Current Search: Foo, Timothy (x)
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Title
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Characterization of Selenazole Compounds as IDO Inhibitors.
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Creator
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Foo, Timothy, Sempertegui Plaza, Tito S., Terentis, Andrew C.
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Abstract/Description
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FAU's Office of Undergraduate Research and Inquiry hosts an annual symposium where students engaged in undergraduate research may present their findings either through a poster presentation or an oral presentation.
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Date Issued
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2011
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PURL
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http://purl.flvc.org/fau/fd/FA00005432
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Format
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Document (PDF)
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Title
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MECHANISTIC STUDIES OF THE PLP-DEPENDENT ENZYME, METHIONINE GAMMA-LYASE AND THE HEME-DEPENDENT ENZYME, INDOLEAMINE 2,3-DIOXYGENASE.
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Creator
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Foo, Timothy, Terentis, Andrew C., Florida Atlantic University, Department of Chemistry and Biochemistry, Charles E. Schmidt College of Science
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Abstract/Description
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Methionine-γ-lyase (MGL) is a pyridoxal-5′-phosphate (PLP) dependent enzyme found in bacteria and protozoa that catalyzes a variety of reactions, including the γ-elimination of L-methionine (L-Met). Besides its physiological roles in organisms, MGL is also a therapeutic target for pathogenic diseases and cancer. Since MGL’s catalytic mechanism remains uncertain, a new spectrophotometric assay was validated for measuring the kinetics of MGL catalyzed reactions. Kinetic data and density...
Show moreMethionine-γ-lyase (MGL) is a pyridoxal-5′-phosphate (PLP) dependent enzyme found in bacteria and protozoa that catalyzes a variety of reactions, including the γ-elimination of L-methionine (L-Met). Besides its physiological roles in organisms, MGL is also a therapeutic target for pathogenic diseases and cancer. Since MGL’s catalytic mechanism remains uncertain, a new spectrophotometric assay was validated for measuring the kinetics of MGL catalyzed reactions. Kinetic data and density functional theory (DFT) data for the γ-elimination reaction of L-Met and several other substrate analogues by MGL from P. gingivalis is reported. A direct correlation between experimental kcat values and DFT-calculated activation energies of the γ-cleavage reaction of the enamine intermediate was identified for various substrates. Considering these data, we propose a catalytic mechanism for MGL catalysis, whereby the γ-cleavage step is rate-limiting. This conclusion has direct implications for the rational design of substrates or inhibitors aimed at regulating MGL activity. PLP-dependent enzymes are present in all organisms and account for ~4% of all discovered enzyme activities. They all possess a common external aldimine and quinonoid intermediate at the start of their reaction pathway but likely diverge thereafter into different reaction pathways based on their substrate(s) and active site environment. To yield insight into the divergent reactivity of the quinonoid intermediate, DFT calculations of several PLP-dependent enzymes with unique reactivity revealed that the charge distribution is modulated on Cα and C4’, which allows for the regioselectivity of the quinonoid intermediate. The mammalian heme enzyme indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the first reaction of L-tryptophan (L-Trp) oxidation along the kynurenine pathway. IDO1 is a central immunoregulatory enzyme with important implications for inflammation, infectious disease, autoimmune disorders, and cancer. Since IDO1’s catalytic mechanism remains uncertain, kinetic data and DFT data for the dioxygenation reaction of L-Trp and several other substrate analogues by human IDO1 is reported. A direct correlation between experimental kcat values and DFT-calculated activation energies of the C2-O cleavage reaction of the L-Trp-epoxide intermediate was identified for various substrates. This conclusion has direct implications for the rational design of substrates or inhibitors aimed at regulating IDO1 activity and yields insight into heme-dependent dioxygenation chemistry.
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Date Issued
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2021
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PURL
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http://purl.flvc.org/fau/fd/FA00013870
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Subject Headings
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Lyases, Enzymes
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Format
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Document (PDF)
