Parimal Misra, Ph.D.
Stress induced type 2 diabetes: The roles of transcriptional co-activator binding protein PIMT and energy sensor AMPK
Education & Training
1988-1995: Ph.D. Molecular Biology, Indian Institute of Chemical Biology, Kolkata, India..
1995-1996: Post-doctoral fellow, Institute of Microbial Technology, Chandigarh, India.
1996 to 2008: Scientist- Senior Director, Preclinical Biology and Genomics-Proteomics, Discovery Biology, Dr. Reddy’s Laboratories Ltd, Hyderabad.
2000-2002: Visiting Scientist, Northwestern University, Chicago, USA.
2008 - 2009: Head, Metabolic Disorders, Wockhardt Research Center, Aurangabad, India
2009-2012: Head, Biology, Institute of Life Sciences.
2012 onwards: Professor of Biology and Dean of Administration, Dr. Reddy’s Institute of Life Sciences.
Parimal works in the area of transcriptional complexes, co-factors, gene-regulation and signal transduction related to PPAR and AMPK research. He worked with the PPAR and AMPK group of Dr. Reddy’s and contributed to five NCEs in different clinical phases including Balaglitazone, Ragaglitazar and AMPK activator. He has published 38 articles in scientific journals (including journal of biological chemistry, journal of pharmaceuticals and experimental therapeutics, journal of medicinal chemistry, expert opinion on therapeutic targets, Springer, Biochimie), authored two book chapters and filled 15 international and national patents. He has mentored 40 drug discovery scientists, one Ph.D student, three Research Associates and two post-doctoral fellows. His laboratory is also involved in drug discovery in the area of metabolic disorder s and tuberculosis.
Stress induced type 2 diabetes: The role of transcriptional co-activator binding protein PIMT and energy sensor AMPK
Grant: Understanding the role of transcriptional co-activator binding protein PIMT in the control of hepatic gluconeogenesis. Sanctioned by DBT Basic science panel (2011-14), PI: Dr .Parimal Misra, CO-PI: Dr. Kishore Parsa, Collaborator: Prof. Janardan K Reddy, Northwestern University, Chicago, USA
Stress increases blood glucose level quickly in human even upto 600mg/dl which in some patients very difficult to be controlled even by insulin. It is observed that these diabetic patients maintained normal blood glucose level when stress has been reduced. It is known that some hormones are involved in regulating glucose level in stressed condition by regulating hepatic gluconeogenesis but mechanism is poorly understood, which prompted us to identify and characterize novel cellular factor(s) responsible for regulation of gluconeogenesis and hepatic glucose output.
PEPCK is the rate limiting enzyme of hepatic gluconeogenesis. PIMT was isolated as PRIP (NCoA) interacting protein and was reported to possess RNA methyl transferase activity [Zhu et al: (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 10380–10385]. PIMT/NCoA6IP is a transcriptional co-activator binding protein that is proposed to serve as a molecular bridge between CBP/p300-anchored (HAT) and Med1-anchored coactivator (non-HAT) complexes and modulates PPARγ mediated transcription [Misra et al .J Biol Chem 2002 Mar 23; 277(22): 20011-19]. Using Adenoviral and liver specific knock out techniques in animals we have shown that ERK2-mediated phosphorylation of PIMT at Ser298 is essential in hepatic gluconeogenesis, demonstrating an important role of PIMT in the pathogenesis of hyperglycemia (Kapadia et al: PLoS One, Dec 17, 2013)
Grant 2: Understanding the functions of Selective AMPKγ Modulators (SAMPKγM) in dissecting the pharmacological role of different AMPK isozymes in metabolic diseases
Recommended by DBT Basic Science panel (2014-17), PI: Dr. Parimal Misra, CO-PIs: Drs. Rajamohan Reddy and Bulusu Gopalakrishnan
Exercise distresses, keeps people healthy and exercise activates AMP activated protein kinase (AMPK). AMP-activated Protein Kinase (AMPK) belongs to the family of energy-sensing enzymes that are activated by cellular stresses resulting in ATP depletion, thus acting like a ‘fuel gauge’. On activation, AMPK functions to restore cellular ATP by inhibiting ATP consumption processes, but accelerating ATP generation processes. AMPK is activated by an increase in creatine/phosphocreatine and AMP/ATP ratios, resulting in allosteric modification. AMPK is composed of three different subunitsa, b andg. In mammals, the heterotrimeric complexes contain catalytic a subunit (a1 or a2), with b (b1 or b2) and g (g1, g2 or g3) regulatory subunits encoded by separate genes yielding to 12 heterotrimeric combinations. The observation that small molecules namely PT1and A-769662 can activate α (both α1 and α2) (Pang et al., 2008) and b (b1 and b2) (Cool et al) respectively suggest that it is feasible to activate all 12 AMPK complexes by a single compound. However, it is not clear whether all 12 AMPK complexes could be or need to be activated to the same degree in order to realize the maximum benefits of AMPK activation in vivo leading to the hypothesis of isozyme specific AMPK activators.
Fig.2: AMPKγ subunits differ in length in N-terminal (A). Ligand binds to the N-terminal or CBS domain of the AMPKγ subunit. Each ligand- isozyme complex assumes a somewhat different three-dimensional conformation, leading to differential activation of isozymes through phosphorylation by upstream kinases like LKB1 or CAMKβ etc. As a result of this differential activation of isozymes, each AMPKγ ligand- isozyme complex leads to a differential, but overlapping, pattern of substrate specificity. Thus, each ligand-isozyme will activate or repress a certain set of enzymes and transcription factors some of which are in common with other ligand-isozymes, and some of which are not leading to differential biological activities (B)
We are proposing to find any allosteric site(s) in the different N-terminal of γ subunits or any additional allosteric sites other than CBS domains in the γ-subunits by the help of molecular modeling tools and to design specific Non-AMP mimetic (Chemical probes) as AMP being a natural metabolite modulates activities for several proteins including AMPK and it is not a specific activator of AMPK and use these Selective AMPKγ Modulators (SAMPKγM) in dissecting the pharmacological role of different AMPK isozymes in metabolic diseases.
Grant 3: Small molecular inhibitors targeting essential enzymes like chorismate mutase and other validated targets Sanctioned by DBT for COE-TB project on Chorismate mutase (2009-14): Project Coordinator: Prof .Syed Hasnain, PIs: Drs. Manojit Pal and Parimal Misra
Tuberculosis (TB), kills more than two million people a year worldwide. Thus identification of new drugs is highly desirable. The Shikimate pathway involves the biosynthesis of aromatic amino acids catalyzed by an enzyme chorismate mutase (CM). Due to the absence of this pathway in animals but not in bacteria CM is considered as a promising target for the identification of new drugs. However, only a few small molecules have been reported to possess inhibitory activity against CM. Consequently, we have identified a novel heterocyclic class of compounds as inhibitors of CM.
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