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Recently, Nature Chemical Biology, a journal belonging to the Nature Publishing Group and one of the world’s leading authorities in the field of chemical biology, published a research paper based on the work of the E-Institute of Chemical Biology, an institute built mainly by the Shanghai Jiaotong University School of Medicine and supported by other institutions of higher learning in Shanghai. The paper is titled “Adenanthin Targets Peroxiredoxin I and II to Induce Differentiation of Leukemic Cells.” The researchers found that adenanthin extracted from Rabdosia adenantha could induce differentiation of leukemic cells, on the basis of which they successfully captured the target proteins, peroxiredoxin I/II, and elucidated a new mechanism for the differentiation of leukemic cells.
According to Dr. Guoqiang Chen, the corresponding author of the paper, cell-permeant small-molecule compounds can quickly bind to target proteins, thus affecting the gene expression profile of the whole organism by either suppressing or enhancing the ability of target proteins to regulate biological pathways or networks. Therefore, small molecules with specific targets have evolved into an effective tool in the studies of gene functions and complicated biological pathways and processes. The unique combination of chemistry and biology gave rise to a new interdisciplinary approach, named chemical biology, which has become one of the key disciplines in the advancement of life sciences. The objective along this line of research is to identify small-molecule compounds that show binding specificity to large biological molecules (mostly proteins) and to use these compounds as probes for the research on gene functions and for the discovery of targets, pathways, and networks relevant to disease treatments. In 2009, Shanghai Municipal Education Commission approved the establishment of the E-Institute of Chemical Biology of Institutions of Higher Learning in Shanghai, with the Key Laboratory of Cell Differentiation and Apoptosis under the Ministry of Education of the Shanghai Jiaotong University School of Medicine as the backbone, supported by experts in this area from universities and research institutes in Shanghai and around the country. The strategic goals of the E-Institute include pioneering the research in the field of chemical biology by using the country’s rich natural resources, training talented interdisciplinary professionals, and thereby enhancing the academic development of the discipline.
Under the meticulous supervision of Dr. Guoqiang Chen, who is a chief research fellow of the E-Institute of Chemical Biology, doctoral students, Chuanxu Liu, Qianqian Yin, and others used leukemic cells as in vitro models to screen more than 500 natural small-molecule of the isodon diterpenoids, provided by Dr. Handong Sun of Kunming Institute of Botany under the Chinese Academy of Sciences, and found that adenanthin extracted from Rabdosia adenantha could induce morphological and functional differentiation of leukemic cells. They found that the induced differentiation was not only seen in leukemic cells sensitive to all-trans retinoic acid (ATRA), but also in those resistant to ATRA. Further in vivo study on both ATRA-sensitive and ATRA-resistant transgenic mice showed that adenanthin effectively induced differentiation of leukemic cells in both types of mice and significantly prolonged their survival.
Based on these findings, the research group of Dr. Hucheng Zhou of Shanghai Jiaotong University College of Pharmacology, who is also a member of the E-Institute of Chemical Biology, chemically modified the molecular structure of adenanthin. After identifying its active functional groups, they synthesized biotin-labeled adenanthin. Using proteomic and bioinformatic platforms, researchers “fished out” candidate target proteins in leukemic cells with the biotin-labeled adenanthin as the “bait.” It was discovered that adenanthin could bind covalently to peroxiredoxins, Prx I and Prx II.
The peroxiredoxin family is composed of antioxidant enzymes with hydrogen peroxidase activity. In the human body there are at least six members, Prx I-VI, which all contain a conserved cysteine (Cys) residue, called a peroxidatic Cys (CP), which can be oxidized by peroxides. When the thiol group (SH) of CP is oxidized into Cys-SOH, the latter forms a disulfide bond with another Cys called a resolving Cys (CR) to remove peroxides. Depending on the different structures of Cys, they are subdivided into 2-Cys Prx (including Prx I-IV), atypical 2-Cys Prx (Prx V), and 1-Cys Prx (Prx VI). There is mounting evidence that the expression levels of Prx family members are closely associated with major human diseases such as cancers, cardiovascular diseases, diabetes, and neurodegenerative disorders. Accordingly, Prx proteins, especially the 2-Cys Prx’s, were shown to be effective drug targets in the treatment of some diseases. Chen’s group showed that adenanthin did not bind with Prx IV, V, and VI, and exhibited low affinity to Prx III, which is a protein in the mitochondria, where no adenanthin is present. Therefore, they focused on the implications of the binding of adenanthin to Prx I and Prx II. Interestingly, knocking down Prx I and Prx II expression directly induced the differentiation of leukemic cells. Subsequent mass spectroscopy and mutagenesis analyses showed that adenanthin could specifically and covalently bind to the CR of Prx I and Prx II and could suppress the enzymatic activity of Prx II, and especially that of Prx I, while increasing intracellular H2O2 level. In the presence of N-acetyl-l-cysteine (NAC), an H2O2 scavenger, the effect of differentiation induction by adenanthin was almost completely abolished, suggesting the role of H2O2 in adenanthin-induced differentiation. There is growing evidence that as a second messenger, H2O2 is extensively involved in the regulation of signal transduction pathways and various cellular activities. Chen’s group also showed that increased level of H2O2 could activate extracellular signal-regulated protein kinases (ERK1/2), thereby raising the expression level of C/EBP, which is related to the differentiation of hematopoietic cells, and inducing cell differentiation. This research is funded by the major research program titled “Studying the process of signal transduction using small molecules as probes”, sponsored by the National Natural Science Foundation of China, and grants from Major Scientific Projects under the Ministry of Science and Technology and Shanghai Municipal Commission of Science and Technology.
(The original paper can be found athttp://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.935.html)