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A facile chemoenzymatic approach: one-step syntheses of monoterpenoid indole alkaloids.
2010
Facile chemoenzymatic syntheses of cytotoxic monoterpenoid indole alkaloids with novel skeletons and multiple chiral centers are described. Synthesis of these alkaloids was achieved by a simple one-step reaction using strictosidine and 12-aza-strictosidine as the key intermediates. Strictosidines were prepared by coupling of secologanin with tryptamine and 7-aza-tryptamine, respectively, using the immobilized recombinant Rauvolfia strictosidine synthase. A detailed stereochemical analysis is presented herein. The results provide an opportunity for a chemoenzymatic approach that leads to an increased diversification of complex alkaloids with improved structures and activities.
3D-Structure and function of strictosidine synthase--the key enzyme of monoterpenoid indole alkaloid biosynthesis.
2008
Strictosidine synthase (STR; EC 4.3.3.2) plays a key role in the biosynthesis of monoterpenoid indole alkaloids by catalyzing the Pictet-Spengler reaction between tryptamine and secologanin, leading exclusively to 3alpha-(S)-strictosidine. The structure of the native enzyme from the Indian medicinal plant Rauvolfia serpentina represents the first example of a six-bladed four-stranded beta-propeller fold from the plant kingdom. Moreover, the architecture of the enzyme-substrate and enzyme-product complexes reveals deep insight into the active centre and mechanism of the synthase highlighting the importance of Glu309 as the catalytic residue. The present review describes the 3D-structure and …
Improved Expression of His6-Tagged Strictosidine Synthase cDNA for Chemo-Enzymatic Alkaloid Diversification
2010
Strictosidine synthase (STR1) catalyzes the stereoselective formation of 3alpha(S)-strictosidine from tryptamine and secologanin. Strictosidine is the key intermediate in the biosynthesis of 2,000 plant monoterpenoid indole alkaloids, and it is a key precursor of enzyme-mediated synthesis of alkaloids. An improved expression system is described which leads to optimized His(6)-STR1 synthesis in Escherichia coli. Optimal production of STR1 was achieved by determining the impact of co-expression of chaperones pG-Tf2 and pG-LJE8. The amount and activity of STR1 was doubled in the presence of chaperone pG-Tf2 alone. His(6)-STR1 immobilized on Ni-NTA can be used for enzymatic synthesis of stricto…
Crystallization and preliminary X-ray analysis of strictosidine synthase and its complex with the substrate tryptamine
2005
Strictosidine synthase (STR1) is a central enzyme that participates in the biosynthesis of almost all plant monoterpenoid indole alkaloids. After heterologous expression in Escherichia coli, crystals of STR1 and its substrate complex with tryptamine were obtained by the hanging-drop technique at 302–304 K with potassium sodium tartrate tetrahydrate as precipitant. All crystals belong to space group R3. The native STR1 crystals diffract to 2.95 Å and have unit-cell parameters a = b = 150.3, c = 122.4 Å. The tryptamine complex crystals diffract to 2.38 Å, with unit-cell parameters a = b = 147.3, c = 122.3 Å.
Abstract 4372: Chronic myeloid leukemia (CML) exosomes promote angiogenesis in a Src-dependent fashion in vitro and in vivo
2012
Abstract CML is an uncontrolled proliferation of bone marrow myeloid cells driven by the constitutively active fusion product tyrosine kinase BCR/ABL. Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is newly recognized as a factor in CML progression. Exosomes, released by a broad spectrum of cells, are microvesicles that play an important role in cell-to-cell communication both in physiological and pathological conditions. The role of exosomes released by CML cells in angiogenesis is emerging; however, little is known about the mechanisms involved in this process. We first isolated and characterized exosomes released by K562 CML cells and we demonstrated thei…
Longitudinal analysis of Mycobacterium tuberculosis 19-kDa antigen-specific T cells in patients with pulmonary tuberculosis: association with disease…
2003
CD8(+) T cells play a central role in immune protection against infection with Mycobacterium tuberculosis. One of the target epitopes for anti-M. tuberculosis directed CD8(+) T cells is the HLA-A2-restricted 19-kDa lipoprotein peptide VLTDGNPPEV. T cell clones directed against this epitope recognized not only the nominal peptide ligand, but also a closely related peptide (VPTDPNPPEV) from the HIV envelope gp120 (HIV(env) gp120) protein characterized by IFN-gamma release. This cross-reactivity was confirmed in ex vivo in M. tuberculosis 19-kDa tetramer-sorted T cells from patients with tuberculosis and in HIVgp120 tetramer-reactive T cells sorted from HIV(+) patients. M. tuberculosis 19-kDa …
p53 Isoform D133p53a: A Novel Transcriptional Enhancer of T-Cell Effector Function to Improve T-Cell Based Cancer Immunotherapy
2018
Abstract Background: Adoptive transfer of genetically modified T lymphocytes with tumor antigen-specific receptor has proven efficacy in cancer immunotherapy. However, in many patients the overall benefit is still limited due to various tumor escape mechanisms. Cell damage and metabolic/hypoxic stress in the tumor microenvironment (TME) can lead to a dysfunctional anti-tumor T cell response called T cell senescence. The tumor suppressor TP53 is a master molecule in the regulation of cell cycle and senescence. Few studies have demonstrated the critical role of p53 isoforms in the regulation of cellular senescence mainly in tumor cells. However, their role in tumor infiltrating lymphocytes (T…
CCL3 and CCL4, the Major Chemokines Produced by CD38+ Chronic Lymphocytic Leukemia Cells, Facilitate Microenvironmental Interactions of Neoplastic Ce…
2008
Abstract CD38, a negative prognostic marker for patients with CLL, has been demonstrated to be a key molecule in the interactions occurring in the context of tumor microenvironment, mediating both survival and migratory signals for CLL cells. By taking advantage of gene expression profiling studies (GEP) comparing 11 CD38pos (CD38>30%) and 15 CD38neg (CD38<10%) CLLs, we identified as over-expressed in CD38pos CLL cells: i) genes for the two C-C chemokines CCL3 and CCL4 (median-log difference, MLD-CCL3= 3.5; MLD-CCL4=4.4); real-time quantitative PCR (RTQ-PCR) of selected cases confirmed GEP results; ii) the gene for CD49d (MLD=4.4); a high correlation between CD38 and CD49d pro…
Tumor infiltration by chemokine receptor 7 (CCR7)+ T-lymphocytes is a favorable prognostic factor in metastatic colorectal cancer
2012
The immune interactions occurring within the tumor microenvironment have a critical role in determining the outcome of colorectal cancer patients. We carried-out an immunohistochemical analysis of tumor infiltrating T-lymphocytes expressing chemokine receptor 7 (CCR7) in a series of colorectal cancer patients enrolled in a prospective clinical trial. We demonstrated that a high tumor infiltration score of this lymphocyte subset is predictive of longer progression free survival and overall survival. © 2012 Landes Bioscience.
Tumor-infiltrating lymphocytes and breast cancer: Beyond the prognostic and predictive utility
2017
The importance of the immune system as a potent anti-tumor defense has been consolidated in recent times, and novel immune-related therapies are today demonstrating a strong clinical benefit in the setting of several solid neoplasms. Tumor-infiltrating lymphocytes reflect the attempt of the host to eradicate malignancies, and during the last decades, they have been shown to possess an interesting prognostic utility for breast cancer, especially in case of HER2 positive and triple-negative molecular subtypes. In parallel, the clinical evaluation of tumor-infiltrating lymphocytes has been shown to effectively predict treatment outcomes in both neoadjuvant and adjuvant settings. Currently, tu…