Immanuel Dhanasingh | Chosun University (original) (raw)

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Papers by Immanuel Dhanasingh

Research paper thumbnail of Crystal structure of Betaaspartyl dipeptidase from thermophilic keratin degrading Fervidobacterium islandicum-AW-1

Research paper thumbnail of Crystal structure of MazF (Form-I) from Deinococcus radiodurans

Research paper thumbnail of Crystal structure of Arabinose isomerase from hyper thermophilic bacterium Thermotoga maritima (TMAI) wt

Research paper thumbnail of Crystal structure of Arabinose isomerase from hybrid AI8 with Adonitol

Research paper thumbnail of Crystal structure of pyrrolidone carboxyl peptidase from thermophilic keratin degrading bacterium Fervidobacterium islandicum AW-1 (FiPcp)

Research paper thumbnail of Crystal structure of Putative iron-sulfur cluster assembly scaffold protein for SUF system (FiSufU) from thermophilic Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of thermostable Carboxypeptidase (FisCP) from Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of thermostable FiSufS-SufU complex from thermophilic Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of MazE-MazF (Form-III) from Deinococcus radiodurans

Research paper thumbnail of Crystal structure of Beta-aspartyl dipeptidase from thermophilic keratin degrading Fervidobacterium islandicum AW-1 in complex with beta-Asp-Leu dipeptide

Research paper thumbnail of Crystal structure of thermostable Cysteine desulfurase (FiSufS) from thermophilic Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of hybrid Arabinose isomerase AI-10

Research paper thumbnail of Small Molecule Therapeutics Combined MET Inhibition and Topoisomerase I Inhibition Block Cell

Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly im... more Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38).MET and TOP1 gene copynumbers andprotein expressionwere determined in 29patientswith limited (n 11) and extensive (n 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly high...

Research paper thumbnail of PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma

Research paper thumbnail of Biochemical and Structural Characterization of a Keratin-Degrading M32 Carboxypeptidase from Fervidobacterium islandicum AW-1

Biochemical and biophysical research communications, Jan 18, 2015

Comparative genomics of the keratin-degrading extremophilic eubacterium Fervidobacterium islandic... more Comparative genomics of the keratin-degrading extremophilic eubacterium Fervidobacterium islandicum AW-1 and the closely related F. nodosum with no keratinolytic activity suggested that the FIAW1_1600 gene encoding a carboxypeptidase (CP) plays an important role in keratin degradation. The presumptive 489 amino acid sequence of the gene showed a conserved HEXXH motif with low levels of sequence identity (<38%) to reported thermostable M32 CPs. To identify its functional role, the FIAW1_1600 gene was overexpressed in Escherichia coli, and the recombinant enzyme was purified and characterized in detail. F. islandicum AW-1 CP (FisCP) formed a homodimer with a molecular mass of 107 kDa, and its apoenzyme exhibited maximal activity at 80°C and pH 7.0 in the presence of Co(2+). This metalloenzyme mainly cleaved the C-termini of peptides with a basic amino acid sequence. The crystal structure of FisCP at 2.2 Å resolution showed high levels of structural similarities (root-mean-square de...

Research paper thumbnail of C. elegans and mutants with chronic nicotine exposure as a novel model of cancer phenotype

Cancer Biology & Therapy, 2015

Research paper thumbnail of MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

Research paper thumbnail of Loss of Hemolectin reduces the survival of Drosophila larvae after wounding

Developmental & Comparative Immunology, 2012

Coagulation involving both hemocytes and humoral factors is important for insect survival and imm... more Coagulation involving both hemocytes and humoral factors is important for insect survival and immune defense. Hemolectin is a major larval clotting factor in Drosophila, and hemolymph from hml mutants does not clot ex vivo. Yet surprisingly third instar hml larvae survived injury as well as controls. The number of hemocytes in circulation changes during larval development. Reasoning that this could affect coagulation, we studied larval survival after injury at different stages. We found that hml larvae survived less than controls when injured during the feeding stage with fewer hemocytes. This important in vivo result reinforces the role of Hemolectin in larval hemostasis. A subtle effect of hml on immunity was found in adults. Similar experiments on hml mutant larvae gave different results, but feeding stage hml larvae were differentially sensitive to infections with different strains of Serratia marcescens.

Research paper thumbnail of Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer

Research paper thumbnail of Financial

Small cell lung cancer (SCLC) is a devastating disease and current therapies have not greatly imp... more Small cell lung cancer (SCLC) is a devastating disease and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MET to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n=11) and extensive (n=18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared to limited disease (p=0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (p=0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r=0.5). In vitro stimulation of H82 cells revealed HGF-induced nuclear co-localization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared to either drug alone. Collectively, these findings suggest that combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC.

Research paper thumbnail of Crystal structure of Betaaspartyl dipeptidase from thermophilic keratin degrading Fervidobacterium islandicum-AW-1

Research paper thumbnail of Crystal structure of MazF (Form-I) from Deinococcus radiodurans

Research paper thumbnail of Crystal structure of Arabinose isomerase from hyper thermophilic bacterium Thermotoga maritima (TMAI) wt

Research paper thumbnail of Crystal structure of Arabinose isomerase from hybrid AI8 with Adonitol

Research paper thumbnail of Crystal structure of pyrrolidone carboxyl peptidase from thermophilic keratin degrading bacterium Fervidobacterium islandicum AW-1 (FiPcp)

Research paper thumbnail of Crystal structure of Putative iron-sulfur cluster assembly scaffold protein for SUF system (FiSufU) from thermophilic Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of thermostable Carboxypeptidase (FisCP) from Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of thermostable FiSufS-SufU complex from thermophilic Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of MazE-MazF (Form-III) from Deinococcus radiodurans

Research paper thumbnail of Crystal structure of Beta-aspartyl dipeptidase from thermophilic keratin degrading Fervidobacterium islandicum AW-1 in complex with beta-Asp-Leu dipeptide

Research paper thumbnail of Crystal structure of thermostable Cysteine desulfurase (FiSufS) from thermophilic Fervidobacterium Islandicum AW-1

Research paper thumbnail of Crystal structure of hybrid Arabinose isomerase AI-10

Research paper thumbnail of Small Molecule Therapeutics Combined MET Inhibition and Topoisomerase I Inhibition Block Cell

Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly im... more Small cell lung cancer (SCLC) is a devastating disease, and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MNNG HOS transforming gene (MET) to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38).MET and TOP1 gene copynumbers andprotein expressionwere determined in 29patientswith limited (n 11) and extensive (n 18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared with limited disease (P 0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed a significantly high...

Research paper thumbnail of PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma

Research paper thumbnail of Biochemical and Structural Characterization of a Keratin-Degrading M32 Carboxypeptidase from Fervidobacterium islandicum AW-1

Biochemical and biophysical research communications, Jan 18, 2015

Comparative genomics of the keratin-degrading extremophilic eubacterium Fervidobacterium islandic... more Comparative genomics of the keratin-degrading extremophilic eubacterium Fervidobacterium islandicum AW-1 and the closely related F. nodosum with no keratinolytic activity suggested that the FIAW1_1600 gene encoding a carboxypeptidase (CP) plays an important role in keratin degradation. The presumptive 489 amino acid sequence of the gene showed a conserved HEXXH motif with low levels of sequence identity (<38%) to reported thermostable M32 CPs. To identify its functional role, the FIAW1_1600 gene was overexpressed in Escherichia coli, and the recombinant enzyme was purified and characterized in detail. F. islandicum AW-1 CP (FisCP) formed a homodimer with a molecular mass of 107 kDa, and its apoenzyme exhibited maximal activity at 80°C and pH 7.0 in the presence of Co(2+). This metalloenzyme mainly cleaved the C-termini of peptides with a basic amino acid sequence. The crystal structure of FisCP at 2.2 Å resolution showed high levels of structural similarities (root-mean-square de...

Research paper thumbnail of C. elegans and mutants with chronic nicotine exposure as a novel model of cancer phenotype

Cancer Biology & Therapy, 2015

Research paper thumbnail of MET and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma

Research paper thumbnail of Loss of Hemolectin reduces the survival of Drosophila larvae after wounding

Developmental & Comparative Immunology, 2012

Coagulation involving both hemocytes and humoral factors is important for insect survival and imm... more Coagulation involving both hemocytes and humoral factors is important for insect survival and immune defense. Hemolectin is a major larval clotting factor in Drosophila, and hemolymph from hml mutants does not clot ex vivo. Yet surprisingly third instar hml larvae survived injury as well as controls. The number of hemocytes in circulation changes during larval development. Reasoning that this could affect coagulation, we studied larval survival after injury at different stages. We found that hml larvae survived less than controls when injured during the feeding stage with fewer hemocytes. This important in vivo result reinforces the role of Hemolectin in larval hemostasis. A subtle effect of hml on immunity was found in adults. Similar experiments on hml mutant larvae gave different results, but feeding stage hml larvae were differentially sensitive to infections with different strains of Serratia marcescens.

Research paper thumbnail of Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer

Research paper thumbnail of Financial

Small cell lung cancer (SCLC) is a devastating disease and current therapies have not greatly imp... more Small cell lung cancer (SCLC) is a devastating disease and current therapies have not greatly improved the 5-year survival rates. Topoisomerase (Top) inhibition is a treatment modality for SCLC; however, the response is short lived. Consequently, our research has focused on improving SCLC therapeutics through the identification of novel targets. Previously, we identified MET to be overexpressed and functional in SCLC. Herein, we investigated the therapeutic potential of combinatorial targeting of MET using SU11274 and Top1 using 7-ethyl-10-hydroxycamptothecin (SN-38). MET and TOP1 gene copy numbers and protein expression were determined in 29 patients with limited (n=11) and extensive (n=18) disease. MET gene copy number was significantly increased (>6 copies) in extensive disease compared to limited disease (p=0.015). Similar TOP1 gene copy numbers were detected in limited and extensive disease. Immunohistochemical staining revealed significantly higher Top1 nuclear expression in extensive (0.93) versus limited (0.15) disease (p=0.04). Interestingly, a significant positive correlation was detected between MET gene copy number and Top1 nuclear expression (r=0.5). In vitro stimulation of H82 cells revealed HGF-induced nuclear co-localization of p-MET and Top1. Furthermore, activation of the HGF/MET axis enhanced Top1 activity, which was abrogated by SU11274. Combination of SN-38 with SU11274 dramatically decreased SCLC growth as compared to either drug alone. Collectively, these findings suggest that combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for SCLC.

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