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      Facile synthesis of covalent probes to capture enzymatic intermediates during E1 enzyme catalysis

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      Chemical Communications
      Royal Society of Chemistry (RSC)

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          Abstract

          Electrophilic UBL–AMP probes form a covalent bond with the catalytic cysteine of cognate E1s, mimicking the ternary E1–UBL–AMP intermediates.

          Abstract

          We report a facile synthetic strategy to prepare UBL–AMP electrophilic probes that form a covalent bond with the catalytic cysteine of cognate E1s, mimicking the tetrahedral intermediate of the E1–UBL–AMP complex. These probes enable the structural and biochemical study of both canonical- and non-canonical E1s.

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          Most cited references17

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          Synthesis of proteins by native chemical ligation.

          A simple technique has been devised that allows the direct synthesis of native backbone proteins of moderate size. Chemoselective reaction of two unprotected peptide segments gives an initial thioester-linked species. Spontaneous rearrangement of this transient intermediate yields a full-length product with a native peptide bond at the ligation site. The utility of native chemical ligation was demonstrated by the one-step preparation of a cytokine containing multiple disulfides. The polypeptide ligation product was folded and oxidized to form the native disulfide-containing protein molecule. Native chemical ligation is an important step toward the general application of chemistry to proteins.
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            Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways.

            Attachment of ubiquitin or ubiquitin-like proteins (known as UBLs) to their targets through multienzyme cascades is a central mechanism to modulate protein functions. This process is initiated by a family of mechanistically and structurally related E1 (or activating) enzymes. These activate UBLs through carboxy-terminal adenylation and thiol transfer, and coordinate the use of UBLs in specific downstream pathways by charging cognate E2 (or conjugating) enzymes, which then interact with the downstream ubiquitylation machinery to coordinate the modification of the target. A broad understanding of how E1 enzymes activate UBLs and how they selectively coordinate UBLs with downstream function has come from enzymatic, structural and genetic studies.
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              The autophagic paradox in cancer therapy.

              Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cell-fate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics.
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                Author and article information

                Journal
                CHCOFS
                Chemical Communications
                Chem. Commun.
                Royal Society of Chemistry (RSC)
                1359-7345
                1364-548X
                2016
                2016
                : 52
                : 12
                : 2477-2480
                Article
                10.1039/C5CC08592F
                cf802e87-0b6b-4649-a675-d22111ed605b
                © 2016
                History

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