/physiology , Biosynthetic Pathways , COVID-19 , Circadian Rhythm , Circadian Rhythm Signaling Peptides and Proteins/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/immunology , Humans , Influenza, Human/immunology , Melatonin/immunology , Mitochondria/metabolism , Orthomyxoviridae/physiology , Pandemics , Pineal Gland/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Viruses/classification
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