Displaying publications 41 - 60 of 185 in total

Abstract:
Sort:
  1. Acridone alkaloids from Glycosmis chlorosperma as DYRK1A inhibitors
    Beniddir MA, Le Borgne E, Iorga BI, Loaëc N, Lozach O, Meijer L, et al.
    J Nat Prod, 2014 May 23;77(5):1117-22.
    PMID: 24798019 DOI: 10.1021/np400856h
    Two new acridone alkaloids, chlorospermines A and B (1 and 2), were isolated from the stem bark of Glycosmis chlorosperma, together with the known atalaphyllidine (3) and acrifoline (4), by means of bioguided isolation using an in vitro enzyme assay against DYRK1A. Acrifoline (4) and to a lesser extent chlorospermine B (2) and atalaphyllidine (3) showed significant inhibiting activity on DYRK1A with IC50's of 0.075, 5.7, and 2.2 μM, respectively. Their selectivity profile was evaluated against a panel of various kinases, and molecular docking calculations provided structural details for the interaction between these compounds and DYRK1A.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/antagonists & inhibitors
  2. Fulltext Variable carbon catabolism among Salmonella enterica serovar Typhi isolates
    Chai LC, Kong BH, Elemfareji OI, Thong KL
    PLoS One, 2012;7(5):e36201.
    PMID: 22662115 DOI: 10.1371/journal.pone.0036201
    Salmonella enterica serovar Typhi (S. Typhi) is strictly a human intracellular pathogen. It causes acute systemic (typhoid fever) and chronic infections that result in long-term asymptomatic human carriage. S. Typhi displays diverse disease manifestations in human infection and exhibits high clonality. The principal factors underlying the unique lifestyle of S. Typhi in its human host during acute and chronic infections remain largely unknown and are therefore the main objective of this study.
    Matched MeSH terms: Serine/metabolism
  3. Fulltext Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia
    Ghodsian N, Ismail P, Ahmadloo S, Heidari F, Haghvirdizadeh P, Ataollahi Eshkoor S, et al.
    J Diabetes Res, 2016;2016:8219543.
    PMID: 27314050 DOI: 10.1155/2016/8219543
    With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension. Argumentative consequences have lately arisen on the association of specific single nucleotide polymorphisms of WNK4 gene and essential hypertension (EHT). The aim of this study was to determine the association of Ala589Ser polymorphism of WNK4 gene with essential hypertensive patients in Malaysia. WNK4 gene polymorphism was specified utilizing mutagenically separated polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method in 320 subjects including 163 cases and 157 controls. Close relation between Ala589Ser polymorphism and elevated systolic and diastolic blood pressure (SBP and DBP) was recognized. Sociodemographic factors including body mass index (BMI), age, the level of fasting blood sugar (FBS), low density lipoprotein (LDL), and triglyceride (TG) in the cases and healthy subjects exhibited strong differences (p < 0.05). The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences (p < 0.05) between EHT subjects with or without type 2 diabetes mellitus (T2DM) and normotensive subjects, statistically. The WNK4 gene variation influences significantly blood pressure increase. Ala589Ser probably has effects on the enzymic activity leading to enhanced predisposition to the disorder.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics*
  4. Fulltext An S188V mutation alters substrate specificity of non-stereospecific α-haloalkanoic acid dehalogenase E (DehE)
    Hamid AA, Hamid TH, Wahab RA, Omar MS, Huyop F
    PLoS One, 2015;10(3):e0121687.
    PMID: 25816329 DOI: 10.1371/journal.pone.0121687
    The non-stereospecific α-haloalkanoic acid dehalogenase E (DehE) degrades many halogenated compounds but is ineffective against β-halogenated compounds such as 3-chloropropionic acid (3CP). Using molecular dynamics (MD) simulations and site-directed mutagenesis we show here that introducing the mutation S188V into DehE improves substrate specificity towards 3CP. MD simulations showed that residues W34, F37, and S188 of DehE were crucial for substrate binding. DehE showed strong binding ability for D-2-chloropropionic acid (D-2CP) and L-2-chloropropionic acid (L-2CP) but less affinity for 3CP. This reduced affinity was attributed to weak hydrogen bonding between 3CP and residue S188, as the carboxylate of 3CP forms rapidly interconverting hydrogen bonds with the backbone amide and side chain hydroxyl group of S188. By replacing S188 with a valine residue, we reduced the inter-molecular distance and stabilised bonding of the carboxylate of 3CP to hydrogens of the substrate-binding residues. Therefore, the S188V can act on 3CP, although its affinity is less strong than for D-2CP and L-2CP as assessed by Km. This successful alteration of DehE substrate specificity may promote the application of protein engineering strategies to other dehalogenases, thereby generating valuable tools for future bioremediation technologies.
    Matched MeSH terms: Serine/metabolism
  5. Actions of three clostridial IgA proteases on distinct forms of immunoglobulin A molecules
    Hashim OH, Hassan H
    Immunology, 1991 Jun;73(2):235-8.
    PMID: 2071167
    Three bacterial species of Clostridium (septicum, tertium and sporogenes) were identified to produce extracellular proteases cleaving IgA to Fab and Fc fragments, as demonstrated by SDS-PAGE and immunoelectrophoretic procedures. These enzymes acted on monometric IgA1 paraproteins and normal serum IgA1 but had no activity on IgA2 paraproteins and intact secretory IgA1 from human colostrum. Their action on polyclonal serum IgA1 suggested the absence of neutralizing anti-clostridial IgA protease activity. Although the enzymes were shown not to act on secretory IgA1, they were, however, able to digest free alpha-heavy chains of the dimeric IgA molecules. Susceptibility of the alpha-heavy chain to the proteases was more likely due to the change to a more accessible conformation than because of the absence of neutralizing anti-enzymic activity.
    Matched MeSH terms: Serine Endopeptidases*
  6. DEPDC5 mutations in familial and sporadic focal epilepsy
    Tsai MH, Chan CK, Chang YC, Yu YT, Chuang ST, Fan WL, et al.
    Clin Genet, 2017 Oct;92(4):397-404.
    PMID: 28170089 DOI: 10.1111/cge.12992
    BACKGROUND AND AIMS: Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.

    MATERIALS AND METHODS: We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.

    RESULTS: We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene.

    DISCUSSION AND CONCLUSIONS: Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.

    Matched MeSH terms: TOR Serine-Threonine Kinases/genetics*
  7. STK15 Phe31Ile and Val57Ile polymorphisms increase the risk of gastrointestinal cancer
    TianXin Lai, Eric Tzyy Jiann Chong, Ping-Chin Lee, Jitt Aun Chuah, Kek Heng Chua
    Sains Malaysiana, 2018;47:141-148.
    STK15 is a serine/threonine kinase that regulates chromosomal segregation during mitosis. Single nucleotide polymorphisms (SNPs) in this gene, Phe31Ile (rs2273535) and Val57Ile (rs1047972), are inconsistently associated with gastrointestinal cancer (GIC) across different populations. However, this association is unclear in Malaysian population. Therefore, this study investigated the association of STK15 Phe31Ile and Val57Ile polymorphisms to GIC risk in Malaysia. Genomic DNA was extracted from 185 GIC patients and 1110 healthy controls and was subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. SNPs were further confirmed using sequencing. We found that the 31Phe allele and 31Phe/Phe genotype in the Phe31Ile SNP significantly increased GIC risk in Malaysian population, particularly in gastric cancer (p<0.017). The combined analysis for both SNPs also increased the risk of GIC in this study. Etiological factors such as age, gender and ethnicity were not associated with GIC in the population. This is the first study to report the association of STK15 Phe31Ile and Val57Ile SNPs with an increased risk of GIC in Malaysians; the 31Phe allele is exclusively associated with the risk of gastric cancer. In addition, GIC incidences among Malaysians have significantly shifted to a younger age (<50 years).
    Matched MeSH terms: Serine; Protein-Serine-Threonine Kinases
  8. Tryptophan-tagged peptide from serine threonine-protein kinase of Channa striatus improves antioxidant defence in L6 myotubes and attenuates caspase 3-dependent apoptotic response in zebrafish larvae
    Issac PK, Lite C, Guru A, Velayutham M, Kuppusamy G, Saraswathi NT, et al.
    Fish Physiol Biochem, 2021 Apr;47(2):293-311.
    PMID: 33394283 DOI: 10.1007/s10695-020-00912-7
    This study reports the antioxidant property and molecular mechanism of a tryptophan-tagged peptide derived from a teleost fish Channa striatus of serine threonine-protein kinase (STPK). The peptide was tagged with tryptophan to enhance the antioxidant property of STPK and named as IW13. The antioxidant activity of IW13 peptide was investigated using in vitro methods such as DPPH, ABTS, superoxide anion radical scavenging and hydrogen peroxide scavenging assay. Furthermore, to investigate the toxicity and dose response of IW13 peptide on antioxidant defence in vitro, L6 myotubes were induced with generic oxidative stress due to exposure of hydrogen peroxide (H2O2). IW13 peptide exposure was found to be non-cytotoxic to L6 cells in the tested concentration (10, 20, 30, 40 and 50 μM). Also, the pre-treatment of IW13 peptide decreased the lipid peroxidation level and increased glutathione enzyme activity. IW13 peptide treatment upregulated the antioxidant enzyme genes: GPx (glutathione peroxidase), GST (glutathione S transferase) and GCS (glutamine cysteine synthase), in vitro in L6 myotubes and in vivo in zebrafish larvae against the H2O2-induced oxidative stress. The results demonstrated that IW13 renders protection against the H2O2-induced oxidative stress through a cellular antioxidant defence mechanism by upregulating the gene expression, thus enhancing the antioxidant activity in the cellular or organismal level. The findings exhibited that the tryptophan-tagged IW13 peptide from STPK of C. striatus could be a promising candidate for the treatment of oxidative stress-associated diseases.
    Matched MeSH terms: Serine; Protein-Serine-Threonine Kinases
  9. An overview of signaling pathways regulating YAP/TAZ activity
    Heng BC, Zhang X, Aubel D, Bai Y, Li X, Wei Y, et al.
    Cell Mol Life Sci, 2021 Jan;78(2):497-512.
    PMID: 32748155 DOI: 10.1007/s00018-020-03579-8
    YAP and TAZ are ubiquitously expressed homologous proteins originally identified as penultimate effectors of the Hippo signaling pathway, which plays a key role in maintaining mammalian tissue/organ size. Presently, it is known that YAP/TAZ also interact with various non-Hippo signaling pathways, and have diverse roles in multiple biological processes, including cell proliferation, tissue regeneration, cell lineage fate determination, tumorigenesis, and mechanosensing. In this review, we first examine the various microenvironmental cues and signaling pathways that regulate YAP/TAZ activation, through the Hippo and non-Hippo signaling pathways. This is followed by a brief summary of the interactions of YAP/TAZ with TEAD1-4 and a diverse array of other non-TEAD transcription factors. Finally, we offer a critical perspective on how increasing knowledge of the regulatory mechanisms of YAP/TAZ signaling might open the door to novel therapeutic applications in the interrelated fields of biomaterials, tissue engineering, regenerative medicine and synthetic biology.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/metabolism
  10. Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA polymerase β activity
    Homouz D, Joyce-Tan KH, ShahirShamsir M, Moustafa IM, Idriss HT
    J Mol Graph Model, 2018 09;84:236-241.
    PMID: 30138833 DOI: 10.1016/j.jmgm.2018.08.007
    DNA polymerase β is a 39 kDa enzyme that is a major component of Base Excision Repair in human cells. The enzyme comprises two major domains, a 31 kDa domain responsible for the polymerase activity and an 8 kDa domain, which bind ssDNA and has a deoxyribose phosphate (dRP) lyase activity. DNA polymerase β was shown to be phosphorylated in vitro with protein kinase C (PKC) at serines 44 and 55 (S44 and S55), resulting in loss of its polymerase enzymic activity, but not its ability to bind ssDNA. In this study, we investigate the potential phosphorylation-induced structural changes for DNA polymerase β using molecular dynamics simulations. The simulations show drastic conformational changes of the polymerase structure as a result of S44 phosphorylation. Phosphorylation-induced conformational changes transform the closed (active) enzyme structure into an open one. Further analysis of the results points to a key hydrogen bond and newly formed salt bridges as potential drivers of these structural fluctuations. The changes observed with S55/44 and S55 phosphorylation were less dramatic and the integrity of the H-bond was not compromised. Thus the phosphorylation of S44 is the major contributor to structural fluctuations that lead to loss of enzymatic activity.
    Matched MeSH terms: Serine/chemistry*
  11. CHEK2*1100delC does not contribute to risk to breast cancer among Malay, Chinese and Indians in Malaysia
    Thirthagiri E, Cheong LS, Yip CH, Teo SH
    Fam Cancer, 2009;8(4):355-8.
    PMID: 19399639 DOI: 10.1007/s10689-009-9244-x
    A truncating mutation (1100delC) in the cell cycle checkpoint kinase-2 gene, CHEK2, has been identified as a risk factor for familial and sporadic breast cancer in some Northern and Western European populations. However, the prevalence of CHEK2*1100delC in breast cancer appears to be population dependent. We analysed the prevalence of CHEK2*1100delC in 668 breast cancer cases, of which 542 were invasive breast cancers, from a hospital-based cohort of breast cancer patients from Kuala Lumpur, Malaysia. The variant was not found in any patients in this cohort, suggesting that CHEK2*1100delC is rare in our population, and unlikely to contribute significantly to risk to breast cancer among the Malay, Chinese and Indian ethnic groups in Malaysia. This suggests that screening for this allele should not be routinely conducted in Malaysia.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/genetics*
  12. Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda (L.), towards dengue-2 virus NS3 protease
    Kiat TS, Pippen R, Yusof R, Ibrahim H, Khalid N, Rahman NA
    Bioorg Med Chem Lett, 2006 Jun 15;16(12):3337-40.
    PMID: 16621533
    Boesenbergia rotunda (L.) cyclohexenyl chalcone derivatives, 4-hydroxypanduratin A and panduratin A, showed good competitive inhibitory activities towards dengue 2 virus NS3 protease with the Ki values of 21 and 25 microM, respectively, whilst those of pinostrobin and cardamonin were observed to be non-competitive. NMR and GCMS spectroscopic data formed the basis of assignment of structures of the six compounds isolated.
    Matched MeSH terms: Serine Endopeptidases/metabolism*
  13. Role of the Serine/Threonine Kinase 11 (STK11) or Liver Kinase B1 (LKB1) Gene in Peutz-Jeghers Syndrome
    Altamish M, Dahiya R, Singh AK, Mishra A, Aljabali AAA, Satija S, et al.
    Crit Rev Eukaryot Gene Expr, 2020;30(3):245-252.
    PMID: 32749111 DOI: 10.1615/CritRevEukaryotGeneExpr.2020033451
    Peutz-Jeghers syndrome (PJS) is a well-described inherited syndrome, characterized by the development of gastrointestinal polyps and characteristic mucocutaneous freckling. PJS is an autosomal prevailing disease, due to genetic mutation on chromosome 19p, manifested by restricted mucocutaneous melanosis in association with gastrointestinal (GI) polyposis. The gene for PJS has recently been shown to be a serine/threonine kinase, known as LKB1 or STK11, which maps to chromosome subband 19p13.3. This gene has a putative coding region of 1302 bp, divided into nine exons, and acts as a tumor suppressor in the hamartomatous polyps of PJS patients and in the other neoplasms that develop in PJS patients. It is probable that these neoplasms develop from hamartomas, but it remains possible that the LKB1 or STK11 locus plays a role in a different genetic pathway of tumor growth in the cancers of PJS patients. This article focuses on the role of LKB1 or STK11 gene expression in PJS and related cancers.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/physiology*
  14. Fulltext Clinical Phenotype of LRRK2 R1441C in 2 Chinese Sisters
    Lim SY, Lim JL, Ahmad-Annuar A, Lohmann K, Tan AH, Lim KB, et al.
    Neurodegener Dis, 2020;20(1):39-45.
    PMID: 32580205 DOI: 10.1159/000508131
    Pathogenic and risk variants in the LRRK2 gene are among the main genetic contributors to Parkinson's disease (PD) worldwide, and LRRK2-targeted therapies for patients with PARK-LRRK2are now entering clinical trials. However, in contrast to the LRRK2 G2019S mutation commonly found in Caucasians, North-African Arabs, and Ashkenazi Jews, relatively little is known about other causative LRRK2 mutations, and data on genotype-phenotype correlations are largely lacking. This report is from an ongoing multicentre study in which next-generation sequencing-based PD gene panel testing has so far been conducted on 499 PD patients of various ethnicities from Malaysia. We describe 2 sisters of Chinese ancestry with PD who carry the R1441C mutation in LRRK2 (which in Asians has been reported in only 2 Chinese patients previously), and highlight interesting clinical observations made over a decade of close follow-up. We further explored the feasibility of using a brief, expert-administered rating scale (the Clinical Impression of Severity Index; CISI-PD) to capture data on global disease severity in a large (n = 820) unselected cohort of PD patients, including severely disabled individuals typically excluded from research studies. All patients in this study were managed and evaluated by the same PD neurologist, and these data were used to make broad comparisons between the monogenic PD cases versus the overall "real world" PD cohort. This report contributes to the scarce literature on R1441C PARK-LRRK2, offering insights into natural history and epidemiological aspects, and provides support for the application of a simple and reliable clinical tool that can improve the inclusion of under-represented patient groups in PD research.
    Matched MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics*
  15. Fulltext Genome-wide CRISPR screens of oral squamous cell carcinoma reveal fitness genes in the Hippo pathway
    Chai AWY, Yee PS, Price S, Yee SM, Lee HM, Tiong VK, et al.
    Elife, 2020 09 29;9.
    PMID: 32990596 DOI: 10.7554/eLife.57761
    New therapeutic targets for oral squamous cell carcinoma (OSCC) are urgently needed. We conducted genome-wide CRISPR-Cas9 screens in 21 OSCC cell lines, primarily derived from Asians, to identify genetic vulnerabilities that can be explored as therapeutic targets. We identify known and novel fitness genes and demonstrate that many previously identified OSCC-related cancer genes are non-essential and could have limited therapeutic value, while other fitness genes warrant further investigation for their potential as therapeutic targets. We validate a distinctive dependency on YAP1 and WWTR1 of the Hippo pathway, where the lost-of-fitness effect of one paralog can be compensated only in a subset of lines. We also discover that OSCCs with WWTR1 dependency signature are significantly associated with biomarkers of favorable response toward immunotherapy. In summary, we have delineated the genetic vulnerabilities of OSCC, enabling the prioritization of therapeutic targets for further exploration, including the targeting of YAP1 and WWTR1.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/physiology*
  16. Antioxidant Modulation of mTOR and Sirtuin Pathways in Age-Related Neurodegenerative Diseases
    Abdullah A, Mohd Murshid N, Makpol S
    Mol Neurobiol, 2020 Dec;57(12):5193-5207.
    PMID: 32865663 DOI: 10.1007/s12035-020-02083-1
    In the human body, cell division and metabolism are expected to transpire uneventfully for approximately 25 years. Then, secondary metabolism and cell damage products accumulate, and ageing phenotypes are acquired, causing the progression of disease. Among these age-related diseases, neurodegenerative diseases have attracted considerable attention because of their irreversibility, the absence of effective treatment and their relationship with social and economic pressures. Mechanistic (formerly mammalian) target of rapamycin (mTOR), sirtuin (SIRT) and insulin/insulin growth factor 1 (IGF1) signalling pathways are among the most important pathways in ageing-associated conditions, such as neurodegeneration. These longevity-related pathways are associated with a diversity of various processes, including metabolism, cognition, stress reaction and brain plasticity. In this review, we discuss the roles of sirtuin and mTOR in ageing and neurodegeneration, with an emphasis on their regulation of autophagy, apoptosis and mitochondrial energy metabolism. The intervention of neurodegeneration using potential antioxidants, including vitamins, phytochemicals, resveratrol, herbals, curcumin, coenzyme Q10 and minerals, specifically aimed at retaining mitochondrial function in the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease is highlighted.
    Matched MeSH terms: TOR Serine-Threonine Kinases/metabolism*
  17. Venomics of Calloselasma rhodostoma, the Malayan pit viper: A complex toxin arsenal unraveled
    Tang EL, Tan CH, Fung SY, Tan NH
    J Proteomics, 2016 10 04;148:44-56.
    PMID: 27418434 DOI: 10.1016/j.jprot.2016.07.006
    The venom of Malayan pit viper (Calloselasma rhodostoma) is highly toxic but also valuable in drug discovery. However, a comprehensive proteome of the venom that details its toxin composition and abundance is lacking. This study aimed to unravel the venom complexity through a multi-step venomic approach. At least 96 distinct proteins (29 basic, 67 acidic) in 11 families were identified from the venom. The venom consists of mainly snake venom metalloproteinases (SVMP, 41.17% of total venom proteins), within which the P-I (kistomin, 20.4%) and P-II (rhodostoxin, 19.8%) classes predominate. This is followed by C-type lectins (snaclec, 26.3%), snake venom serine protease (SVSP, 14.9%), L-amino acid oxidase (7.0%), phospholipase A2 (4.4%), cysteine-rich secretory protein (2.5%), and five minor toxins (nerve growth factor, neurotrophin, phospholipase B, 5' nucleotidase and phosphodiesterase, totaling 2.6%) not reported in the proteome hitherto. Importantly, all principal hemotoxins unveiled correlate with the syndrome: SVSP ancrod causes venom-induced consumptive coagulopathy, aggravated by thrombocytopenia caused by snaclec rhodocytin, a platelet aggregation inducer, while P-II rhodostoxin mediates hemorrhage, exacerbated by P-I kistomin and snaclec rhodocetin that inhibit platelet plug formation. These toxins exist in multiple isoforms and/or complex subunits, deserving further characterization for the development of an effective, polyspecific regional antivenom.

    BIOLOGICAL SIGNIFICANCE: Advents in proteomics and bioinformatics have vigorously propelled the scientific discoveries of toxins from various lineages of venomous snakes. The Malayan pit viper, Calloselasma rhodostoma, is a medically important species in Southeast Asia as its bite can cause envenomation, while the venom is also a source of bioactive compounds for drug discovery. Detailed profiling of the venom, however, is inadequate possibly due to the complex nature of the venom and technical limitation in separating the constituents into details. Integrating a multi-step fractionation method, this study successfully revealed a comprehensive and quantitative profile of the composition of the venom of this medically important venomous snake. The relative abundance of the various venom proteins is determined in a global profile, providing useful information for understanding the pathogenic roles of the different toxins in C. rhodostoma envenomation. Notably, the principal hemotoxins were identified in great details, including the variety of toxin subunits and isoforms. The findings indicate that these toxins are the principal targets for effective antivenom neutralization, and should be addressed in the production of a pan-regional polyspecific antivenom. In addition, minor toxin components not reported previously in the venom were also detected in this study, enriching the current toxin database for the venomous snakes.

    Matched MeSH terms: Serine Proteases/analysis
  18. Fulltext The Sec61 translocon limits IRE1α signaling during the unfolded protein response
    Sundaram A, Plumb R, Appathurai S, Mariappan M
    Elife, 2017 05 15;6.
    PMID: 28504640 DOI: 10.7554/eLife.27187
    IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in cells with blue native PAGE immunoblotting. We find that IRE1α forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in the complex. In addition, IRE1α oligomerization, activation, and inactivation during ER stress are regulated by Sec61. Loss of the IRE1α-Sec61 translocon interaction as well as severe ER stress conditions causes IRE1α to form higher-order oligomers that exhibit continuous activation and extended cleavage of XBP1u mRNA. Thus, we propose that the Sec61-IRE1α complex defines the extent of IRE1α activity and may determine cell fate decisions during ER stress conditions.
    Matched MeSH terms: Protein-Serine-Threonine Kinases/metabolism*
  19. Enzyme-Mimic Peptide Assembly To Achieve Amidolytic Activity
    Wong YM, Masunaga H, Chuah JA, Sudesh K, Numata K
    Biomacromolecules, 2016 Oct 10;17(10):3375-3385.
    PMID: 27642764
    Amyloid fibers are classified as a new generation of tunable bionanomaterials that exhibit new functions related to their distinctive characteristics, such as their universality, tunability, and stiffness. Here, we introduce the catalytic residues of serine protease into a peptide catalyst (PC) via an enzyme-mimic approach. The rational design of a repeating pattern of polar and nonpolar amino acids favors the conversion of the peptides into amyloid-like fibrils via self-assembly. Distinct fibrous morphologies have been observed at different pH values and temperatures, which indicates that different fibril packing schemes can be designed; hence, fibrillar peptides can be used to generate efficient artificial catalysts for amidolytic activities at mild pH values. The results of atomic force microscopy, Raman spectroscopy, and wide-angle X-ray scattering analyses are used to discuss and compare the fibril structure of a fibrillar PC with its amidolytic activity. The pH of the fibrillation reaction crucially affects the pKa of the side chains of the catalytic triads and is important for stable fibril formation. Temperature is another important parameter that controls the self-assembly of peptides into highly stacked and laminated morphologies. The morphology and stability of fibrils are crucial and represent important factors for demonstrating the capability of the peptides to exert amidolytic activity. The observed amidolytic activity of PC4, one of the PCs, was validated using an inhibition assay, which revealed that PC4 can perform enzyme-like amidolytic catalysis. These results provide insights into the potential use of designed peptides in the generation of efficient artificial enzymes.
    Matched MeSH terms: Serine Proteases/chemistry
  20. Trichinella spiralis: RNAi-mediated silencing of serine protease results in reduction of intrusion, development and fecundity
    Yang DQ, Zeng Y, Sun XY, Yue X, Hu CX, Jiang P, et al.
    Trop Biomed, 2020 Dec 01;37(4):932-946.
    PMID: 33612747 DOI: 10.47665/tb.37.4.932
    In previous studies, a Trichinella spiralis serine protease (TsSP) was identified in excretion/secretion (ES) products from intestinal infective L1 larvae (IIL1) using immunoproteomics. The complete cDNA sequence of TsSP gene was 1372 bp, which encoded 429 amino acids with 47.55 kDa. The TsSP was transcribed and expressed at all T. spiralis life cycle phases, as well as mainly located at the cuticle and stichosome of the parasitic nematode. Recombinant TsSP bind to intestinal epithelial cells (IEC) and promoted larva invasion, however, its exact function in invasion, development and reproduction are still unknown. The aim of this study was to confirm the biological function of TsSP during T. spiralis invasion and growth using RNA interference (RNAi) technology. The results showed that on 1 day after electroporation using 2.5 µM siRNA156, TsSP mRNA and protein expression of muscle larvae (ML) was suppressed by 48.35 and 59.98%, respectively. Meanwhile, silencing of TsSP gene by RNAi resulted in a 61.38% decrease of serine protease activity of ML ES proteins, and a significant reduction of the in vitro and in vivo invasive capacity of IIL1 to intrude into the IEC monolayer and intestinal mucosa. When mice were infected with siRNA 156-transfected larvae, adult worm and muscle larva burdens were decreased by 58.85 and 60.48%, respectively. Moreover, intestinal worm growth and female fecundity were evidently inhibited after TsSP gene was knockdown, it was demonstrated that intestinal adults became smaller and the in vitro newborn larval yield of females obviously declined compared with the control siRNA group. The results indicated that knockdown of TsSP gene by RNAi significantly reduced the TsSP expression and enzymatic activity, impaired larvae intrusion and growth, and lowered the female reproductive capacity, further verified that TsSP might participate in diverse processes of T. spiralis life cycle, it will be a new prospective candidate molecular target of anti-Trichinella vaccines.
    Matched MeSH terms: Serine Proteases/genetics*
Related Terms
Filters
Contact Us

Please provide feedback to Administrator (afdal@afpm.org.my)

External Links