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  1. Article ; Online: Impact of the T296S mutation in P450 GcoA for aryl-O-demethylation

    Sonia F. G. Santos / Rajesh Reddy Bommareddy / Gary W. Black / Warispreet Singh

    Frontiers in Chemistry, Vol

    a QM/MM study

    2024  Volume 11

    Abstract: Lignin, a complex plant cell wall component, holds promise as a renewable aromatic carbon feedstock. p-Vanillin is a key product of lignin depolymerization and a precursor of protocatechuic acid (PCA) that has tremendous potential for biofuel production. ...

    Abstract Lignin, a complex plant cell wall component, holds promise as a renewable aromatic carbon feedstock. p-Vanillin is a key product of lignin depolymerization and a precursor of protocatechuic acid (PCA) that has tremendous potential for biofuel production. While the GcoAB enzyme, native to Amycolatopsis sp., naturally catalyzes aryl-O-demethylation toward guaiacol, recent research introduced a single mutation, T296S, into the GcoAP450 enzyme, enabling it to catalyze aryl-O-demethylation of p-vanillin. This structural modification increases the efficiency of GcoAP450 for the natural substrate while being active for p-vanillin. This study reveals the increased flexibility of p-vanillin and its ability to adapt a favorable conformation by aligning the methoxy group in close proximity to Fe(IV) = O of Cpd I in the active site of the T296S variant. The QM/MM calculations in accordance with the experimental data validated that the rate-limiting step for the oxidation of p-vanillin is hydrogen atom abstraction and provided a detailed geometric structure of stationary and saddle points for the oxidation of p-vanillin.
    Keywords catalysis ; aryl-O-demethylation ; Cytochrome P450 ; molecular dynamics ; QM/MM ; Chemistry ; QD1-999
    Subject code 540
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: The complex structure of bile salt hydrolase from Lactobacillus salivarius reveals the structural basis of substrate specificity

    Fuzhou Xu / Xiao-Jian Hu / Warispreet Singh / Wenjing Geng / Irina G. Tikhonova / Jun Lin

    Scientific Reports, Vol 9, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: Abstract The gut bacterial bile salt hydrolase (BSH) plays a critical role in host lipid metabolism and energy harvest. Therefore, BSH is a promising microbiome target to develop new therapies to regulate obesity in humans and novel non-antibiotic growth ...

    Abstract Abstract The gut bacterial bile salt hydrolase (BSH) plays a critical role in host lipid metabolism and energy harvest. Therefore, BSH is a promising microbiome target to develop new therapies to regulate obesity in humans and novel non-antibiotic growth promoters for food animals. We previously reported the 1.90 Å apo crystal structure of BSH from Lactobacillus salivarius (lsBSH). In this study, we soaked the lsBSH crystal with glycocholic acid (GCA), a substrate, and obtained a 2.10 Å structure containing complex of lsBSH bound to GCA and cholic acid (CA), a product. The substrate/product sits in the water-exposed cavity molded by Loops 2 and 3. While the glycine moiety of GCA is exposed into a highly polar pocket, the sterane core of GCA is stabilized by aromatic and hydrophobic interactions. Comparison of product binding with BSH from Clostridium perfringenes reveals a distinct orientation of the sterane core in the binding site. The stability of the substrate-lsBSH complex and the putative catalytic mechanism were explored with molecular dynamics simulations. Site-directed mutagenesis of lsBSH demonstrated that Cys2 and Asn171 are critical for enzymatic activity, while Tyr24, Phe65 and Gln257 contribute to the substrate specificity. Together, this study provides structural insights into BSH-substrate interaction, the mechanism of catalysis and substrate specificity, which facilitate rational design of BSH inhibitors.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Structural basis of the membrane intramolecular transacylase reaction responsible for lyso-form lipoprotein synthesis

    Samir Olatunji / Katherine Bowen / Chia-Ying Huang / Dietmar Weichert / Warispreet Singh / Irina G. Tikhonova / Eoin M. Scanlan / Vincent Olieric / Martin Caffrey

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 14

    Abstract: In Gram-positive bacteria, lipoprotein intramolecular transacylase Lit produces a lipoprotein variant with less immunogenicity. As such, Lit can be viewed as a virulence factor. Here, structural and functional characterization of the enzyme provides ... ...

    Abstract In Gram-positive bacteria, lipoprotein intramolecular transacylase Lit produces a lipoprotein variant with less immunogenicity. As such, Lit can be viewed as a virulence factor. Here, structural and functional characterization of the enzyme provides insight into its catalytic mechanism, setting the stage for future studies of Lit as a target for new antibiotics.
    Keywords Science ; Q
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Artificial cysteine-lipases with high activity and altered catalytic mechanism created by laboratory evolution

    Yixin Cen / Warispreet Singh / Mamatjan Arkin / Thomas S. Moody / Meilan Huang / Jiahai Zhou / Qi Wu / Manfred T. Reetz

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 10

    Abstract: Candida antarctica lipase B (CALB) is a serine lipase. Here, the authors use directed evolution to exchange serine with cysteine in the catalytic triad of the enzyme, thereby obtaining a highly active CALB variant that — unlike the wild type — ... ...

    Abstract Candida antarctica lipase B (CALB) is a serine lipase. Here, the authors use directed evolution to exchange serine with cysteine in the catalytic triad of the enzyme, thereby obtaining a highly active CALB variant that — unlike the wild type — accommodates bulky substrates.
    Keywords Science ; Q
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Artificial cysteine-lipases with high activity and altered catalytic mechanism created by laboratory evolution

    Yixin Cen / Warispreet Singh / Mamatjan Arkin / Thomas S. Moody / Meilan Huang / Jiahai Zhou / Qi Wu / Manfred T. Reetz

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 10

    Abstract: Candida antarctica lipase B (CALB) is a serine lipase. Here, the authors use directed evolution to exchange serine with cysteine in the catalytic triad of the enzyme, thereby obtaining a highly active CALB variant that — unlike the wild type — ... ...

    Abstract Candida antarctica lipase B (CALB) is a serine lipase. Here, the authors use directed evolution to exchange serine with cysteine in the catalytic triad of the enzyme, thereby obtaining a highly active CALB variant that — unlike the wild type — accommodates bulky substrates.
    Keywords Science ; Q
    Language English
    Publishing date 2019-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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  6. Article ; Online: Effects of Mutations on Structure–Function Relationships of Matrix Metalloproteinase-1

    Warispreet Singh / Gregg B. Fields / Christo Z. Christov / Tatyana G. Karabencheva-Christova

    International Journal of Molecular Sciences, Vol 17, Iss 10, p

    2016  Volume 1727

    Abstract: Matrix metalloproteinase-1 (MMP-1) is one of the most widely studied enzymes involved in collagen degradation. Mutations of specific residues in the MMP-1 hemopexin-like (HPX) domain have been shown to modulate activity of the MMP-1 catalytic (CAT) ... ...

    Abstract Matrix metalloproteinase-1 (MMP-1) is one of the most widely studied enzymes involved in collagen degradation. Mutations of specific residues in the MMP-1 hemopexin-like (HPX) domain have been shown to modulate activity of the MMP-1 catalytic (CAT) domain. In order to reveal the structural and conformational effects of such mutations, a molecular dynamics (MD) study was performed of in silico mutated residues in the X-ray crystallographic structure of MMP-1 complexed with a collagen-model triple-helical peptide (THP). The results indicate an important role of the mutated residues in MMP-1 interactions with the THP and communication between the CAT and the HPX domains. Each mutation has a distinct impact on the correlated motions in the MMP-1•THP. An increased collagenase activity corresponded to the appearance of a unique anti-correlated motion and decreased correlated motions, while decreased collagenase activity corresponded both to increased and decreased anti-correlated motions.
    Keywords matrix metalloproteinase-1 ; conformational flexibility ; molecular dynamics simulations ; mutations ; correlated motions ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2016-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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