Member SpotlightsProteomics Research: An Analysis of MetalloProteins Govindasamy Mugesh, Ph.D. One of the newest members to The Science Advisory Board.  Mugesh (far right) with friends during a trip to the Great Wall of China. This week The Science Advisory Board discussed proteomics research, metalloproteins in particular, with Govindasamy Mugesh, Ph.D., an Associate Professor in the Inorganic & Physical Chemistry Department of the Indian Institute of Science in Bangalore, India. After receiving his undergraduate and masters degrees in chemistry, he studied organometallic chemistry for his Ph.D at the Indian Institute of Technology in 1998. Under the instruction of Prof. Harkesh Singh, he was able to analyze the, " synthesis, structure and reactivity of organochalcogen (S, Se, Te) compounds.", as a Research Associate. In 2000, Mugesh was accepted as an Alexander von Humboldt Fellow for research conducted at the Institute of Inorganic and Analytical Chemistry, Technical University, Braunschweig. This research opportunity took him to Germany, where he received training in organoselenium compound synthesis from Professor Wolf-Walther du Mont. While there, he was also able to receive biochemical experiment training from Prof. Helmut Sies at Heinrich Heine University. In 2001, Mugesh decided to add more organic chemistry training in addition to his inorganic chemistry expertise; he worked as a postdoctoral fellow at The Scripps Research Institute, USA for the synthetic organic chemist Prof. K.C. Nicolaou. In 2002, he returned to India where he currently teaches and continues research in inorganic chemistry at the Indian Institute of Science. Although he admits to spending the majority of his time in the lab, his off-time is filled with reading, driving long distances, and spending time with his two sons. Mugesh belongs to the International Editorial Board of the journal Bioinorganic Chemistry and Applications, the American Association for the Advancement of Science (AAAS), the International Union for Pure and Applied Chemistry (IUPAC), the Chemical Research Society of India (CRSI) and the Alexander von Humboldt (AvH) Association. He has co-authored about forty conference papers and fifty peer-reviewed publications. Please describe your role and current research interests at the Indian Institute of Science. The department in which I am currently working is one of the well-recognized departments at the Indian Institute of Science and is devoted to advanced research and teaching in chemistry. My main job here is teaching and research. I guide Ph.D and M.S. students, post-docs and young students from colleges and universities and train them in the techniques and methodologies involved in bioinorganic chemistry research. The main interest of our research group is to understand the chemistry and biology of medicinally important metalloproteins (including selenoproteins) and to develop novel synthetic methodologies for functionally mimicking the active site of certain enzymes. The current research in our laboratory is directed towards the synthesis and antioxidant activity of various organoselenium compounds, including the anti-inflammatory drug ebselen. Our group is also interested in the design and synthesis of novel compounds as inhibitors of heme peroxidases and zinc hydrolases. We approach these problems by employing spectroscopic, crystallographic and biophysical methods in combination with chemical synthesis. My long-term research goal is to develop novel therapeutic agents based on the inhibition of metalloenzymes. In this regard, we have started working on two enzyme systems; the first one is based on the inhibition of thyroid peroxidase and the second one is related to the bacterial drug resistance enzyme metallo-beta-lactamase. Your career has enabled you to develop expertise in both organic and inorganic chemistry. What were your initial motivations and has your career progressed as expected? Although I am a synthetic chemist by training, I have developed a strong interest towards biological systems, particularly metalloproteins and their functions. When I joined the Indian Institute of Technology, Bombay, for my Ph.D., I never thought that I would become a chemical biologist or bioinorganic chemist. Bioinorganic chemistry is a fast-expanding frontier area of research, bridging inorganic chemistry and biology. A few years ago, the Department of Science and Technology (DST), India has identified “metalloenzymes and their mimics” as one of the thrust areas in the country. Recently, the DST launched three types of programs (major collaborative programs, individual/collaborative projects, bioinorganic research fellowships) for strengthening research in the area of bioinorganic chemistry. The uninterrupted financial support from DST and encouragements from my colleagues and friends motivated me to pursue research in this exciting area. I had never imagined I would become a faculty member of one of the premier research institutions in India. Without any proper guidance, I completed all my early education in remote places where there was no appreciation for good education, and at that stage, it was difficult for me to imagine my career path. In fact, I never had an opportunity to interact with scientists from leading research institutions until completion of my M.S. degree and I had no idea about the top-class research institutions in India or abroad. My only expectation was that I should get a decent job somewhere and support my family. Now I'm happy that I am working in one of the best institutions in the world with all necessary facilities to carry out internationally competitive research. What would you like to achieve with your research in the future? I believe in the statement of Prof. Kwan Choi (Iowa State University, USA) that survival is more important than glory in the early stages. I also followed the suggestion to diversify the research into new areas, which is very important during the first 5-6 years of the career when each publication counts heavily. For this, I would like to pick up some important biological problems related to protein structure and function and apply my chemistry knowledge to address them. My long-term goal is to take my laboratory research to medicinal applications. We do have some promising preliminary results on a few compounds, and I hope to bring them further into the drug development process. The following questions are specific to proteomics research on metalloproteins. Please explain the utilization of proteomics to your current research. My group is working on multidisciplinary areas related to some medicinally important metalloproteins such as heme peroxidases and zinc hydrolases. Although the facilities in my group/department are not sufficient to carry out high level proteomics research, we interact with scientists in the biological sciences and work on problems of mutual interests. We are currently studying the biochemical halogenations catalyzed by heme peroxidases. We are also studying the redox regulation of protein tyrosine phosphatase 1B, an enzyme involved in insulin signaling. In collaboration with Dr Patrick D’ Silva at the Department of Biochemistry, we are planning to develop some small organic/organometallic molecules (e. g. ADP analogues, and peptide-mimetics) as Hsp70 modulators. This study would not only help in understanding the mechanism of the interaction of Hsp70 with various small molecule modulators, but also lead to the development of novel drugs for the treatment of specific cancers, infections, and protein conformational diseases. As proteomics is being applied to medical challenges with respect to the identification of new pathological markers and therapeutic targets, do you believe the current generation of proteomic tools can meet this challenge? The application of proteomics in biomedicine is an important area. I think the current generation of proteomics tools is sufficient to identify new pathological markers and therapeutic targets. The improvements in the traditional two-dimensional electrophoresis and the development of new off-gel methods can certainly address the problems. The currently available mass spectrometric techniques, either alone or in combination with liquid chromatography, not only help protein identification with increasing sensitivity, but also increase our understanding about the protein-protein interactions and post-translational modifications such as phosphorylation, glycosylation, ubiquitination and methylation. The application of mass spectrometry in peptide mass fingerprinting and tandem mass sequence analysis is becoming very important in identification and characterization of low-abundant proteins. As far as the applications of these techniques in biomedicine are concerned, the large-scale high-throughput analysis, which allows the functional investigation of proteins, should help in identifying potential pathological markers and therapeutic targets. How effective is today's technology to conduct large-scale, high-throughput analyses for the detection, identification, and functional investigation of low-abundant proteins? The current proteomic tools certainly allow large-scale, high-throughput analyses for the detection, identification, and functional investigation of low abundant proteins. For example, Oxford GlycoSciences developed an integrated system that helps in separating, detecting, quantifying, and identifying proteins expressed in clinical material. In recent years, protein arrays are becoming key technologies for high-throughput analyses of proteins. There is also a “chemical printer” technology, which combines the advantages of both protein chips and 2-D electrophoresis. This appears to be an interesting tool for the identification of novel protein targets for biomedical and diagnostic applications. Research projects that aim to identify & catalogue the entire proteome for an organism is a giant undertaking. The result has been international collaborations & associations, often with online databases, that attempt to speed up this process by data sharing. Do you belong to any of these associations, and if so, do you find them effective? How do you think research at the Indian Institute of Science is contributing to the national & international efforts in proteomics? I do not belong to these associations. The research at the Indian Institute of Science (IISc), particularly, at the Division of Biological Sciences, contributes significantly to the national and international efforts in proteomics. The proteomics research at IISc is not only aimed at solving some fundamental biological problems, but also designed to address real life problems such as those involving tuberculosis, malaria and disorders of various kinds. IISc has excellent proteomics research facilities and the research at IISc is supported by grants from various national funding agencies such as Department of Science and Technology (DST), Department of Biotechnology (DBT), Council of Scientific and Industrial Research (CSIR), Department of Atomic Energy (DAE), Indian Council of Medical Research (ICMR) and international agencies such as The Wellcome Trust, UK. The following are publications by Mugesh that are relevant to this Member Spotlight. Sarma, B. K.; Mugesh, G. Redox Regulation of Protein Tyrosine Phosphatase 1B (PTP1B): A Biomimetic Study on the Unexpected Formation of a Sulfenyl Amide Intermediate, J. Am. Chem. Soc., 129, 8872 - 8881 (2007). Bhabak, K. P.; Mugesh, G. Synthesis, Characterization and Antioxidant Activity of Some Ebselen Analogues. Chem. Eur. J., 13, 4594 - 4601 (2007). Tamilselvi, A.; Nethaji, M.; Mugesh, G. Antibiotic Resistance: Mono- and Dinuclear Zinc Complexes as Metallo-beta-Lactamase Mimics. Chem. Eur. J., 12, 7797 - 7806 (2006). Roy, G.; Mugesh, G. Anti-Thyroid Drugs and Thyroid Hormone Synthesis: Effect of Methimazole Derivatives on Peroxidase-Catalyzed Reactions, J. Am. Chem. Soc., 127, 15207 - 15217 (2005). Sarma, B. K.; Mugesh, G. Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen: Unexpected Complications with Thiol Exchange Reactions, J. Am. Chem. Soc., 127, 11477 - 11485 (2005). Roy, G.; Nethaji, M.; Mugesh, G. “Biomimetic Studies on Anti-Thyroid Drugs and Thyroid Hormone Synthesis”, J. Am. Chem. Soc., 126, 2712 - 2713 (2004). ### << Previous Next >> [ View All Member Spotlights ] |
|
