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Articles by Rakhi Agarwal
Total Records ( 3 ) for Rakhi Agarwal
  Reena Chetandas Jhamtani , Saurabh Shukla , Mohinder Singh Dahiya and Rakhi Agarwal
  Background and Objective: Lead (Pb) has a variety of uses, namely in making bullets, pipes, wires, sinks, containers, leaded gasoline, paints, battery and radiators. Lead emissions cause environmental contamination which affects nervous, renal and cardiovascular systems. Lead is known to cause biochemical alterations in tissues. The present study evaluates the acute effects of lead at sub-lethal concentrations in zebrafish. Materials and Methods: A total 72 zebrafish were divided into four groups viz. control and exposed groups which were given 0.5, 1.0 and 2.0 mL L–1 (ppm) of lead CRM for 24 h. Levels of malionaldehyde, glutathione and antioxidant enzyme activities were determined in liver, kidney and brain. Statistical significance was determined using one-way ANOVA where p<0.05 was considered as significant. Results: Acute exposure of zebrafish to lead caused increased lipid peroxidation and elevated activity of glutathione peroxidase in a concentration dependent manner. However, no change in glutathione content was observed at 0.5 mL L–1 concentration while it was elevated at 1 mL L–1. There was alteration in the activity of other enzymes in a concentration dependent manner. Increased concentration of lead affected the brain tissue more as compared to liver and kidney. Conclusion: Lead exposure induces oxidative stress and a decline in enzyme activity presumably causes lipid peroxidation due to increase in the levels of reactive oxygen species. The biochemical mechanisms mediating low-level toxicity are not clearly understood but in several biological systems lead (Pb) alters cellular processes. Studies suggest that no threshold levels for lead have been prescribed which causes adverse effects. Safe disposals of domestic sewage and industrial effluents as well as enforcement of laws to protect our environment are therefore advocated.
  Rakhi Agarwal , Stephen K. Burley and Subramanyam Swaminathan
  Protein phosphorylation plays a crucial role in mitogenic signal transduction and regulation of cell growth and differentiation. Dual specificity protein phosphatase 23 (DUSP23) or VHZ mediates dephosphorylation of phospho-tyrosyl (pTyr) and phospho-seryl/threonyl (pSer/pThr) residues in specific proteins. In vitro, it can dephosphorylate p44ERK1 but not p54SAPK-β and enhance activation of c-Jun N-terminal kinase (JNK) and p38. Human VHZ, the smallest of the catalytically active protein-tyrosine phosphatases (PTP) reported to date (150 residues), is a class I Cys-based PTP and bears the distinctive active site signature motif HCXXGXXRS(T). We present the crystal structure of VHZ determined at 1.93Å resolution. The polypeptide chain adopts the typical αβα PTP fold, giving rise to a shallow active site cleft that supports dual phosphorylated substrate specificity. Within our crystals, the Thr-135–Tyr-136 from a symmetry-related molecule bind in the active site with a malate ion, where they mimic the phosphorylated TY motif of the MAPK activation loop in an enzyme-substrate/product complex. Analyses of intermolecular interactions between the enzyme and this pseudo substrate/product along with functional analysis of Phe-66, Leu-97, and Phe-99 residues provide insights into the mechanism of substrate binding and catalysis in VHZ.

  Rakhi Agarwal and Subramanyam Swaminathan
  Clostridium botulinum neurotoxins are the most potent toxins to humans. The recognition and cleavage of SNAREs are prime evente in exhibiting their toxicity. We report here the crystal structure of the catalytically active full-length botulinum serotype E catalytic domain (BoNT E) in complex with SNAP-25 (a SNARE protein) substrate peptide Arg180-Ile181-Met182-Glu183 (P1–P3`). It is remarkable that the peptide spanning the scissile bond binds to but bypasses cleavage by the enzyme and inhibits the catalysis fairly with Ki ~69 µM. The inhibitory peptide occupies the active site of BoNT E and shows well defined electron density. The catalytic zinc and the conserved key residue Tyr350 of the enzyme facilitate the docking of Arg180 (P1) by interacting with its carbonyl oxygen that displaces the nucleophilic water. The general base Glu212 side chain interacts with the main chain amino group of P1 and P1`. Conserved Arg347 of BoNT E stabilizes the proper docking of the Ile181 (P1`) main chain, whereas the hydrophobic pockets stabilize the side chains of Ile181 (P1`) and Met182 (P2`), and the 250 loop stabilizes Glu183 (P3`). Structural and functional analysis revealed an important role for the P1` residue and S1` pocket in driving substrate recognition and docking at the active site. This study is the first of its kind and rationalizes the substrate cleavage strategy of BoNT E. Also, our complex structure opens up an excellent opportunity of structure-based drug design for this fast acting and extremely toxic high priority BoNT E.
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