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6. Novel advances in biotransformation and bioactivation research – 2020 year in review

Author

Khojasteh, S Cyrus, Argikar, Upendra A, Driscoll, James P, Heck, Carley JS, King, Lloyd, Jackson, Klarissa D, Jian, Wenying, Kalgutkar, Amit S, Miller, Grover P, Kramlinger, Valerie, Rietjens, Ivonne MCM, Teitelbaum, Aaron M, Wang, Kai, Wei, Cong, Johnson, Benjamin M, Shu, Yue-Zhong, Zhuo, Xiaoliang, Meanwell, Nicholas A, Cerny, Matthew A, Obach, R Scott, Sharma, Raman, Spracklin, Douglas K, Walker, Gregory S, Goracci, Laura, Desantis, Jenny, Valeri, Aurora, Castellani, Beatrice, Eleuteri, Michela, Cruciani, Gabriele, Lall, Manjinder S, Bassyouni, Asser, Bradow, James, Brown, Maria, Bundesmann, Mark, Chen, Jinshan, Ciszewski, Gregory, Hagen, Anne E, Hyek, Dennis, Jenkinson, Stephen, Liu, Bo, Pan, Senliang, Reilly, Usa, Sach, Neal, Smaltz, Daniel J, Starr, Jeremy, Wagenaar, Melissa, de Bruyn Kops, Christina, Sicho, Martin, Mazzolari, Angelica, Kirchmair, Johannes, Korprasertthaworn, Porntipa, Chau, Nuy, Nair, Pramod C, Rowland, Andrew, Miners, John O, Wrobleski, Stephen T, Moslin, Ryan, Lin, Shuqun, Zhang, Yanlei, Spergel, Steven, Kempson, James, Tokarski, John S, Strnad, Joann, Zupa-Fernandez, Adriana, Cheng, Lihong, Shuster, David, Gillooly, Kathleen, Yang, Xiaoxia, Heimrich, Elizabeth, McIntyre, Kim W, Chaudhry, Charu, Khan, Javed, Ruzanov, Max, Tredup, Jeffrey, Mulligan, Dawn, Xie, Dianlin, Sun, Huadong, Huang, Christine, D'Arienzo, Celia, Aranibar, Nelly, Chiney, Manoj, Chimalakonda, Anjaneya, Pitts, William J, Lombardo, Louis, Carter, Percy H, Burke, James R, Weinstein, David S, Li, Jing, Liu, Ju, Enders, Jennifer, Arciprete, Michael, Tran, Chris, Aluri, Krishna, Guan, Li-Hua, O'Shea, Jonathan, Bisbe, Anna, Charisse, Klaus, Zlatev, Ivan, Najarian, Diana, Xu, Yuanxin, Kim, Jaeah, El Zahar, Noha M, Bartlett, Michael G, Katyayan, Kishore, Yi, Ping, Monk, Scott, Cassidy, Kenneth, Takahashi, Ryan H, Grandner, Jessica M, Bobba, Sudheer, Liu, Yanzhou, Beroza, Paul, Zhang, Donglu, Ma, Shuguang, Post, Noah, Yu, Rosie, Greenlee, Sarah, Gaus, Hans, Hurh, Eunju, Matson, John, Wang, Yanfeng, Tajima, Yuya, Toyoda, Takeshi, Hirayama, Yuichiro, Matsushita, Kohei, Yamada, Takanori, Ogawa, Kumiko, Watanabe, Kenji, Takamura-Enya, Takeji, Totsuka, Yukari, Wakabayashi, Keiji, Miyoshi, Noriyuki, Zhang, Jiayin, Chan, Chi-Kong, Ham, Yat-Hing, Chan, Wan, Schleiff, Mary Alexandra, Flynn, Noah R, Payakachat, Sasin, Schleiff, Benjamin Mark, Pinson, Anna O, Province, Dennis W, Swamidass, S Joshua, Boysen, Gunnar, Nardone-White, Dasean T, Bissada, Jennifer E, Abouda, Arsany A, Zhang, Zhuming, Connolly, Peter J, Lim, Heng Keang, Pande, Vineet, Meerpoel, Lieven, Teleha, Christopher, Branch, Jonathan R, Ondrus, Janine, Hickson, Ian, Bush, Tammy, Luistro, Leopoldo, Packman, Kathryn, Bischoff, James R, Ibrahim, Salam, Parrett, Christopher, Chong, Yolanda, Gottardis, Marco M, Bignan, Gilles, Mulder, Teresa, Bobba, Sudder, Johnson, Kevin M, Wang, Wei, Zhang, Chenghong, Cai, Jingwei, Choo, Edna F, Crawford, James J, Landry, Matthew L, Chen, Huifen, Kenny, Jane R, Lee, Wendy, Young, Wendy B, Geib, Timon, Thulasingam, Madhuranayaki, Haeggstrom, Jesper Z, Sleno, Lekha, Monroe, James J, Tanis, Keith Q, Podtelezhnikov, Alexei A, Nguyen, Truyen, Machotka, Sam V, Lynch, Donna, Evers, Raymond, Palamanda, Jairam, Miller, Randy R, Pippert, Todd, Cabalu, Tamara D, Johnson, Timothy E, Aslamkhan, Amy G, Kang, Wen, Tamburino, Alex M, Mitra, Kaushik, Agrawal, Nancy GB, and Sistare, Frank D

Subjects
METABOLISM, Toxicology, 030226 pharmacology & pharmacy, 03 medical and health sciences, nonp450 enzymes, 0302 clinical medicine, p450 enzymes, Biotransformation, INTRINSIC CLEARANCE, Political science, MASS-BALANCE, Humans, Pharmacology (medical), Pharmacology & Pharmacy, P450 Enzymes, General Pharmacology, Toxicology and Pharmaceutics, ANTISENSE OLIGONUCLEOTIDE, Toxicologie, VLAG, ARISTOLOCHIC ACID, Drug metabolism, Science & Technology, WIMEK, bioactivation, IDENTIFICATION, Year in review, IN-VITRO, NONHEPATOTOXIC DRUGS, Drug metabolizing enzymes, Drug development, 030220 oncology & carcinogenesis, COVALENT BINDING DATA, Engineering ethics, biotransformation, LIVER-MICROSOMES, Life Sciences & Biomedicine
Abstract

This annual review is the sixth of its kind since 2016 (see references). Our objective is to explore and share articles which we deem influential and significant in the field of biotransformation and bioactivation. These fields are constantly evolving with new molecular structures and discoveries of corresponding pathways for metabolism that impact relevant drug development with respect to efficacy and safety. Based on the selected articles, we created three sections: (1) drug design, (2) metabolites and drug metabolizing enzymes, and (3) bioactivation and safety (Table 1). Unlike in years past, more biotransformation experts have joined and contributed to this effort while striving to maintain a balance of authors from academic and industry settings.[Table: see text]. ispartof: DRUG METABOLISM REVIEWS vol:53 issue:3 pages:384-433 ispartof: location:England status: published

Published
2021
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7. Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction

Author

Tang, Xiao, Ronnberg, Elin, Safholm, Jesper, Thulasingam, Madhuranayaki, Trauelsen, Mette, Schwartz, Thue W., Wheelock, Craig E., Dahlen, Sven-Erik, Nilsson, Gunnar, Haeggstrom, Jesper Z., Tang, Xiao, Ronnberg, Elin, Safholm, Jesper, Thulasingam, Madhuranayaki, Trauelsen, Mette, Schwartz, Thue W., Wheelock, Craig E., Dahlen, Sven-Erik, Nilsson, Gunnar, and Haeggstrom, Jesper Z.

Abstract

Background SUCNR1 is a sensor of extracellular succinate, a Krebs cycle intermediate generated in excess during oxidative stress and has been linked to metabolic regulation and inflammation. While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated. Methods Cord blood-derived mast cells and human mast cell line LAD-2 challenged by SUCNR1 ligands were analyzed for the activation and mediator release. Effects on mast cell-dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti-IgE, respectively. Results SUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non-metabolite agonist cis-epoxysuccinate, renders mast cells hypersensitive to IgE-dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate-potentiated mast cell reactivity was attenuated by SUCNR1 knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal-regulated kinase. Both succinate and cis-epoxysuccinate dose-dependently potentiated antigen-induced contraction in a mast cell-dependent guinea pig airway model, associated with increased generation of cysteinyl-leukotrienes and histamine in trachea. Similarly, cis-epoxysuccinate aggravated IgE-receptor-induced contraction of human bronchi, which was blocked by SUCNR1 antagonism. Conclusion SUCNR1 amplifies IgE-receptor-induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell-dependent inflammation.

Published
2022
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12. Catalytic Conversion of Lipophilic Substrates by Phase constrained Enzymes in the Aqueous or in the Membrane Phase

Author

Cebula, Marcus, Turan, Ilke Simsek, Sjodin, Birgitta, Thulasingam, Madhuranayaki, Brock, Joseph, Chmyrov, Volodymyr, Widengren, Jerker, Abe, Hiroshi, Mannervik, Bengt, Haeggstrom, Jesper Z., Rinaldo-Matthis, Agnes, Akkaya, Engin U., Morgenstern, Ralf, Cebula, Marcus, Turan, Ilke Simsek, Sjodin, Birgitta, Thulasingam, Madhuranayaki, Brock, Joseph, Chmyrov, Volodymyr, Widengren, Jerker, Abe, Hiroshi, Mannervik, Bengt, Haeggstrom, Jesper Z., Rinaldo-Matthis, Agnes, Akkaya, Engin U., and Morgenstern, Ralf

Abstract

Both soluble and membrane-bound enzymes can catalyze the conversion of lipophilic substrates. The precise substrate access path, with regard to phase, has however, until now relied on conjecture from enzyme structural data only (certainly giving credible and valuable hypotheses). Alternative methods have been missing. To obtain the first experimental evidence directly determining the access paths (of lipophilic substrates) to phase constrained enzymes we here describe the application of a BODIPY-derived substrate (PS1). Using this tool, which is not accessible to cytosolic enzymes in the presence of detergent and, by contrast, not accessible to membrane embedded enzymes in the absence of detergent, we demonstrate that cytosolic and microsomal glutathione transferases (GSTs), both catalyzing the activation of PS1, do so only within their respective phases. This approach can serve as a guideline to experimentally validate substrate access paths, a fundamental property of phase restricted enzymes. Examples of other enzyme classes with members in both phases are xenobiotic-metabolizing sulphotransferases/UDP-glucuronosyl transferases or epoxide hydrolases. Since specific GSTs have been suggested to contribute to tumor drug resistance, PS1 can also be utilized as a tool to discriminate between phase constrained members of these enzymes by analyzing samples in the absence and presence of Triton X-100., QC 20170119

Published
2016
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13. Catalytic Conversion of Lipophilic Substrates by Phase constrained Enzymes in the Aqueous or in the Membrane Phase

Author

Cebula, Marcus, primary, Turan, Ilke Simsek, additional, Sjödin, Birgitta, additional, Thulasingam, Madhuranayaki, additional, Brock, Joseph, additional, Chmyrov, Volodymyr, additional, Widengren, Jerker, additional, Abe, Hiroshi, additional, Mannervik, Bengt, additional, Haeggström, Jesper Z., additional, Rinaldo-Matthis, Agnes, additional, Akkaya, Engin U., additional, and Morgenstern, Ralf, additional

Published
2016
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14. Characterization of S almonella typhi OmpC and OmpF porins engineered with HIV-gp41 epitope on the surface loops.

Author

Thulasingam, Madhuranayaki, Damodharan, Subha, Madhana Vigneshwari, Gopal, P. J. Pandaranayaka, Eswari, Elizabeth Hanna, Luke, Usha, Ramakrishnan, and Krishnaswamy, Sankaran

Abstract

ABSTRACT Porins form trimers in the outer membrane and help transport nutrients and waste products across the bacterial cell membrane. Porin loops are suitable candidates as display systems due to their high immunogenicity and presentation at the bacterial cell surface. In this study, Salmonella typhi porins (OmpC and OmpF) engineered with the Kennedy peptide from gp41 of HIV were characterised. The chimeric OmpC carrying the Kennedy peptide in loop7 did not trimerise, whereas the chimeric OmpF with the epitope in loop5 formed trimers and also was recognised by the antibodies in the HIV patient serum. The results suggest that chimeric S. typhi OmpF may be taken further as a potential candidate to develop as an epitope display system. Proteins 2017; 85:657-664. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2017
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15. Characterization of Salmonella typhi OmpC and OmpF porins engineered with HIV-gp41 epitope on the surface loops.

Author

Thulasingam M, Damodharan S, Madhana Vigneshwari G, P J Pandaranayaka E, Elizabeth Hanna L, Usha R, and Krishnaswamy S

Subjects
Amino Acid Sequence, Bacterial Proteins genetics, Bacterial Proteins immunology, Binding Sites, Cloning, Molecular, Epitopes genetics, Epitopes immunology, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, HIV genetics, HIV immunology, HIV Envelope Protein gp41 genetics, HIV Envelope Protein gp41 immunology, HIV Infections immunology, HIV Infections virology, Humans, Immune Sera chemistry, Peptide Library, Porins genetics, Porins immunology, Protein Binding, Protein Conformation, beta-Strand, Protein Engineering, Protein Interaction Domains and Motifs, Protein Multimerization, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Salmonella typhi metabolism, Sequence Alignment, Bacterial Proteins chemistry, Epitopes chemistry, HIV Envelope Protein gp41 chemistry, Porins chemistry, Salmonella typhi genetics
Abstract

Porins form trimers in the outer membrane and help transport nutrients and waste products across the bacterial cell membrane. Porin loops are suitable candidates as display systems due to their high immunogenicity and presentation at the bacterial cell surface. In this study, Salmonella typhi porins (OmpC and OmpF) engineered with the Kennedy peptide from gp41 of HIV were characterised. The chimeric OmpC carrying the Kennedy peptide in loop7 did not trimerise, whereas the chimeric OmpF with the epitope in loop5 formed trimers and also was recognised by the antibodies in the HIV patient serum. The results suggest that chimeric S. typhi OmpF may be taken further as a potential candidate to develop as an epitope display system. Proteins 2017; 85:657-664. © 2016 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Published
2017
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