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  1. Article ; Online: Blueprints for the rational design of therapeutic mutacin 1140 variants.

    Kers, Johan A / Sharp, R Eryl / Muley, Sheela / Mayo, Melissa / Colbeck, Jeffrey / Zhu, Yihui / DeFusco, Anthony W / Park, Jae H / Handfield, Martin

    Chemical biology & drug design

    2018  Volume 92, Issue 6, Page(s) 1940–1953

    Abstract: Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Saturation mutagenesis was employed to substitute every amino acid of a lantibiotic called mutacin 1140 (MU1140), creating an unbiased ... ...

    Abstract Lantibiotics represent a large untapped pipeline of attractive scaffolds for the development of novel antibiotics. Saturation mutagenesis was employed to substitute every amino acid of a lantibiotic called mutacin 1140 (MU1140), creating an unbiased expression library of 418 variants that was used to study the permissiveness to mutagenesis and the "drugability" of several compounds. Contrasting previous reports, the results from this study supported that not all residues involved in lanthionine bridge formation were critical for maintaining optimal activity. While substitutions in lanthionine bridges in Ring A, C, and D invariably lead to inactive variants, permissive substitutions in Abu8 and Ala11 (Ring B) were observed, albeit infrequently. Further, the data generated suggested that the unsaturated bond from Dha5 (Ser5) may not be critically involved in Lipid-II binding but still important for conferring optimal activity. This study identified additional permissive mutations of Ser5, including Ser5His, Ser5Met, Ser5Gln, and Ser5Leu. In contrast, no permissive substitutions were identified for Dhb14, which suggested that this residue may be critical for optimal activity. Novel blueprints are proposed for directing further development of MU1140 variants and other lantibiotics, which may enable the rational design, development, manufacture, and formulation of an entirely new class of anti-infectives.
    MeSH term(s) Amino Acid Sequence ; Bacteriocins/genetics ; Bacteriocins/metabolism ; Bacteriocins/pharmacology ; Gene Library ; Microbial Sensitivity Tests ; Mutagenesis, Site-Directed ; Peptides/genetics ; Peptides/metabolism ; Peptides/pharmacology ; Plasmids/genetics ; Plasmids/metabolism ; Streptococcus/chemistry ; Streptococcus/genetics ; Streptococcus/metabolism ; Structure-Activity Relationship
    Chemical Substances Bacteriocins ; Peptides ; mutacin 1140
    Language English
    Publishing date 2018-08-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2216600-2
    ISSN 1747-0285 ; 1747-0277
    ISSN (online) 1747-0285
    ISSN 1747-0277
    DOI 10.1111/cbdd.13365
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  2. Article ; Online: A pathogenesis-related 10 protein catalyzes the final step in thebaine biosynthesis.

    Chen, Xue / Hagel, Jillian M / Chang, Limei / Tucker, Joseph E / Shiigi, Stacey A / Yelpaala, Yuora / Chen, Hsiang-Yun / Estrada, Rodrigo / Colbeck, Jeffrey / Enquist-Newman, Maria / Ibáñez, Ana B / Cottarel, Guillaume / Vidanes, Genevieve M / Facchini, Peter J

    Nature chemical biology

    2018  Volume 14, Issue 7, Page(s) 738–743

    Abstract: The ultimate step in the formation of thebaine, a pentacyclic opiate alkaloid readily converted to the narcotic analgesics codeine and morphine in the opium poppy, has long been presumed to be a spontaneous reaction. We have detected and purified a novel ...

    Abstract The ultimate step in the formation of thebaine, a pentacyclic opiate alkaloid readily converted to the narcotic analgesics codeine and morphine in the opium poppy, has long been presumed to be a spontaneous reaction. We have detected and purified a novel enzyme from opium poppy latex that is capable of the efficient formation of thebaine from (7S)-salutaridinol 7-O-acetate at the expense of labile hydroxylated byproducts, which are preferentially produced by spontaneous allylic elimination. Remarkably, thebaine synthase (THS), a member of the pathogenesis-related 10 protein (PR10) superfamily, is encoded within a novel gene cluster in the opium poppy genome that also includes genes encoding the four biosynthetic enzymes immediately upstream. THS is a missing component that is crucial to the development of fermentation-based opiate production and dramatically improves thebaine yield in engineered yeast.
    MeSH term(s) Molecular Conformation ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/metabolism ; Thebaine/chemistry ; Thebaine/metabolism
    Chemical Substances Saccharomyces cerevisiae Proteins ; Thebaine (2P9MKG8GX7)
    Language English
    Publishing date 2018-05-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2202962-X
    ISSN 1552-4469 ; 1552-4450
    ISSN (online) 1552-4469
    ISSN 1552-4450
    DOI 10.1038/s41589-018-0059-7
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  3. Article: Genotypic profile of the outer membrane proteins BabA and BabB in clinical isolates of Helicobacter pylori.

    Colbeck, Jeffrey C / Hansen, Lori M / Fong, Julie M / Solnick, Jay V

    Infection and immunity

    2006  Volume 74, Issue 7, Page(s) 4375–4378

    Abstract: Helicobacter pylori BabA is the ABO blood group antigen binding adhesin, which has a closely related paralogue (BabB) whose function is unknown. PCR and DNA sequence analysis showed extensive genotypic diversity in babA and babB across different strains, ...

    Abstract Helicobacter pylori BabA is the ABO blood group antigen binding adhesin, which has a closely related paralogue (BabB) whose function is unknown. PCR and DNA sequence analysis showed extensive genotypic diversity in babA and babB across different strains, as well as within a strain colonizing an individual patient. We hypothesize that diverse profiles of babA and babB reflect selective pressures for adhesion, which may differ across different hosts and within an individual over time.
    MeSH term(s) Adhesins, Bacterial/biosynthesis ; Adhesins, Bacterial/genetics ; Adhesins, Bacterial/physiology ; Bacterial Adhesion/genetics ; Bacterial Outer Membrane Proteins/biosynthesis ; Bacterial Outer Membrane Proteins/genetics ; Bacterial Outer Membrane Proteins/physiology ; Gene Expression Profiling ; Genetic Variation ; Genotype ; Helicobacter pylori/genetics ; Helicobacter pylori/isolation & purification ; Humans ; Molecular Sequence Data
    Chemical Substances Adhesins, Bacterial ; BabA protein, Helicobacter pylori ; BabB protein, Helicobacter pylori ; Bacterial Outer Membrane Proteins
    Language English
    Publishing date 2006-07
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 218698-6
    ISSN 1098-5522 ; 0019-9567
    ISSN (online) 1098-5522
    ISSN 0019-9567
    DOI 10.1128/IAI.00485-06
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  4. Article: Genotypic Profile of the Outer Membrane Proteins BabA and BabB in Clinical Isolates of Helicobacter pylori

    Colbeck, Jeffrey C / Hansen, Lori M / Fong, Julie M / Solnick, Jay V

    Infection and immunity. 2006 July, v. 74, no. 7

    2006  

    Abstract: Helicobacter pylori BabA is the ABO blood group antigen binding adhesin, which has a closely related paralogue (BabB) whose function is unknown. PCR and DNA sequence analysis showed extensive genotypic diversity in babA and babB across different strains, ...

    Abstract Helicobacter pylori BabA is the ABO blood group antigen binding adhesin, which has a closely related paralogue (BabB) whose function is unknown. PCR and DNA sequence analysis showed extensive genotypic diversity in babA and babB across different strains, as well as within a strain colonizing an individual patient. We hypothesize that diverse profiles of babA and babB reflect selective pressures for adhesion, which may differ across different hosts and within an individual over time.
    Keywords DNA ; Helicobacter pylori ; adhesion ; antigens ; blood groups ; genetic variation ; hosts ; nucleotide sequences ; outer membrane proteins ; patients ; polymerase chain reaction ; sequence analysis
    Language English
    Size p. 4375-4378.
    Publishing place American Society for Microbiology
    Document type Article
    ZDB-ID 218698-6
    ISSN 1098-5522 ; 0019-9567
    ISSN (online) 1098-5522
    ISSN 0019-9567
    Database NAL-Catalogue (AGRICOLA)

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  5. Article: Biocatalytic Asymmetric Synthesis of Chiral Amines from Ketones Applied to Sitagliptin Manufacture

    Savile, Christopher K / Brands, Jos / Colbeck, Jeffrey C / Devine, Paul N / Fleitz, Fred J / Hughes, Gregory J / Huisman, Gjalt W / Janey, Jacob M / Jarvis, William R / Krebber, Anke / Moore, Jeffrey C / Mundorff, Emily C / Tam, Sarena

    Science. 2010 July 16, v. 329, no. 5989

    2010  

    Abstract: Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the ... ...

    Abstract Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.
    Keywords amines ; biocatalysis ; biocatalysts ; drugs ; hydrogenation ; ketones ; manufacturing ; models ; mutation
    Language English
    Dates of publication 2010-0716
    Size p. 305-309.
    Publishing place American Association for the Advancement of Science
    Document type Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1188934
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  6. Article ; Online: Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture.

    Savile, Christopher K / Janey, Jacob M / Mundorff, Emily C / Moore, Jeffrey C / Tam, Sarena / Jarvis, William R / Colbeck, Jeffrey C / Krebber, Anke / Fleitz, Fred J / Brands, Jos / Devine, Paul N / Huisman, Gjalt W / Hughes, Gregory J

    Science (New York, N.Y.)

    2010  Volume 329, Issue 5989, Page(s) 305–309

    Abstract: Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the ... ...

    Abstract Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.
    MeSH term(s) Amines/chemical synthesis ; Biocatalysis ; Catalytic Domain ; Directed Molecular Evolution ; Hypoglycemic Agents/chemical synthesis ; Hypoglycemic Agents/metabolism ; Ketones/chemistry ; Ketones/metabolism ; Models, Molecular ; Molecular Structure ; Mutagenesis ; Protein Conformation ; Protein Engineering ; Pyrazines/chemical synthesis ; Pyrazines/metabolism ; Sitagliptin Phosphate ; Solubility ; Stereoisomerism ; Substrate Specificity ; Transaminases/chemistry ; Transaminases/genetics ; Transaminases/metabolism ; Triazoles/chemical synthesis ; Triazoles/metabolism
    Chemical Substances Amines ; Hypoglycemic Agents ; Ketones ; Pyrazines ; Triazoles ; Transaminases (EC 2.6.1.-) ; Sitagliptin Phosphate (TS63EW8X6F)
    Language English
    Publishing date 2010-07-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.1188934
    Database MEDical Literature Analysis and Retrieval System OnLINE

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