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8. Discovery of a novel homocysteine thiolactone hydrolase and the catalytic activity of its natural variants.

Author

Hou, Shurong, Liu, Huan, Hu, Yihui, Zhang, Jie, Deng, Xingyu, Li, Zhenzhen, Zhang, Yun, Li, Xiaoxuan, Li, Yishuang, Ma, Lei, Yao, Jianzhuang, and Chen, Xiabin

Abstract

Homocysteine thiolactone (HTL), a toxic metabolite of homocysteine (Hcy) in hyperhomocysteinemia (HHcy), is known to modify protein structure and function, leading to protein damage through formation of N‐Hcy‐protein. HTL has been highly linked to HHcy‐associated cardiovascular and neurodegenerative diseases. The protective role of HTL hydrolases against HTL‐associated vascular toxicity and neurotoxicity have been reported. Although several endogeneous enzymes capable of hydrolyzing HTL have been identified, the primary enzyme responsible for its metabolism remains unclear. In this study, three human carboxylesterases were screened to explore new HTL hydrolase and human carboxylesterase 1 (hCES1) demonstrates the highest catalytic activity against HTL. Given the abundance of hCES1 in the liver and the clinical significance of its single‐nucleotide polymorphisms (SNPs), six common hCES1 nonsynonymous coding SNP (nsSNPs) variants were examined and characterized for their kinetic parameters. Variants E220G and G143E displayed 7.3‐fold and 13.2‐fold lower catalytic activities than its wild‐type counterpart. In addition, the detailed catalytic mechanism of hCES1 for HTL hydrolysis was computational investigated and elucidated by Quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) method. The function of residues E220 and G143 in sustaining its hydrolytic activity of hCES1 was analyzed, and the calculated energy difference aligns well with experimental‐derived results, supporting the validity of our computational insights. These findings provide insights into the potential protective role of hCES1 against HTL‐associated toxicity, and warrant future studies on the possible association between specific genetic variants of hCES1 with impaired catalytic function and clinical susceptibility of HTL‐associated cardiovascular and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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31. Terragines F–G produced by endophytic Bacillus sp. SH-1.2-ROOT-18 from Dendrobium officinale.

Author

Zhu, Youjuan, Li, Shiyang, Kong, Yichao, Zhao, Huimin, Hu, Yuanzhuo, Meng, Jingyi, Chen, Xiabin, Hou, Shurong, and Wang, Xiachang

Subjects
BACILLUS (Bacteria), DENDROBIUM, SUCCINIMIDES, DATA analysis, MOIETIES (Chemistry)
Abstract

Two new terragine analogs (1‒2) with special succinimide and aminopentane moieties were isolated from the fermentation broth of Bacillus sp. SH-1.2-ROOT-18, an endophyte previously discovered from the root of Dendrobium officinale. The structures were elucidated base on comprehensive 1 D/2D NMR and MS data analysis. Complete NMR assignments for the first reported naturally occurring metabolite 3 was also provided. [ABSTRACT FROM AUTHOR]

Published
2022
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41. The protonation state of Glu202 in acetylcholinesterase.

Author

Wang, Jiye, Lai, Suitian, Kong, Yichao, Yao, Weixuan, Chen, Xiabin, and Liu, Junjun

Abstract

Acetylcholinesterase (AChE) is the crucial enzyme in the central nervous system. It is the target of various organophosphorus nerve agents and pesticides, and the inhibition of AChE is a therapeutic strategy for the treatment of various neurological‐related diseases. The Glu202 is a key residue adjacent to the catalytic His447 and plays important role in catalysis. Although the Glu202 has long been considered as negatively charged in many studies, more and more evidences support a protonated Glu202. However, Glu202 is freely accessible by solvent, and thus it seems more reasonable for Glu202 to majorly take the deprotonated state. In the present work, we carried out a series of molecular dynamics simulations with the Glu202 adopting different protonation states. Our results show that the protonated Glu202 is important in maintaining the key hydrogen bond network that supports the catalytic triad, whereas the deprotonated Glu202 results in the collapse of the key hydrogen bond network which consequently destabilizes the catalytic His447. We also notice that different protonation states of Glu202 merely alters the binding mode of ACh. However, since the catalytic His447 is disrupted if Glu202 is deprotonated, His447 cannot facilitate the nucleophilic attack performed by Ser203. Therefore, the catalytic efficiency of ACh hydrolysis should be remarkably decreased if Glu202 is deprotonated. Our findings suggest that, when designing and developing highly active AChE inhibitors or proposing mechanistic hypotheses for AChE‐catalyzed reactions, the protonated state of Glu202 should be considered. [ABSTRACT FROM AUTHOR]

Published
2022
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42. Drug delivery systems for elemene, its main active ingredient β-elemene, and its derivatives in cancer therapy

Author

Zhai,Bingtao, Zeng,Yiying, Zeng,Zhaowu, Zhang,Nana, Li,Chenxi, Zeng,Yijun, You,Yu, Wang,Shuling, Chen,Xiabin, Sui,Xinbing, and Xie,Tian

Subjects
International Journal of Nanomedicine
Abstract

Bingtao Zhai,1 Yiying Zeng,2–5 Zhaowu Zeng,2–4 Nana Zhang,2–4 Chenxi Li,2–4 Yijun Zeng,2–4 Yu You,1 Shuling Wang,2–4 Xiabin Chen,2–4 Xinbing Sui,2–4 Tian Xie2–4 1College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China; 2Holistic Integrative Pharmacy Institutes, Hangzhou Normal University, Hangzhou, Zhejiang, China; 3Key Laboratory of Elemene Class Anti-cancer Chinese Medicine of Zhejiang Province, Hangzhou, Zhejiang, China; 4Engineering Laboratory of Development and Application of Traditional Chinese Medicine from Zhejiang Province, Hangzhou, Zhejiang, China; 5College of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China Abstract: β-elemene is a noncytotoxic Class II antitumor drug extracted from the traditional Chinese medicine Curcuma wenyujin Y. H. Chen et C. Ling. β-elemene exerts its effects by inhibiting cell proliferation, arresting the cell cycle, inducing cell apoptosis, exerting antiangiogenesis and antimetastasis effects, reversing multiple-drug resistance (MDR), and enhancing the immune system. Elemene injection and oral emulsion have been used to treat various tumors, including cancer of the lung, liver, brain, breast, ovary, gastric, prostate, and other tissues, for >20years. The safety of both elemene injection and oral emulsion in the clinic has been discussed. Recently, the secondary development of β-elemene has attracted the attention of researchers and made great progress. On the one hand, studies have been carried out on liposome-based systems (including solid lipid nanoparticles [SLNs], nanostructured lipid carriers [NLCs], long-circulating liposomes, active targeting liposomes, and multidrug-loaded liposomes) and emulsion systems (including microemulsions, self-emulsion drug delivery systems [SEDDSs], and active targeting microemulsion) to solve the issues of poor solubility in water, low bioavailability, and severe phlebitis, as well as to improve antitumor efficacy. The pharmacokinetics of different drug delivery systems of β-elemene are also summarized. On the other hand, a number of highly active anticancer β-elemene derivatives have been obtained through modification of the structure of β-elemene. This review focuses on the two drug delivery systems and derivatives of β-elemene for cancer therapy. Keywords: β-elemene, pharmacokinetics, drug delivery system, derivative, safety

Published
2018

48. DEVELOPMENT OF COCAINE HYDROLASE FOR THERAPEUTIC TREATMENT OF COCAINE ABUSE

Author

Chen, Xiabin

Subjects
Pharmaceutics and Drug Design
Abstract

Cocaine abuse is a world-wide public health and social problem without a U.S. Food and Drug Administration (FDA)-approved medication. An ideal anti-cocaine medication would accelerate cocaine metabolism producing biologically inactive metabolites by administration of an efficient cocaine-specific exogenous enzyme. Recent studies in our lab have led to discovery of the desirable, highly efficient human cocaine hydrolases (hCocHs) that can efficiently detoxify and inactivate cocaine without affecting normal functions of central nervous system (CNS). Preclinical and clinical data have demonstrated that these hCocHs are safe for use in humans and effective for accelerating cocaine metabolism. However, the actual therapeutic use of a hCocH in cocaine addiction treatment is limited by the short biological half-life (e.g. 8 hours or shorter in rats) of the hCocH. In the investigation described in this thesis, we have demonstrated that mCocH and hCocH have improved the catalytic efficiency of mBChE and hBChE against cocaine by ~8- and ~2000-fold, respectively, although the catalytic efficiencies of mCocH and hCocH against other substrates, including acetylcholine (ACh) and butyrylthiocholine (BTC), are close to those of the corresponding wild-type enzymes mBChE and hBChE. In addition, we have identified the first benzoylecgonine-metabolizing enzymes that can hydrolyze benzoylecgonine and accelerate its clearance in rats. The developed LC-MS/MS method has enabled us to simultaneously determine cocaine and nine cocaine-related metabolites in whole blood samples. In development of the long-acting hCocHs, we have designed and discovered a novel hCocH form, catalytic antibody analog, which is an Fc-fused hCocH dimer (hCocH-Fc). The hCocH-Fc has not only a high catalytic efficiency against cocaine, but also a considerably longer biological half-life. A single dose of hCocH-Fc was able to accelerate cocaine metabolism in rats even after 20 days and, thus, block cocaine-induced hyperactivity for a long period of time. In consideration of the general observation that the biological half-life of a protein drug in humans is significantly longer than that in rodents, the hCocH-Fc could allow dosing once every 2-4 weeks, or longer for cocaine addiction treatment in humans.

Published
2016
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50. Bi- and Tetracyclic Spirotetronates from the Coal Mine Fire Isolate Streptomyces sp. LC-6-2

Author

Wang, Xiachang, primary, Elshahawi, Sherif I., additional, Cai, Wenlong, additional, Zhang, Yinan, additional, Ponomareva, Larissa V., additional, Chen, Xiabin, additional, Copley, Gregory C., additional, Hower, James C., additional, Zhan, Chang-Guo, additional, Parkin, Sean, additional, Rohr, Jürgen, additional, Van Lanen, Steven G., additional, Shaaban, Khaled A., additional, and Thorson, Jon S., additional

Published
2017
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