amino acid residues
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Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 130
Ayana Yoshihara ◽  
Haru Kawasaki ◽  
Hiroyuki Masuno ◽  
Koki Takada ◽  
Nobutaka Numoto ◽  

1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, 1] is an active form of vitamin D3 and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)2D3, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3.

2022 ◽  
Vol 2 (1) ◽  
pp. 22
I Putu Ari Anggara Catur Pratama ◽  
I Made Harimbawa Putra ◽  
Luh Wayan Sita Pujasari ◽  
Komang Dian Merta Sari Dewi ◽  
Ni Putu Linda Laksmiani

COVID-19 infection induces inflammation by increasing cytokines such as IL-1b, IL-6, IL-18, IFN-γ, and TNF-α. IL-1b is generated by the involvement of caspase-1. Therefore, caspase-1 inhibitor can be potential for inflammation therapy caused by COVID-19 infection. This study aims to determine the potential of blumeatin and luteolin as anti-inflammatory agents by inhibiting caspase-1 using a molecular docking approach. This study was carried out by caspase-1 (PDB ID: 1RWK) preparation, blumeatin and luteolin structure optimization, docking protocol validation, and docking of blumeatin and luteolin on caspase-1. Bluematin and luteolin had a binding affinity of -5,63 kcal/mol and -5,93 kcal/mol, lower than Q158 native ligand (-3.92 kcal/mol). Similar amino acid residues in hydrogen bonds interaction were observed between Q158 native ligand, blumeatin, and luteolin with caspase-1 (GLN 283 and ARG 179). Blumeatin and luteolin are potentially anti-inflammation agents through the inhibition of the caspase-1 in silico.

2022 ◽  
William P Robins ◽  
John J Mekalanos

SARS-CoV-2 is one of three recognized coronaviruses (CoVs) that have caused epidemics or pandemics in the 21st century and that likely emerged from animal reservoirs. Differences in nucleotide and protein sequence composition within related lower case Greek beta-coronaviruses are often used to better understand CoV evolution, host adaptation, and their emergence as human pathogens. Here we report the comprehensive analysis of amino acid residue changes that have occurred in lineage B lower case Greek betacoronaviruses (sarbecoviruses) that show covariance with each other. This analysis revealed patterns of covariance within conserved viral proteins that potentially define conserved interactions within and between core proteins encoded by SARS-CoV-2 related lower case Greek beta-coranaviruses. We identified not only individual pairs but also networks of amino acid residues that exhibited statistically high frequencies of covariance with each other using an independent pair model followed by a tandem model approach. Using 149 different CoV genomes that vary in their relatedness, we identified networks of unique combinations of alleles that can be incrementally traced genome by genome within different phylogenic lineages. Remarkably, covariant residues and their respective regions most abundantly represented are implicated in the emergence of SARS-CoV-2 and are also enriched in dominant SARS-CoV-2 variants.

2022 ◽  
Vol 18 (1) ◽  
pp. e1009828
Benjamin J. Hulme ◽  
Kathrin K. Geyer ◽  
Josephine E. Forde-Thomas ◽  
Gilda Padalino ◽  
Dylan W. Phillips ◽  

α-galactosidase (α-GAL) and α-N-acetylgalactosaminidase (α-NAGAL) are two glycosyl hydrolases responsible for maintaining cellular homeostasis by regulating glycan substrates on proteins and lipids. Mutations in the human genes encoding either enzyme lead to neurological and neuromuscular impairments seen in both Fabry- and Schindler/Kanzaki- diseases. Here, we investigate whether the parasitic blood fluke Schistosoma mansoni, responsible for the neglected tropical disease schistosomiasis, also contains functionally important α-GAL and α-NAGAL proteins. As infection, parasite maturation and host interactions are all governed by carefully-regulated glycosylation processes, inhibiting S. mansoni’s α-GAL and α-NAGAL activities could lead to the development of novel chemotherapeutics. Sequence and phylogenetic analyses of putative α-GAL/α-NAGAL protein types showed Smp_089290 to be the only S. mansoni protein to contain the functional amino acid residues necessary for α-GAL/α-NAGAL substrate cleavage. Both α-GAL and α-NAGAL enzymatic activities were higher in females compared to males (p<0.05; α-NAGAL > α-GAL), which was consistent with smp_089290’s female biased expression. Spatial localisation of smp_089290 revealed accumulation in parenchymal cells, neuronal cells, and the vitellaria and mature vitellocytes of the adult schistosome. siRNA-mediated knockdown (>90%) of smp_089290 in adult worms significantly inhibited α-NAGAL activity when compared to control worms (siLuc treated males, p<0.01; siLuc treated females, p<0.05). No significant reductions in α-GAL activities were observed in the same extracts. Despite this, decreases in α-NAGAL activities correlated with a significant inhibition in adult worm motility as well as in egg production. Programmed CRISPR/Cas9 editing of smp_089290 in adult worms confirmed the egg reduction phenotype. Based on these results, Smp_089290 was determined to act predominantly as an α-NAGAL (hereafter termed SmNAGAL) in schistosome parasites where it participates in coordinating movement and oviposition processes. Further characterisation of SmNAGAL and other functionally important glycosyl hydrolases may lead to the development of a novel anthelmintic class of compounds.

2022 ◽  
Vol 23 (2) ◽  
pp. 840
Li-Min Mao ◽  
Alaya Bodepudi ◽  
Xiang-Ping Chu ◽  
John Q. Wang

Group I metabotropic glutamate (mGlu) receptors (mGlu1/5 subtypes) are G protein-coupled receptors and are broadly expressed in the mammalian brain. These receptors play key roles in the modulation of normal glutamatergic transmission and synaptic plasticity, and abnormal mGlu1/5 signaling is linked to the pathogenesis and symptomatology of various mental and neurological disorders. Group I mGlu receptors are noticeably regulated via a mechanism involving dynamic protein–protein interactions. Several synaptic protein kinases were recently found to directly bind to the intracellular domains of mGlu1/5 receptors and phosphorylate the receptors at distinct amino acid residues. A variety of scaffolding and adaptor proteins also interact with mGlu1/5. Constitutive or activity-dependent interactions between mGlu1/5 and their interacting partners modulate trafficking, anchoring, and expression of the receptors. The mGlu1/5-associated proteins also finetune the efficacy of mGlu1/5 postreceptor signaling and mGlu1/5-mediated synaptic plasticity. This review analyzes the data from recent studies and provides an update on the biochemical and physiological properties of a set of proteins or molecules that interact with and thus regulate mGlu1/5 receptors.

Marine Drugs ◽  
2022 ◽  
Vol 20 (1) ◽  
pp. 66
Mingpeng Wang ◽  
Lei Chen ◽  
Zhengyu Lou ◽  
Xueting Yuan ◽  
Guiping Pan ◽  

As a low molecular weight alginate, alginate oligosaccharides (AOS) exhibit improved water solubility, better bioavailability, and comprehensive health benefits. In addition, their biocompatibility, biodegradability, non-toxicity, non-immunogenicity, and gelling capability make them an excellent biomaterial with a dual curative effect when applied in a drug delivery system. In this paper, a novel alginate lyase, Algpt, was cloned and characterized from a marine bacterium, Paenibacillus sp. LJ-23. The purified enzyme was composed of 387 amino acid residues, and had a molecular weight of 42.8 kDa. The optimal pH of Algpt was 7.0 and the optimal temperature was 45 °C. The analysis of the conserved domain and the prediction of the three-dimensional structure indicated that Algpt was a novel alginate lyase. The dominant degradation products of Algpt on alginate were AOS dimer to octamer, depending on the incubation time, which demonstrated that Algpt degraded alginate in an endolytic manner. In addition, Algpt was a salt-independent and thermo-tolerant alginate lyase. Its high stability and wide adaptability endow Algpt with great application potential for the efficient preparation of AOS with different sizes and AOS-based products.

BMC Genomics ◽  
2022 ◽  
Vol 23 (1) ◽  
Nosheen Kabir ◽  
Xin Zhang ◽  
Le Liu ◽  
Ghulam Qanmber ◽  
Lian Zhang ◽  

Abstract Background RADIALIS (RAD), belongs to the MYB gene family and regulates a variety of functions including floral dorsoventral asymmetry in Antirrhinum majus and development of fruit proteins in Solanum lycopersicum. RAD genes contain an SNF2_N superfamily domain. Here, we comprehensively identified 68 RAD genes from six different species including Arabidopsis and five species of cotton. Results Phylogenetic analysis classified RAD genes into five groups. Gene structure, protein motifs and conserved amino acid residues indicated that GhRAD genes were highly conserved during the evolutionary process. Chromosomal location information showed that GhRAD genes were distributed unevenly on different chromosomes. Collinearity and selection pressure analysis indicated RAD gene family expansion in G. hirsutum and G. barbadense with purifying selection pressure. Further, various growth and stress related promotor cis-acting elements were observed. Tissue specific expression level indicated that most GhRAD genes were highly expressed in roots and flowers (GhRAD2, GhRAD3, GhRAD4 and GhRAD11). Next, GhRAD genes were regulated by phytohormonal stresses (JA, BL and IAA). Moreover, Ghi-miRN1496, Ghi-miR1440, Ghi-miR2111b, Ghi-miR2950a, Ghi-miR390a, Ghi-miR390b and Ghi-miR7495 were the miRNAs targeting most of GhRAD genes. Conclusions Our study revealed that RAD genes are evolutionary conserved and might be involved in different developmental processes and hormonal stress response. Data presented in our study could be used as the basis for future studies of RAD genes in cotton.

Yu. I. Matveev ◽  
E. V. Averyanova

The limited use of plant proteins for food is explained by their low bioavailability and poor digestibility by enzymes of the gastrointestinal tract. Partially reproduced enzymatic processes of limited proteolysis that occur during seed germination are used to modify and improve the edibility characteristics of seed proteins. The present work discusses the possibility of reducing the duration of seed germination processes by optimising the conditions and parameters of limited proteolysis. To optimise manufacturing high-quality final product, enzymes (additional to the natural enzymes in the seed) and proteolysis conditions (in this case, temperature), as well as added substances (hydrolysis activators), were selected. The influence of cysteine on the formation of domain structures of proteins (enzymes and globulins) was evaluated. The proposed expressions can be used to determine those fragments of protein molecules that form stable domains and become unstructured when exposed to enzymes. Optimal conditions for limited proteolysis were identified based on the physical mechanism of action of papain-like proteolytic enzymes on pea legumin LegA (3KSC, CAA10722). It is shown that the decomposition of protein secondary structures takes 6–8 times longer, since the formed hydrogen bonds limit the access of enzymes to the corresponding amino-acid residues. It is also demonstrated that the decomposition of hydrogen bonds, e.g. by preliminary heat treatment of proteins, will broaden the prospects for limited proteolysis.

2022 ◽  
Vic De Roo ◽  
Yentl Verleysen ◽  
Benjamin Kovacs ◽  
Matthias De Vleeschouwer ◽  
Lea Girard ◽  

Cyclic lipopeptides (CLiPs) are secondary metabolites secreted by a range of bacterial phyla. CLiPs display diverse structural variations in terms of the number of the amino acid residues, macrocycle size, amino acid identity and stereochemistry (e.g. D- vs. L-amino acids). Reports detailing the discovery of novel or already characterized CLiPs from new sources appear regularly in literature. However, in some cases, the lack of characterization detail threatens to cause considerable confusion, especially if configurational heterogeneity is present for one or more amino acids. The NMR fingerprint matching approach introduced in this work exploits the fact that the 1H and 13C NMR chemical shift fingerprint is sufficiently sensitive to differentiate the diastereomers of a particular CLiP even when they only differ in a single D/L configuration. This provides a means for a fast screening to determine whether an extracted CLiP has been reported before, by simply comparing the fingerprint of a novel CLiP with that of a reference CLiP. Even when the stereochemistry of a particular reference CLiP is unknown, the NMR fingerprint approach still allows to verify whether a CLiP from a novel source is identical to the reference. To facilitate this, we have made a publicly available knowledge base at, where we present an overview of published NMR fingerprint data of characterized CLiPs, together with literature data on the originally determined structures. The latter includes a description of the CLiPs original description, molecular mass, three dimensional structures (if available), and a summary of published antimicrobial activities. Moreover, a detailed protocol will be made available for researchers that wish to record NMR data of their newly extracted lipopeptides to compare them to the publicly available reference data.

2022 ◽  
Vol 12 ◽  
Hye Jin Ko ◽  
Bharat Bhusan Patnaik ◽  
Ki Beom Park ◽  
Chang Eun Kim ◽  
Snigdha Baliarsingh ◽  

The inhibitor of nuclear factor-kappa B (NF-κB) kinase (IKK) is the core regulator of the NF-κB pathway against pathogenic invasion in vertebrates or invertebrates. IKKβ, -ε and -γ have pivotal roles in the Toll and immune deficiency (IMD) pathways. In this study, a homolog of IKKε (TmIKKε) was identified from Tenebrio molitor RNA sequence database and functionally characterized for its role in regulating immune signaling pathways in insects. The TmIKKε gene is characterized by two exons and one intron comprising an open reading frame (ORF) of 2,196 bp that putatively encodes a polypeptide of 731 amino acid residues. TmIKKε contains a serine/threonine protein kinases catalytic domain. Phylogenetic analysis established the close homology of TmIKKε to Tribolium castaneum IKKε (TcIKKε) and its proximity with other IKK-related kinases. The expression of TmIKKε mRNA was elevated in the gut, integument, and hemocytes of the last-instar larva and the fat body, Malpighian tubules, and testis of 5-day-old adults. TmIKKε expression was significantly induced by Escherichia coli, Staphylococcus aureus, and Candida albicans challenge in whole larvae and tissues, such as hemocytes, gut, and fat body. The knockdown of the TmIKKε messenger RNA (mRNA) expression significantly reduced the survival of the larvae against microbial challenges. Further, we investigated the induction patterns of 14 T. molitor antimicrobial peptides (AMPs) genes in TmIKKε gene-silencing model after microbial challenges. While in hemocytes, the transcriptional regulation of most AMPs was negatively regulated in the gut and fat body tissue of T. molitor, AMPs, such as TmTenecin 1, TmTenecin 4, TmDefensin, TmColeoptericin A, TmColeoptericin B, TmAttacin 1a, and TmAttacin 2, were positively regulated in TmIKKε-silenced individuals after microbial challenge. Collectively, the results implicate TmIKKε as an important factor in antimicrobial innate immune responses in T. molitor.

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