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Amino Acid Ester

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Gordon L. Amidon – One of the best experts on this subject based on the ideXlab platform.

  • enhanced cancer cell growth inhibition by dipeptide prodrugs of floxuridine increased transporter affinity and metabolic stability
    Molecular Pharmaceutics, 2008
    Co-Authors: Yasuhiro Tsume, John M. Hilfinger, Gordon L. Amidon

    Abstract:

    Dipeptide monoEster prodrugs of floxuridine were synthesized, and their chemical stability in buffers, resistance to glycosidic bond metabolism, affinity for PEPT1, enzymatic activation and permeability in cancer cells were determined and compared to those of mono Amino Acid monoEster floxuridine prodrugs. Prodrugs containing glycyl moieties were the least stable in pH 7.4 buffer ( t 1/2 < 100 min). The activation of all floxuridine prodrugs was 2- to 30-fold faster in cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. The enzymatic activation of dipeptide monoEster prodrugs containing aromatic promoieties in cell homogenates was 5- to 20-fold slower than that of other dipeptide and most mono Amino Acid monoEster prodrugs ( t 1/2 approximately 40 to 100 min). All prodrugs exhibited enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase compared to parent floxuridine. In general, the 5′-O-dipeptide monoEster floxuridine prodrugs exhibited higher affinity for PEPT1 than the corresponding 5′-O-mono Amino Acid Ester prodrugs. The permeability of dipeptide monoEster prodrugs across Caco-2 and Capan-2 monolayers was 2- to 4-fold higher than the corresponding mono Amino Acid Ester prodrug. Cell proliferation assays in AsPC-1 and Capan-2 pancreatic ductal cell lines indicated that the dipeptide monoEster prodrugs were equally as potent as mono Amino Acid prodrugs. The transport and enzymatic profiles of 5′- l-phenylalanyl- l-tyrosyl-floxuridine, 5′- l-phenylalanyl- l-glycyl-floxuridine, and 5′- l-isoleucyl- l-glycyl-floxuridine suggest their potential for increased oral uptake, delayed enzymatic bioconversion and enhanced resistance to metabolism to 5-fluorouracil, as well as enhanced uptake and cytotoxic activity in cancer cells, attributes that would facilitate prolonged systemic circulation for enhanced therapeutic action.

  • molecular basis of prodrug activation by human valacyclovirase an α Amino Acid Ester hydrolase
    Journal of Biological Chemistry, 2008
    Co-Authors: Zhaohui Xu, Jiahai Zhou, Gordon L. Amidon

    Abstract:

    Chemical modification to improve biopharmaceutical properties, especially oral absorption and bioavailability, is a common strategy employed by pharmaceutical chemists. The approach often employs a simple structural modification and utilizes ubiquitous endogenous Esterases as activation enzymes, although such enzymes are often unidentified. This report describes the crystal structure and specificity of a novel activating enzyme for valacyclovir and valganciclovir. Our structural insights show that human valacyclovirase has a unique binding mode and specificity for Amino Acid Esters. Biochemical data demonstrate that the enzyme hydrolyzes Esters of-Amino Acids exclusively and displays a broad specificity spectrum for the Aminoacyl moiety similar to tricorn-interacting Aminopeptidase F1. Crystal structures of the enzyme, two mechanistic mutants, and a complex with a product analogue, when combined with biochemical analysis, reveal the key determinants for substrate recognition; that is, a flexible and mostly hydrophobic acyl pocket, a localized negative electrostatic potential, a large open leaving group-accommodating groove, and a pivotal Acidic residue, Asp-123, after the nucleophile Ser-122. This is the first time that a residue immediately after the nucleophile has been found to have its side chain directed into the substrate binding pocket and play an essential role in substrate discrimination in serine hydrolases. These results as well as a phylogenetic analysis establish that the enzyme functions as a specific –Amino Acid Ester hydrolase. Valacyclovirase is a valuable target for Amino Acid Ester prodrugbased oral drug delivery enhancement strategies. Chemical modification through reversible prodrug, modification of a candidate drug, is a frequently employed strategy to improve biopharmaceutical properties of a candidate drug. Notable successes include oseltamivir, enalapril, and capecitabine (1). Membrane transport and absorption are usually thought to be improved by the increased lipophilicity and result in improved passive membrane transport (2). More recently we have shown that prodrugs may be transported by carrier-mediated transport mechanisms (3). A second essential step in effective prodrug therapy is the activation (hydrolysis) of the prodrug to the active therapeutic agent. CarboxylEsterase is a common target for lipophilic approaches to improved membrane permeability (4 – 6). However, often the activation enzymes are unidentified. This manuscript reports the results of structural and biochemical studies on a novel prodrug activating enzyme,

  • floxuridine Amino Acid Ester prodrugs enhancing caco 2 permeability and resistance to glycosidic bond metabolism
    Pharmaceutical Research, 2005
    Co-Authors: Christopher P. Landowski, Philip L. Lorenzi, John M. Hilfinger, Xueqin Song, Gordon L. Amidon

    Abstract:

    Purpose
    The aim of this study was to synthesize Amino Acid Ester prodrugs of 5-fluoro-2′-deoxyuridine (floxuridine) to enhance intestinal absorption and resistance to glycosidic bond metabolism.

Thomas R M Barends – One of the best experts on this subject based on the ideXlab platform.

  • Acetobacter turbidans alpha-Amino Acid Ester hydrolase: merohedral twinning in P21 obscured by pseudo-translational NCS.
    Acta crystallographica. Section D Biological crystallography, 2003
    Co-Authors: Thomas R M Barends, Bauke W. Dijkstra

    Abstract:

    The structure elucidation of the alpha-Amino Acid Ester hydrolase from Acetobacter turbidans by molecular replacement is described. In the monoclinic crystal, the molecules are related by both rotational and pseudo-crystallographic translational NCS (non-crystallographic symmetry). Refinement of the structure converged at unacceptably high R factors. After re-evaluation of the data, it was found that the crystal was merohedrally twinned, with a high twinning fraction. It is shown that the pseudo-crystallographic NCS causes aberrant behaviour of conventional twinning indicators, which explains why the twinning was only realized at the refinement stage.

  • Acetobacter turbidans alpha-Amino Acid Ester hydrolase
    Acta Crystallographica Section D Biological Crystallography, 2003
    Co-Authors: Thomas R M Barends, Bauke W. Dijkstra

    Abstract:

    The structure elucidation of the alpha-Amino Acid Ester hydrolase from Acetobacter turbidans by molecular replacement is described. In the monoclinic crystal, the molecules are related by both rotational and pseudo-crystallographic translational NCS (non-crystallographic symmetry). Refinement of the structure converged at unacceptably high R factors. After re-evaluation of the data, it was found that the crystal was merohedrally twinned, with a high twinning fraction. It is shown that the pseudo-crystallographic NCS causes aberrant behaviour of conventional twinning indicators, which explains why the twinning was only realized at the refinement stage.

  • the sequence and crystal structure of the alpha Amino Acid Ester hydrolase from xanthomonas citri define a new family of beta lactam antibiotic acylases
    Journal of Biological Chemistry, 2003
    Co-Authors: Thomas R M Barends, Jolanda Polderman Tijmes, Peter A Jekel, Cmh Hensgens, Erik De Vries, Dick B. Janssen, Bebauke W Dijkstra

    Abstract:

    Abstract α-Amino Acid Ester hydrolases (AEHs) catalyze the hydrolysis and synthesis of Esters and amides with an α-Amino group. As such, they can synthesize β-lactam antibiotics from acyl compounds and β-lactam nuclei obtained from the hydrolysis of natural antibiotics. This article describes the gene sequence and the 1.9-A resolution crystal structure of the AEH from Xanthomonas citri. The enzyme consists of an α/β-hydrolase fold domain, a helical cap domain, and a jellyroll β-domain. Structural homology was observed to the Rhodococcus cocaine Esterase, indicating that both enzymes belong to the same class of bacterial hydrolases. Docking of a β-lactam antibiotic in the active site explains the substrate specificity, specifically the necessity of an α-Amino group on the substrate, and explains the low specificity toward the β-lactam nucleus.

Bauke W. Dijkstra – One of the best experts on this subject based on the ideXlab platform.

  • Acetobacter turbidans alpha-Amino Acid Ester hydrolase
    Acta Crystallographica Section D Biological Crystallography, 2003
    Co-Authors: Thomas R M Barends, Bauke W. Dijkstra

    Abstract:

    The structure elucidation of the alpha-Amino Acid Ester hydrolase from Acetobacter turbidans by molecular replacement is described. In the monoclinic crystal, the molecules are related by both rotational and pseudo-crystallographic translational NCS (non-crystallographic symmetry). Refinement of the structure converged at unacceptably high R factors. After re-evaluation of the data, it was found that the crystal was merohedrally twinned, with a high twinning fraction. It is shown that the pseudo-crystallographic NCS causes aberrant behaviour of conventional twinning indicators, which explains why the twinning was only realized at the refinement stage.

  • Acetobacter turbidans alpha-Amino Acid Ester hydrolase: merohedral twinning in P21 obscured by pseudo-translational NCS.
    Acta crystallographica. Section D Biological crystallography, 2003
    Co-Authors: Thomas R M Barends, Bauke W. Dijkstra

    Abstract:

    The structure elucidation of the alpha-Amino Acid Ester hydrolase from Acetobacter turbidans by molecular replacement is described. In the monoclinic crystal, the molecules are related by both rotational and pseudo-crystallographic translational NCS (non-crystallographic symmetry). Refinement of the structure converged at unacceptably high R factors. After re-evaluation of the data, it was found that the crystal was merohedrally twinned, with a high twinning fraction. It is shown that the pseudo-crystallographic NCS causes aberrant behaviour of conventional twinning indicators, which explains why the twinning was only realized at the refinement stage.