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  1. Rasineni GK, Loh PC, Lim BH
    Biochim Biophys Acta Gen Subj, 2017 Feb;1861(2):79-85.
    PMID: 27816753 DOI: 10.1016/j.bbagen.2016.10.027
    BACKGROUND: Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is the chloroplast enzyme that fixes CO2 in photosynthesis, but the enzyme also fixes O2, which leads to the wasteful photorespiratory pathway. If we better understand the structure-function relationship of the enzyme, we might be able to engineer improvements. When the crystal structure of Chlamydomonas Rubisco was solved, four new posttranslational modifications were observed which are not present in other species. The modifications were 4-hydroxylation of the conserved Pro-104 and 151 residues, and S-methylation of the variable Cys-256 and 369 residues, which are Phe-256 and Val-369 in land plants. Because the modifications were only observed in Chlamydomonas Rubisco, they might account for the differences in kinetic properties between the algal and plant enzymes.

    METHODS: Site-directed mutagenesis and chloroplast transformation have been used to test the essentiality of these modifications by replacing each of the residues with alanine (Ala). Biochemical analyses were done to determine the specificity factors and kinetic constants.

    RESULTS: Replacing the modified-residues in Chlamydomonas Rubisco affected the enzyme's catalytic activity. Substituting hydroxy-Pro-104 and methyl-Cys-256 with alanine influenced Rubisco catalysis.

    CONCLUSION: This is the first study on these posttranslationally-modified residues in Rubisco by genetic engineering. As these forms of modifications/regulation are not available in plants, the modified residues could be a means to modulate Rubisco activity.

    GENERAL SIGNIFICANCE: With a better understanding of Rubisco structure-function, we can define targets for improving the enzyme.

  2. Wu YS, Chung I, Wong WF, Masamune A, Sim MS, Looi CY
    Biochim Biophys Acta Gen Subj, 2017 Feb;1861(2):296-306.
    PMID: 27750041 DOI: 10.1016/j.bbagen.2016.10.006
    BACKGROUND: We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process.

    METHODS: Gene expression of IL-6 and IL-6Rα in PSC and PDAC cells was measured with qRT-PCR. The role of PSC-secreted IL-6, JAK/Stat3 signaling, and Nrf2 mediation on EMT-related genes expression was also examined with qRT-PCR. EMT phenotypes were assessed with morphological change, wound healing, migration, and invasion.

    RESULTS: PSC expressed higher mRNA levels of IL-6 but lower IL-6Rα compared to PDAC cells. Neutralizing IL-6 in PSC secretion reduced mesenchymal-like morphology, migration and invasion capacity, and mesenchymal-like gene expression of N-cadherin, vimentin, fibronectin, collagen I, Sip1, Snail, Slug, and Twist2. Inhibition of JAK/Stat3 signaling induced by IL-6 repressed EMT and Nrf2 gene expression. Induction of Nrf2 activity by tert-butylhydroquinone (tBHQ) increased both EMT phenotypes and gene expression (N-cadherin, fibronectin, Twist2, Snail, and Slug) repressed by IL-6 neutralizing antibody. Simultaneous inhibition of Nrf2 expression with siRNA and Stat3 signaling further repressed EMT gene expression, indicating that Stat3/Nrf2 pathway mediates EMT induced by IL-6.

    CONCLUSIONS: IL-6 from PSC promotes EMT in PDAC cells via Stat3/Nrf2 pathway.

    GENERAL SIGNIFICANCE: Targeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC.

  3. Dheyab MA, Aziz AA, Rahman AA, Ashour NI, Musa AS, Braim FS, et al.
    Biochim Biophys Acta Gen Subj, 2023 Apr;1867(4):130318.
    PMID: 36740000 DOI: 10.1016/j.bbagen.2023.130318
    BACKGROUND: Gold nanoparticles (Au NPs) are regarded as potential agents that enhance the radiosensitivity of tumor cells for theranostic applications. To elucidate the biological mechanisms of radiation dose enhancement effects of Au NPs as well as DNA damage attributable to the inclusion of Au NPs, Monte Carlo (MC) simulations have been deployed in a number of studies.

    SCOPE OF REVIEW: This review paper concisely collates and reviews the information reported in the simulation research in terms of MC simulation of radiosensitization and dose enhancement effects caused by the inclusion of Au NPs in tumor cells, simulation mechanisms, benefits and limitations.

    MAJOR CONCLUSIONS: In this review, we first explore the recent advances in MC simulation on Au NPs radiosensitization. The MC methods, physical dose enhancement and enhanced chemical and biological effects is discussed, followed by some results regarding the prediction of dose enhancement. We then review Multi-scale MC simulations of Au NP-induced DNA damages for X-ray irradiation. Moreover, we explain and look at Multi-scale MC simulations of Au NP-induced DNA damages for X-ray irradiation.

    GENERAL SIGNIFICANCE: Using advanced chemical module-implemented MC simulations, there is a need to assess the radiation-induced chemical radicals that contribute to the dose-enhancing and biological effects of multiple Au NPs.

  4. Yap PG, Gan CY
    Biochim Biophys Acta Gen Subj, 2024 Jan;1868(1):130503.
    PMID: 37923180 DOI: 10.1016/j.bbagen.2023.130503
    BACKGROUND: Bioactive peptides have gained attention as potential alternatives to chemical-based skin lightening agents. Based on literature search, the reported articles focused mainly on the sources and preparation methods of tyrosinase inhibitory peptides and there is lacking information regarding the structure-activity relationship (SAR) between peptide property and tyrosinase inhibition. It was hypothesized that peptide properties such as hydrophobicity/hydrophilicity and the amino acid type and position/arrangement at the terminal positions could affect peptide mode of binding hence result in various degrees of tyrosinase inhibition.

    METHODS: In this study, the sequences of 128 tyrosinase inhibitory peptides were collected from peer-reviewed articles. The hydrophobicity/hydrophilicity property and the amino acid profile of peptides at the N- and C-terminals were analyzed using bioinformatics tools. Molecular docking analysis was employed to further elucidate the roles of reactive amino acids in tyrosinase-peptide binding interactions. The peptide-regulated intracellular melanogenesis pathways were also compiled and discussed.

    RESULTS: It was found that hydrophobic and/or polar neutral properties may facilitate or stabilize peptide binding with tyrosinase. Moreover, short peptides featuring a cysteine and tyrosine at the N- and C- terminal ultimate positions tend to bind to the active site of tyrosinase whereas positively charged amino acid such as arginine at the N-terminal does not favor peptide binding to tyrosinase.

    CONCLUSIONS: These findings provide detailed explanation on how peptide/amino acid structures are related and what function they play in tyrosinase inhibition. It could also inspire researchers to account for tyrosinase-peptide SAR and the underlying anti-melanogenesis mechanisms in formulating peptide-based treatments or strategies against skin hyperpigmentation.

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