The Experts below are selected from a list of 1866 Experts worldwide ranked by ideXlab platform
Liang Tong - One of the best experts on this subject based on the ideXlab platform.
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1 deoxy d xylulose 5 phosphate synthase dxs a crucial enzyme for Isoprenoids Biosynthesis
2012Co-Authors: Song Xiang, Gerlinde Usunow, Gudrun Lange, Marco Busch, Liang TongAbstract:Isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP) are the common precursors for the synthesis of all Isoprenoids. While IPP and DMAPP are produced by the mevalonate pathway in archaea, fungi, and animals, they are synthesized by a mevalonate-independent pathway in most bacteria, algae, and plant plastids. DXS (1-deoxy-d-xylulose 5-phosphate synthase) catalyzes the first and the rate-limiting step of the mevalonate-independent pathway and is an attractive target for the development of novel antibiotics, antimalarials, and herbicides. Crystal structures of DXS from E. coli and D. radiodurans, in complex with the coenzyme thiamine pyrophosphate (TPP), show that the enzyme contains three domains (I, II, and III), which share homology to the equivalent domains in transketolase and the E1 subunit of pyruvate dehydrogenase. However, DXS has a novel arrangement of these domains in the monomer and the dimer as compared to the other enzymes. The active site of DXS is located at the interface of domains I and II in the same monomer. The coenzyme TPP is mostly buried in the complex, but the C2 atom of its thiazolium ring is exposed to a solvent-accessible tunnel that is likely the substrate-binding site.
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crystal structure of 1 deoxy d xylulose 5 phosphate synthase a crucial enzyme for Isoprenoids Biosynthesis
Journal of Biological Chemistry, 2007Co-Authors: Song Xiang, Gerlinde Usunow, Gudrun Lange, Marco Busch, Liang TongAbstract:Isopentenyl pyrophosphate (IPP) is a common precursor for the synthesis of all Isoprenoids, which have important functions in living organisms. IPP is produced by the mevalonate pathway in archaea, fungi, and animals. In contrast, IPP is synthesized by a mevalonate-independent pathway in most bacteria, algae, and plant plastids. 1-Deoxy-D-xylulose 5-phosphate synthase (DXS) catalyzes the first and the rate-limiting step of the mevalonate-independent pathway and is an attractive target for the development of novel antibiotics, antimalarials, and herbicides. We report here the first structural information on DXS, from Escherichia coli and Deinococcus radiodurans, in complex with the coenzyme thiamine pyrophosphate (TPP). The structure contains three domains (I, II, and III), each of which bears homology to the equivalent domains in transketolase and the E1 subunit of pyruvate dehydrogenase. However, DXS has a novel arrangement of these domains as compared with the other enzymes, such that the active site of DXS is located at the interface of domains I and II in the same monomer, whereas that of transketolase is located at the interface of the dimer. The coenzyme TPP is mostly buried in the complex, but the C-2 atom of its thiazolium ring is exposed to a pocket that is the substrate-binding site. The structures identify residues that may have important roles in catalysis, which have been confirmed by our mutagenesis studies.
Esteban M Cordero - One of the best experts on this subject based on the ideXlab platform.
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unique behavior of trypanosoma cruzi mevalonate kinase a conserved glycosomal enzyme involved in host cell invasion and signaling
Scientific Reports, 2016Co-Authors: Eden Ramalho Ferreira, E Horjales, Alexis Bonfimmelo, Cristian Cortez, Claudio Vieira Da Silva, Michel De Groote, Tiago J P Sobreira, Mario Cruz, Fabio Mitsuo Lima, Esteban M CorderoAbstract:Mevalonate kinase (MVK) is an essential enzyme acting in early steps of sterol Isoprenoids Biosynthesis, such as cholesterol in humans or ergosterol in trypanosomatids. MVK is conserved from bacteria to mammals, and localizes to glycosomes in trypanosomatids. During the course of T. cruzi MVK characterization, we found that, in addition to glycosomes, this enzyme may be secreted and modulate cell invasion. To evaluate the role of TcMVK in parasite-host cell interactions, TcMVK recombinant protein was produced and anti-TcMVK antibodies were raised in mice. TcMVK protein was detected in the supernatant of cultures of metacyclic trypomastigotes (MTs) and extracellular amastigotes (EAs) by Western blot analysis, confirming its secretion into extracellular medium. Recombinant TcMVK bound in a non-saturable dose-dependent manner to HeLa cells and positively modulated internalization of T. cruzi EAs but inhibited invasion by MTs. In HeLa cells, TcMVK induced phosphorylation of MAPK pathway components and proteins related to actin cytoskeleton modifications. We hypothesized that TcMVK is a bifunctional enzyme that in addition to playing a classical role in isoprenoid synthesis in glycosomes, it is secreted and may modulate host cell signaling required for T. cruzi invasion.
Carlos Fernandezpatron - One of the best experts on this subject based on the ideXlab platform.
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matrix metalloproteinase 2 mediates a mechanism of metabolic cardioprotection consisting of negative regulation of the sterol regulatory element binding protein 2 3 hydroxy 3 methylglutaryl coa reductase pathway in the heart
Hypertension, 2015Co-Authors: Xiang Wang, Evan Berry, Samuel Hernandezanzaldo, Abhijit Takawale, Zamaneh Kassiri, Carlos FernandezpatronAbstract:Previously, we reported that cardiac matrix metalloproteinase (MMP)-2 is upregulated in hypertensive mice. How MMP-2 affects the development of cardiac disease is unclear. Here, we report that MMP-2 protects from hypertensive cardiac disease. In mice infused with angiotensin II, the lack of MMP-2 ( Mmp2 −/− ) did not affect the severity of the hypertension but caused cardiac hypertrophy to develop earlier and to a greater extent versus wild-type ( Mmp2 +/+ ) mice, as measured by heart weight:body weight ratio and upregulation of hypertrophy and fibrosis markers. We further found numerous metabolic and inflammatory gene expression abnormalities in the left ventricle of Mmp2 −/− mice. Interestingly, Mmp2 −/− mice expressed greater amounts of sterol regulatory element–binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (a target of sterol regulatory element–binding protein-2–mediated transcription and rate limiting enzyme in cholesterol and Isoprenoids Biosynthesis) in addition to markers of inflammation including chemokines of the C-C motif ligand family. We focused on the functionally related genes for sterol regulatory binding protein-2 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, lovastatin, attenuated angiotensin II–induced cardiac hypertrophy and fibrosis in Mmp2 −/− and wild-type ( Mmp2 +/+ ) mice, with Mmp2 −/− mice showing resistance to cardioprotection by lovastatin. MMP-2 deficiency predisposes to cardiac dysfunction as well as metabolic and inflammatory gene expression dysregulation. This complex phenotype is, at least in part, because of the cardiac sterol regulatory element–binding protein-2/3-hydroxy-3-methylglutaryl-coenzyme A reductase pathway being upregulated in MMP-2 deficiency.
Song Xiang - One of the best experts on this subject based on the ideXlab platform.
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1 deoxy d xylulose 5 phosphate synthase dxs a crucial enzyme for Isoprenoids Biosynthesis
2012Co-Authors: Song Xiang, Gerlinde Usunow, Gudrun Lange, Marco Busch, Liang TongAbstract:Isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP) are the common precursors for the synthesis of all Isoprenoids. While IPP and DMAPP are produced by the mevalonate pathway in archaea, fungi, and animals, they are synthesized by a mevalonate-independent pathway in most bacteria, algae, and plant plastids. DXS (1-deoxy-d-xylulose 5-phosphate synthase) catalyzes the first and the rate-limiting step of the mevalonate-independent pathway and is an attractive target for the development of novel antibiotics, antimalarials, and herbicides. Crystal structures of DXS from E. coli and D. radiodurans, in complex with the coenzyme thiamine pyrophosphate (TPP), show that the enzyme contains three domains (I, II, and III), which share homology to the equivalent domains in transketolase and the E1 subunit of pyruvate dehydrogenase. However, DXS has a novel arrangement of these domains in the monomer and the dimer as compared to the other enzymes. The active site of DXS is located at the interface of domains I and II in the same monomer. The coenzyme TPP is mostly buried in the complex, but the C2 atom of its thiazolium ring is exposed to a solvent-accessible tunnel that is likely the substrate-binding site.
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crystal structure of 1 deoxy d xylulose 5 phosphate synthase a crucial enzyme for Isoprenoids Biosynthesis
Journal of Biological Chemistry, 2007Co-Authors: Song Xiang, Gerlinde Usunow, Gudrun Lange, Marco Busch, Liang TongAbstract:Isopentenyl pyrophosphate (IPP) is a common precursor for the synthesis of all Isoprenoids, which have important functions in living organisms. IPP is produced by the mevalonate pathway in archaea, fungi, and animals. In contrast, IPP is synthesized by a mevalonate-independent pathway in most bacteria, algae, and plant plastids. 1-Deoxy-D-xylulose 5-phosphate synthase (DXS) catalyzes the first and the rate-limiting step of the mevalonate-independent pathway and is an attractive target for the development of novel antibiotics, antimalarials, and herbicides. We report here the first structural information on DXS, from Escherichia coli and Deinococcus radiodurans, in complex with the coenzyme thiamine pyrophosphate (TPP). The structure contains three domains (I, II, and III), each of which bears homology to the equivalent domains in transketolase and the E1 subunit of pyruvate dehydrogenase. However, DXS has a novel arrangement of these domains as compared with the other enzymes, such that the active site of DXS is located at the interface of domains I and II in the same monomer, whereas that of transketolase is located at the interface of the dimer. The coenzyme TPP is mostly buried in the complex, but the C-2 atom of its thiazolium ring is exposed to a pocket that is the substrate-binding site. The structures identify residues that may have important roles in catalysis, which have been confirmed by our mutagenesis studies.
Eden Ramalho Ferreira - One of the best experts on this subject based on the ideXlab platform.
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unique behavior of trypanosoma cruzi mevalonate kinase a conserved glycosomal enzyme involved in host cell invasion and signaling
Scientific Reports, 2016Co-Authors: Eden Ramalho Ferreira, E Horjales, Alexis Bonfimmelo, Cristian Cortez, Claudio Vieira Da Silva, Michel De Groote, Tiago J P Sobreira, Mario Cruz, Fabio Mitsuo Lima, Esteban M CorderoAbstract:Mevalonate kinase (MVK) is an essential enzyme acting in early steps of sterol Isoprenoids Biosynthesis, such as cholesterol in humans or ergosterol in trypanosomatids. MVK is conserved from bacteria to mammals, and localizes to glycosomes in trypanosomatids. During the course of T. cruzi MVK characterization, we found that, in addition to glycosomes, this enzyme may be secreted and modulate cell invasion. To evaluate the role of TcMVK in parasite-host cell interactions, TcMVK recombinant protein was produced and anti-TcMVK antibodies were raised in mice. TcMVK protein was detected in the supernatant of cultures of metacyclic trypomastigotes (MTs) and extracellular amastigotes (EAs) by Western blot analysis, confirming its secretion into extracellular medium. Recombinant TcMVK bound in a non-saturable dose-dependent manner to HeLa cells and positively modulated internalization of T. cruzi EAs but inhibited invasion by MTs. In HeLa cells, TcMVK induced phosphorylation of MAPK pathway components and proteins related to actin cytoskeleton modifications. We hypothesized that TcMVK is a bifunctional enzyme that in addition to playing a classical role in isoprenoid synthesis in glycosomes, it is secreted and may modulate host cell signaling required for T. cruzi invasion.
