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991.
In the endoplasmic reticulum (ER), nascent glycoproteins that have not acquired the native conformation are either repaired or sorted for degradation by specific quality‐control systems composed by various proteins. Among them, UDP‐glucose:glycoprotein glucosyltransferase (UGGT) serves as a folding sensor in the ER. However, the molecular mechanism of its recognition remains obscure. This study used pseudo‐misfolded glycoproteins, comprising a modified dihydrofolate reductase with artificial pyrene–cysteine moiety on the protein surface (pDHFR) and Man9GlcNAc2‐methotrexate (M9‐MTX). All five M9‐MTX/pDHFR complexes, with a pyrene group at different positions, were found to be good substrates of UGGT, irrespective of the site of pyrene modification. These results suggest UGGT's mode of substrate recognition is fuzzy, thus allowing various glycoproteins to be accommodated in the folding cycle.  相似文献   
992.
Optogenetics, the developing field of research that uses light‐switchable biochemical tools in a sophisticated technological approach to monitor or control neural function, is rapidly evolving with the discovery and development of novel microbial rhodopsins. Light‐absorbing membrane proteins, as tools for brain research, are promoting new applications within the discipline of optogenetics. Light‐gated rhodopsin ion channels with better intrinsic light sensitivity and improved resolution are needed to overcome some of the current limitations of existing molecules. The recent discovery of light‐gated inhibitory anion channels opens new opportunities for studying physiological neural processes and, at the same time, represent a powerful approach for elucidating the mechanisms of neurological and mental disorders that could benefit from this approach.  相似文献   
993.
Capuramycins are one of several known classes of natural products that contain an l ‐Lys‐derived l ‐α‐amino‐?‐caprolactam (l ‐ACL) unit. The α‐amino group of l ‐ACL in a capuramycin is linked to an unsaturated hexuronic acid component through an amide bond that was previously shown to originate by an ATP‐independent enzymatic route. With the aid of a combined in vivo and in vitro approach, a predicted tridomain nonribosomal peptide synthetase CapU is functionally characterized here as the ATP‐dependent amide‐bond‐forming catalyst responsible for the biosynthesis of the remaining amide bond present in l ‐ACL. The results are consistent with the adenylation domain of CapU as the essential catalytic component for l ‐Lys activation and thioesterification of the adjacent thiolation domain. However, in contrast to expectations, lactamization does not require any additional domains or proteins and is likely a nonenzymatic event. The results set the stage for examining whether a similar NRPS‐mediated mechanism is employed in the biosynthesis of other l ‐ACL‐containing natural products and, just as intriguingly, how spontaneous lactamization is avoided in the numerous NRPS‐derived peptides that contain an unmodified l ‐Lys residue.  相似文献   
994.
995.
The enzyme 4‐oxalocrotonate tautomerase (4‐OT), which catalyzes enol–keto tautomerization as part of a degradative pathway for aromatic hydrocarbons, promiscuously catalyzes various carbon–carbon bond‐forming reactions. These include the aldol condensation of acetaldehyde with benzaldehyde to yield cinnamaldehyde. Here, we demonstrate that 4‐OT can be engineered into a more efficient aldolase for this condensation reaction, with a >5000‐fold improvement in catalytic efficiency (kcat/Km) and a >107‐fold change in reaction specificity, by exploring small libraries in which only “hotspots” are varied. The hotspots were identified by systematic mutagenesis (covering each residue), followed by a screen for single mutations that give a strong improvement in the desired aldolase activity. All beneficial mutations were near the active site of 4‐OT, thus underpinning the notion that new catalytic activities of a promiscuous enzyme are more effectively enhanced by mutations close to the active site.  相似文献   
996.
The thiol pKa and standard redox potential of mycothiol, the major low‐molecular‐weight thiol cofactor in the actinomycetes, are reported. The measured standard redox potential reveals substantial discrepancies in one or more of the other previously measured intracellular parameters that are relevant to mycothiol redox biochemistry.  相似文献   
997.
Information embedded in different ubiquitin chains is transduced by proteins with ubiquitin‐binding domains (UBDs) and erased by a set of hydrolytic enzymes referred to as deubiquitinases (DUBs). Understanding the selectivity of UBDs and DUBs is necessary for decoding the functions of different ubiquitin chains. Critical to these efforts is the access to chemically defined ubiquitin chains bearing site‐specific fluorescent labels. One approach toward constructing such molecules involves peptide ligation by sortase (SrtA), a bacterial transpeptidase responsible for covalently attaching cell surface proteins to the cell wall. Here, we demonstrate the utility of SrtA in modifying individual subunits of ubiquitin chains. Using ubiquitin derivatives in which an N‐terminal glycine is unveiled after protease‐mediated digestion, we synthesized ubiquitin dimers, trimers, and tetramers with different isopeptide linkages. SrtA was then used in combination with fluorescent depsipeptide substrates to effect the modification of each subunit in a chain. By constructing branched ubiquitin chains with individual subunits tagged with a fluorophore, we provide evidence that the ubiquitin‐specific protease USP15 prefers ubiquitin trimers but has little preference for a particular isopeptide linkage. Our results emphasize the importance of subunit‐specific labeling of ubiquitin chains when studying how DUBs process these chains.  相似文献   
998.
Quinoline‐based oligoamide foldamers have been identified as a potent class of ligands for G‐quadruplex DNA. Their helical structure is thought to target G‐quadruplex loops or grooves and not G‐tetrads. We report a co‐crystal structure of the antiparallel hairpin dimeric DNA G‐quadruplex (G4T4G4)2 with tetramer 1 —a helically folded oligo‐quinolinecarboxamide bearing cationic side chains—that is consistent with this hypothesis. Multivalent foldamer–DNA interactions that modify the packing of (G4T4G4)2 in the solid state are observed.  相似文献   
999.
S‐adenosyl‐l ‐methionine (SAM)‐dependent methyltransfer is a common biosynthetic strategy to modify natural products. We investigated the previously uncharacterized Aspergillus fumigatus methyltransferase FtpM, which is encoded next to the bimodular fumaric acid amide synthetase FtpA. Structure elucidation of two new A. fumigatus natural products, the 1,11‐dimethyl esters of fumaryl‐l ‐tyrosine and fumaryl‐l ‐phenylalanine, together with ftpM gene disruption suggested that FtpM catalyzes iterative methylation. Final evidence that a single enzyme repeatedly acts on fumaric acid amides came from an in vitro biochemical investigation with recombinantly produced FtpM. Size‐exclusion chromatography indicated that this methyltransferase is active as a dimer. As ftpA and ftpM homologues are found clustered in other fungi, we expect our work will help to identify and annotate natural product biosynthesis genes in various species.  相似文献   
1000.
Microcin J25 (MccJ25) has emerged as an excellent model to understand the maturation of ribosomal precursor peptides into the entangled lasso fold. MccJ25 biosynthesis relies on the post‐translational modification of the precursor McjA by the ATP‐dependent protease McjB and the lactam synthetase McjC. Here, using NMR spectroscopy, we showed that McjA is an intrinsically disordered protein without detectable conformational preference, which emphasizes the active role of the maturation machinery on the three‐dimensional folding of MccJ25. We further showed that the N‐terminal region of the leader peptide is involved in interaction with both maturation enzymes and identified a predominant interaction of V43–S55 in the core McjA sequence with McjC. Moreover, we demonstrated that residues K23–Q34 in the N‐terminal McjA leader peptide tend to adopt a helical conformation in the presence of membrane mimics, implying a role in directing McjA to the membrane in the vicinity of the lasso synthetase/export machinery. These data provide valuable insights into the initial molecular recognition steps in the MccJ25 maturation process.  相似文献   
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