Development of a covalent inhibitor of gut bacterial bile salt hydrolases.


:Bile salt hydrolase (BSH) enzymes are widely expressed by human gut bacteria and catalyze the gateway reaction leading to secondary bile acid formation. Bile acids regulate key metabolic and immune processes by binding to host receptors. There is an unmet need for a potent tool to inhibit BSHs across all gut bacteria to study the effects of bile acids on host physiology. Here, we report the development of a covalent pan-inhibitor of gut bacterial BSHs. From a rationally designed candidate library, we identified a lead compound bearing an alpha-fluoromethyl ketone warhead that modifies BSH at the catalytic cysteine residue. This inhibitor abolished BSH activity in conventional mouse feces. Mice gavaged with a single dose of this compound displayed decreased BSH activity and decreased deconjugated bile acid levels in feces. Our studies demonstrate the potential of a covalent BSH inhibitor to modulate bile acid composition in vivo.


Nat Chem Biol


Nature chemical biology


Adhikari AA,Seegar TCM,Ficarro SB,McCurry MD,Ramachandran D,Yao L,Chaudhari SN,Ndousse-Fetter S,Banks AS,Marto JA,Blacklow SC,Devlin AS




Has Abstract


2020-03-01 00:00:00














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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Gonzalez-Delgado LS,Walters-Morgan H,Salamaga B,Robertson AJ,Hounslow AM,Jagielska E,Sabała I,Williamson MP,Lovering AL,Mesnage S

    更新日期:2020-01-01 00:00:00

  • An enzyme-coupled biosensor enables (S)-reticuline production in yeast from glucose.

    abstract::Benzylisoquinoline alkaloids (BIAs) are a diverse family of plant-specialized metabolites that include the pharmaceuticals codeine and morphine and their derivatives. Microbial synthesis of BIAs holds promise as an alternative to traditional crop-based manufacturing. Here we demonstrate the production of the key BIA i...

    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: DeLoache WC,Russ ZN,Narcross L,Gonzales AM,Martin VJ,Dueber JE

    更新日期:2015-07-01 00:00:00

  • Defining the geometry of the two-component proteasome degron.

    abstract::The eukaryotic 26S proteasome controls cellular processes by degrading specific regulatory proteins. Most proteins are targeted for degradation by a signal or degron that consists of two parts: a proteasome-binding tag, typically covalently attached polyubiquitin chains, and an unstructured region that serves as the i...

    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Inobe T,Fishbain S,Prakash S,Matouschek A

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  • Fluorescent castasterone reveals BRI1 signaling from the plasma membrane.

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Irani NG,Di Rubbo S,Mylle E,Van den Begin J,Schneider-Pizoń J,Hniliková J,Šíša M,Buyst D,Vilarrasa-Blasi J,Szatmári AM,Van Damme D,Mishev K,Codreanu MC,Kohout L,Strnad M,Caño-Delgado AI,Friml J,Madder A,Russinova E

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  • Ceruloplasmin is a NO oxidase and nitrite synthase that determines endocrine NO homeostasis.

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Shiva S,Wang X,Ringwood LA,Xu X,Yuditskaya S,Annavajjhala V,Miyajima H,Hogg N,Harris ZL,Gladwin MT

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Gisin J,Schneider A,Nägele B,Borisova M,Mayer C

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Olson CM,Jiang B,Erb MA,Liang Y,Doctor ZM,Zhang Z,Zhang T,Kwiatkowski N,Boukhali M,Green JL,Haas W,Nomanbhoy T,Fischer ES,Young RA,Bradner JE,Winter GE,Gray NS

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  • A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate.

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Pacold ME,Brimacombe KR,Chan SH,Rohde JM,Lewis CA,Swier LJ,Possemato R,Chen WW,Sullivan LB,Fiske BP,Cho S,Freinkman E,Birsoy K,Abu-Remaileh M,Shaul YD,Liu CM,Zhou M,Koh MJ,Chung H,Davidson SM,Luengo A,Wang AQ,

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  • Probing cell-division phenotype space and Polo-like kinase function using small molecules.

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Peters U,Cherian J,Kim JH,Kwok BH,Kapoor TM

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    journal_title:Nature chemical biology

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    authors: Giganti D,Albesa-Jové D,Urresti S,Rodrigo-Unzueta A,Martínez MA,Comino N,Barilone N,Bellinzoni M,Chenal A,Guerin ME,Alzari PM

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    journal_title:Nature chemical biology

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    authors: Westcott NP,Fernandez JP,Molina H,Hang HC

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    pub_type: 杂志文章


    authors: Li YX,Zhong Z,Hou P,Zhang WP,Qian PY

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    authors: Terasaka N,Hayashi G,Katoh T,Suga H

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    journal_title:Nature chemical biology

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    authors: Levinson NM,Boxer SG

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    authors: Watanabe R,Iino R,Noji H

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    journal_title:Nature chemical biology

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    authors: Kusumi A,Tsunoyama TA,Hirosawa KM,Kasai RS,Fujiwara TK

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    authors: Uchida N,Takahashi K,Iwasaki R,Yamada R,Yoshimura M,Endo TA,Kimura S,Zhang H,Nomoto M,Tada Y,Kinoshita T,Itami K,Hagihara S,Torii KU

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    authors: Bradshaw JM,McFarland JM,Paavilainen VO,Bisconte A,Tam D,Phan VT,Romanov S,Finkle D,Shu J,Patel V,Ton T,Li X,Loughhead DG,Nunn PA,Karr DE,Gerritsen ME,Funk JO,Owens TD,Verner E,Brameld KA,Hill RJ,Goldstein DM,

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    journal_title:Nature chemical biology

    pub_type: 杂志文章,评审


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    journal_title:Nature chemical biology

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    authors: Herschhorn A,Gu C,Espy N,Richard J,Finzi A,Sodroski JG

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Tarrant MK,Rho HS,Xie Z,Jiang YL,Gross C,Culhane JC,Yan G,Qian J,Ichikawa Y,Matsuoka T,Zachara N,Etzkorn FA,Hart GW,Jeong JS,Blackshaw S,Zhu H,Cole PA

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Silvius JR

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Liu F,Somarowthu S,Pyle AM

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Mitchell DA,Marletta MA

    更新日期:2005-08-01 00:00:00

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Li J,Jia S,Chen PR

    更新日期:2014-12-01 00:00:00

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Bachman M,Uribe-Lewis S,Yang X,Burgess HE,Iurlaro M,Reik W,Murrell A,Balasubramanian S

    更新日期:2015-08-01 00:00:00

  • Lipid droplets can promote drug accumulation and activation.

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Dubey R,Stivala CE,Nguyen HQ,Goo YH,Paul A,Carette JE,Trost BM,Rohatgi R

    更新日期:2020-02-01 00:00:00

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Kwok BH,Kapitein LC,Kim JH,Peterman EJ,Schmidt CF,Kapoor TM

    更新日期:2006-09-01 00:00:00

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    journal_title:Nature chemical biology

    pub_type: 杂志文章


    authors: Xiao Y,Bowen CH,Liu D,Zhang F

    更新日期:2016-05-01 00:00:00