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  1. Article ; Online: Propofol: Milk of Amnesia.

    Walsh, Christopher T

    Cell

    2022  Volume 185, Issue 25, Page(s) 4861

    Language English
    Publishing date 2022-12-06
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2022.11.018
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1167: Show issues Location:
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  2. Article ; Online: Tailoring enzyme strategies and functional groups in biosynthetic pathways.

    Walsh, Christopher T

    Natural product reports

    2023  Volume 40, Issue 2, Page(s) 326–386

    Abstract: Covering: 2000 to 2022Secondary metabolites are assembled by drawing off and committing some of the flux of primary metabolic building blocks to sets of enzymes that tailor the maturing scaffold to increase architectural and framework complexity, often ... ...

    Abstract Covering: 2000 to 2022Secondary metabolites are assembled by drawing off and committing some of the flux of primary metabolic building blocks to sets of enzymes that tailor the maturing scaffold to increase architectural and framework complexity, often balancing hydrophilic and hydrophobic surfaces. In this review we examine the small number of chemical strategies that tailoring enzymes employ in maturation of scaffolds. These strategies depend both on the organic functional groups present at each metabolic stage and one of two tailoring enzyme strategies. Nonoxidative tailoring enzymes typically transfer electrophilic fragments, acyl, alkyl and glycosyl groups, from a small set of thermodynamically activated but kinetically stable core metabolites. Oxidative tailoring enzymes can be oxygen-independent or oxygen-dependent. The oxygen independent oxidoreductases are often reversible nicotinamide-utilizing redox catalysts, flipping the nucleophilicity and electrophilicity of functional groups in pathway intermediates. O
    MeSH term(s) Biosynthetic Pathways ; Oxygenases/metabolism ; Oxidoreductases/metabolism ; Oxidation-Reduction ; Oxygen/metabolism
    Chemical Substances Oxygenases (EC 1.13.-) ; Oxidoreductases (EC 1.-) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2023-02-22
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2002546-4
    ISSN 1460-4752 ; 0265-0568
    ISSN (online) 1460-4752
    ISSN 0265-0568
    DOI 10.1039/d2np00048b
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Covalent Catalytic Strategies for Enzymes That Modify RNA Molecules on their Tripartite Building Blocks.

    Walsh, Christopher T

    ACS chemical biology

    2022  Volume 17, Issue 10, Page(s) 2686–2703

    Abstract: The tripartite structures of the four 5'-nucleotide monophosphate (NMP) building blocks in all RNAs enable enzyme-catalyzed chemical modifications to three types of sites: the heterocyclic bases via N- and C-methylations and other alkylations, conversion ...

    Abstract The tripartite structures of the four 5'-nucleotide monophosphate (NMP) building blocks in all RNAs enable enzyme-catalyzed chemical modifications to three types of sites: the heterocyclic bases via N- and C-methylations and other alkylations, conversion of the N-glycoside linkages of the uridine moiety to the C-C glycoside link in pseudouridines, and the phosphodiester-mediated processes of 5'-capping, splicing, and 3'-tailing of premRNAs. We examine known cases for enzymatic covalent catalytic strategies that entail transient formation and breakdown of covalent enzyme-RNA adducts in each catalytic cycle. One case involves generation of the required carbon nucleophile during C
    MeSH term(s) Humans ; RNA, Viral ; Nucleoside Q ; COVID-19 ; SARS-CoV-2 ; Pseudouridine ; RNA, Messenger/genetics ; Guanine ; Guanosine Triphosphate/metabolism ; Catalysis ; Nucleotides ; Cytosine ; Glycosides ; Carbon
    Chemical Substances RNA, Viral ; Nucleoside Q (57072-36-3) ; Pseudouridine (1445-07-4) ; RNA, Messenger ; Guanine (5Z93L87A1R) ; Guanosine Triphosphate (86-01-1) ; Nucleotides ; Cytosine (8J337D1HZY) ; Glycosides ; Carbon (7440-44-0)
    Language English
    Publishing date 2022-09-14
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.2c00584
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Neurosurgery elucidates somatic mutations.

    Maury, Eduardo A / Walsh, Christopher A / Kahle, Kristopher T

    Science (New York, N.Y.)

    2023  Volume 382, Issue 6677, Page(s) 1360–1362

    Abstract: Surgical innovation is helping to identify roles for somatic mutations in brain disorders. ...

    Abstract Surgical innovation is helping to identify roles for somatic mutations in brain disorders.
    MeSH term(s) Humans ; Brain Diseases/genetics ; Brain Diseases/surgery ; Mutation ; Neurosurgery ; Neurosurgical Procedures
    Language English
    Publishing date 2023-12-21
    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.adj2244
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 27: Show issues Location:
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  5. Article ; Online: Biologically generated carbon dioxide: nature's versatile chemical strategies for carboxy lyases.

    Walsh, Christopher T

    Natural product reports

    2019  Volume 37, Issue 1, Page(s) 100–135

    Abstract: Covering: up to 2019Metabolic production of ... ...

    Abstract Covering: up to 2019Metabolic production of CO
    MeSH term(s) Animals ; Biotin/metabolism ; Carbon/metabolism ; Carbon Dioxide/metabolism ; Carboxy-Lyases/chemistry ; Carboxy-Lyases/metabolism ; Carboxylic Acids/metabolism ; Catalysis ; Coenzymes/chemistry ; Coenzymes/metabolism ; Humans ; Metabolic Networks and Pathways ; NAD/metabolism ; Neurotransmitter Agents/metabolism ; Niacinamide/metabolism ; Pyruvate Decarboxylase/metabolism ; Zinc/metabolism
    Chemical Substances Carboxylic Acids ; Coenzymes ; Neurotransmitter Agents ; NAD (0U46U6E8UK) ; Carbon Dioxide (142M471B3J) ; Niacinamide (25X51I8RD4) ; Biotin (6SO6U10H04) ; Carbon (7440-44-0) ; Carboxy-Lyases (EC 4.1.1.-) ; Pyruvate Decarboxylase (EC 4.1.1.1) ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2019-05-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2002546-4
    ISSN 1460-4752 ; 0265-0568
    ISSN (online) 1460-4752
    ISSN 0265-0568
    DOI 10.1039/c9np00015a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Propofol: Milk of Amnesia.

    Walsh, Christopher T

    Cell

    2018  Volume 175, Issue 1, Page(s) 10–13

    Abstract: This year's Lasker Clinical Research Award goes to James Baird Glen for the discovery and development of the anesthetic propofol. Patients benefit from its fast onset and rapid systemic clearance, eliminating the prolonged sedation effects experienced ... ...

    Abstract This year's Lasker Clinical Research Award goes to James Baird Glen for the discovery and development of the anesthetic propofol. Patients benefit from its fast onset and rapid systemic clearance, eliminating the prolonged sedation effects experienced with earlier agents. In just 30 years, propofol has been adopted around the world for safe and controlled induction of anesthesia.
    MeSH term(s) Anesthesia/history ; Anesthesia/methods ; Awards and Prizes ; History, 21st Century ; Humans ; Propofol/history ; Propofol/pharmacology ; Propofol/therapeutic use
    Chemical Substances Propofol (YI7VU623SF)
    Language English
    Publishing date 2018-09-11
    Publishing country United States
    Document type Biography ; Historical Article ; News
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2018.08.031
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Nature Builds Macrocycles and Heterocycles into Its Antimicrobial Frameworks: Deciphering Biosynthetic Strategy.

    Walsh, Christopher T

    ACS infectious diseases

    2018  Volume 4, Issue 9, Page(s) 1283–1299

    Abstract: Natural products with anti-infective activity are largely of polyketide or peptide origin. The nascent scaffolds typically undergo further enzymatic morphing to produce mature active structures. Two kinds of common constraints during maturation of ... ...

    Abstract Natural products with anti-infective activity are largely of polyketide or peptide origin. The nascent scaffolds typically undergo further enzymatic morphing to produce mature active structures. Two kinds of common constraints during maturation of immature scaffolds to active end point metabolites are macrocyclizations and hetrocyclizations. Each builds compact architectures characteristic of many high affinity, specific ligands for therapeutic targets. The chemical logic and enzymatic machinery for macrolactone and macrolactam formations are analyzed for antibiotics such as erythromycins, daptomycin, polymyxins, and vancomycin. In parallel, biosynthetic enzymes build small ring heterocycles, including epoxides, β-lactams, and β-lactones, cyclic ethers such as tetrahydrofurans and tetrahydropyrans, thiazoles, and oxazoles, as well as some seven- and eight-member heterocyclic rings. Combinations of fused heterocyclic scaffolds and heterocycles embedded in macrocycles reveal nature's chemical logic for building active molecular frameworks in short efficient pathways.
    MeSH term(s) Anti-Bacterial Agents/biosynthesis ; Anti-Bacterial Agents/chemistry ; Bacteria/metabolism ; Biological Products/chemistry ; Biological Products/metabolism ; Biosynthetic Pathways ; Heterocyclic Compounds/chemistry ; Heterocyclic Compounds/metabolism ; Macrocyclic Compounds/chemistry ; Macrocyclic Compounds/metabolism ; Molecular Structure
    Chemical Substances Anti-Bacterial Agents ; Biological Products ; Heterocyclic Compounds ; Macrocyclic Compounds
    Language English
    Publishing date 2018-07-23
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2373-8227
    ISSN (online) 2373-8227
    DOI 10.1021/acsinfecdis.8b00101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Biologically generated carbon dioxide: nature's versatile chemical strategies for carboxy lyases

    Walsh, Christopher T.

    Natural product reports. 2020 Jan. 29, v. 37, no. 1

    2020  

    Abstract: Metabolic production of CO₂ is natural product chemistry on a mammoth scale. Just counting humans, among all other respiring organisms, the seven billion people on the planet exhale about 3 billion tons of CO₂ per year. Essentially all of the biogenic CO₂ ...

    Abstract Metabolic production of CO₂ is natural product chemistry on a mammoth scale. Just counting humans, among all other respiring organisms, the seven billion people on the planet exhale about 3 billion tons of CO₂ per year. Essentially all of the biogenic CO₂ arises by action of discrete families of decarboxylases. The mechanistic routes to CO₂ release from carboxylic acid metabolites vary with the electronic demands and structures of specific substrates and illustrate the breadth of chemistry employed for C–COO (C–C bond) disconnections. Most commonly decarboxylated are α-keto acid and β-keto acid substrates, the former requiring thiamin-PP as cofactor, the latter typically cofactor-free. The extensive decarboxylation of amino acids, e.g. to neurotransmitter amines, is synonymous with the coenzyme form of vitamin B₆, pyridoxal-phosphate, although covalent N-terminal pyruvamide residues serve in some amino acid decarboxylases. All told, five B vitamins (B₁, B₂, B₃, B₆, B₇), ATP, S-adenosylmethionine, manganese and zinc ions are pressed into service for specific decarboxylase catalyses. There are additional cofactor-independent decarboxylases that operate by distinct chemical routes. Finally, while most decarboxylases use heterolytic ionic mechanisms, a small number of decarboxylases carry out radical pathways.
    Keywords S-adenosylmethionine ; carbon dioxide ; decarboxylation ; heterolytic cleavage ; lyases ; manganese ; metabolites ; neurotransmitters ; people ; pyridoxal phosphate ; zinc
    Language English
    Dates of publication 2020-0129
    Size p. 100-135.
    Publishing place The Royal Society of Chemistry
    Document type Article
    ZDB-ID 2002546-4
    ISSN 1460-4752 ; 0265-0568
    ISSN (online) 1460-4752
    ISSN 0265-0568
    DOI 10.1039/c9np00015a
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: Are highly morphed peptide frameworks lurking silently in microbial genomes valuable as next generation antibiotic scaffolds?

    Walsh, Christopher T

    Natural product reports

    2017  Volume 34, Issue 7, Page(s) 687–693

    Abstract: Antibiotics are a therapeutic class that, once deployed, select for resistant bacterial pathogens and so shorten their useful life cycles. As a consequence new versions of antibiotics are constantly needed. Among the antibiotic natural products, morphed ... ...

    Abstract Antibiotics are a therapeutic class that, once deployed, select for resistant bacterial pathogens and so shorten their useful life cycles. As a consequence new versions of antibiotics are constantly needed. Among the antibiotic natural products, morphed peptide scaffolds, converting conformationally mobile, short-lived linear peptides into compact, rigidified small molecule frameworks, act on a wide range of bacterial targets. Advances in bacterial genome mining, biosynthetic gene cluster prediction and expression, and mass spectroscopic structure analysis suggests many more peptides, modified both in side chains and peptide backbones, await discovery. Such molecules may turn up new bacterial targets and be starting points for combinatorial or semisynthetic manipulations to optimize activity and pharmacology parameters.
    MeSH term(s) Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/pharmacology ; Bacteria/metabolism ; Biological Products/chemistry ; Biological Products/pharmacology ; Genome, Bacterial ; Genome, Microbial ; Molecular Structure ; Multigene Family ; Peptides/chemistry ; Peptides/pharmacology
    Chemical Substances Anti-Bacterial Agents ; Biological Products ; Peptides
    Language English
    Publishing date 2017-07-01
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2002546-4
    ISSN 1460-4752 ; 0265-0568
    ISSN (online) 1460-4752
    ISSN 0265-0568
    DOI 10.1039/c7np00011a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: At the Intersection of Chemistry, Biology, and Medicine.

    Walsh, Christopher T

    Annual review of biochemistry

    2017  Volume 86, Page(s) 1–19

    Abstract: After an undergraduate degree in biology at Harvard, I started graduate school at The Rockefeller Institute for Medical Research in New York City in July 1965. I was attracted to the chemical side of biochemistry and joined Fritz Lipmann's large, ... ...

    Abstract After an undergraduate degree in biology at Harvard, I started graduate school at The Rockefeller Institute for Medical Research in New York City in July 1965. I was attracted to the chemical side of biochemistry and joined Fritz Lipmann's large, hierarchical laboratory to study enzyme mechanisms. That work led to postdoctoral research with Robert Abeles at Brandeis, then a center of what, 30 years later, would be called chemical biology. I spent 15 years on the Massachusetts Institute of Technology faculty, in both the Chemistry and Biology Departments, and then 26 years on the Harvard Medical School Faculty. My research interests have been at the intersection of chemistry, biology, and medicine. One unanticipated major focus has been investigating the chemical logic and enzymatic machinery of natural product biosynthesis, including antibiotics and antitumor agents. In this postgenomic era it is now recognized that there may be from 10
    MeSH term(s) Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/metabolism ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/metabolism ; Biochemistry/history ; Biochemistry/manpower ; Biochemistry/trends ; Biological Products/chemistry ; Biological Products/metabolism ; Biomedical Research/history ; Biomedical Research/manpower ; Biomedical Research/trends ; Drug Industry/history ; Drug Industry/manpower ; Drug Industry/trends ; Gene Expression Regulation ; History, 20th Century ; History, 21st Century ; Humans ; Ligases/genetics ; Ligases/metabolism ; Multienzyme Complexes/genetics ; Multienzyme Complexes/metabolism ; Vancomycin Resistance/genetics
    Chemical Substances Anti-Bacterial Agents ; Antineoplastic Agents ; Biological Products ; Multienzyme Complexes ; Ligases (EC 6.-) ; enterobactin synthetase (EC 6.-)
    Language English
    Publishing date 2017-06-20
    Publishing country United States
    Document type Autobiography ; Historical Article ; Journal Article ; Portraits ; Review
    ZDB-ID 207924-0
    ISSN 1545-4509 ; 0066-4154
    ISSN (online) 1545-4509
    ISSN 0066-4154
    DOI 10.1146/annurev-biochem-110716-121241
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