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https://www.readbyqxmd.com/read/28911781/theory-and-application-of-the-relationship-between-steady-state-isotope-effects-on-enzyme-intermediate-concentrations-and-net-rate-constants
#1
Mark W Ruszczycky, Hung-Wen Liu
Steady-state kinetic isotope effects on enzyme-catalyzed reactions are often interpreted in terms of the microscopic rate constants associated with the elementary reactions of interest. Unfortunately, this approach can lead to confusion, especially when more than one elementary reaction is isotopically sensitive, because it forces one to consider the full catalytic cycle one step at a time rather than as a complete whole. Herein we argue that shifting focus from intrinsic effects to net rate constants and enzyme intermediate concentrations provides a more natural and holistic interpretation by which the effects of partial rate limitation are more easily understood...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28895719/radical-sam-enzymes-involved-in-ripp-biosynthesis
#2
Nilkamal Mahanta, Graham A Hudson, Douglas A Mitchell
Ribosomally synthesized and post-translationally modified peptides (RiPPs) display a diverse range of structures and continue to expand as a natural product class. Accordingly, RiPPs exhibit a wide array of bioactivities, such as broad and narrow spectrum growth suppressors, antidiabetics, as well as antinociception and anticancer agents. Owing to these properties, and the complex repertoire of post-translational modifications (PTMs) that give rise to these molecules, RiPP biosynthesis has been intensely studied...
September 12, 2017: Biochemistry
https://www.readbyqxmd.com/read/28893989/structures-of-the-peptide-modifying-radical-sam-enzyme-suib-elucidate-the-basis-of-substrate-recognition
#3
Katherine M Davis, Kelsey R Schramma, William A Hansen, John P Bacik, Sagar D Khare, Mohammad R Seyedsayamdost, Nozomi Ando
Posttranslational modification of ribosomally synthesized peptides provides an elegant means for the production of biologically active molecules known as RiPPs (ribosomally synthesized and posttranslationally modified peptides). Although the leader sequence of the precursor peptide is often required for turnover, the exact mode of recognition by the modifying enzymes remains unclear for many members of this class of natural products. Here, we have used X-ray crystallography and computational modeling to examine the role of the leader peptide in the biosynthesis of a homolog of streptide, a recently identified peptide natural product with an intramolecular lysine-tryptophan cross-link, which is installed by the radical S-adenosylmethionine (SAM) enzyme, StrB...
September 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28882206/mechanism-based-strategies-for-structural-characterization-of-radical-sam-reaction-intermediates
#4
Katherine M Davis, Amie K Boal
X-ray crystallographic characterization of enzymes at different stages in their reaction cycles can provide unique insight into the reaction pathway, the number and type of intermediates formed, and their structural context. The known mechanistic diversity in the radical S-adenosylmethionine (SAM) superfamily of enzymes makes it an appealing target for such studies as more than 100,000 sequences have been identified to date with wide-ranging reactivities that share a pattern of complex radical-mediated chemistry...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28882204/tsrm-as-a-model-for-purifying-and-characterizing-cobalamin-dependent-radical-s-adenosylmethionine-methylases
#5
Anthony J Blaszczyk, Roy X Wang, Squire J Booker
Cobalamin-dependent radical S-adenosylmethionine (SAM) methylases play vital roles in the de novo biosynthesis of many antibiotics, cofactors, and other important natural products, yet remain an understudied subclass of radical SAM enzymes. In addition to a [4Fe-4S] cluster that is ligated by three cysteine residues, these enzymes also contain an N-terminal cobalamin-binding domain. In vitro studies of these enzymes have been severely limited because many are insoluble or sparingly soluble upon their overproduction in Escherichia coli...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28874373/hyperbaric-oxygen-sensitizes-anoxic-pseudomonas-aeruginosa-biofilm-to-ciprofloxacin
#6
Mette Kolpen, Christian J Lerche, Kasper N Kragh, Thomas Sams, Klaus Koren, Anna S Jensen, Laura Line, Thomas Bjarnsholt, Oana Ciofu, Claus Moser, Michael Kühl, Niels Høiby, Peter Ø Jensen
Chronic Pseudomonas aeruginosa lung infection is characterized by the presence of endobronchial antibiotic-tolerant biofilm subject to strong oxygen (O2) depletion due to the activity of surrounding polymorphonuclear leukocytes. The exact mechanisms affecting the antibiotic susceptibility of biofilms remain unclear, but accumulating evidence suggests that the efficacy of several bactericidal antibiotics is enhanced by stimulation of aerobic respiration of pathogens, while lack of O2 increases their tolerance...
September 5, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28851582/long-term-psychological-and-quality-of-life-effects-of-active-surveillance-and-watchful-waiting-after-diagnosis-of-low-risk-localised-prostate-cancer
#7
Sam J Egger, Ross J Calopedos, Dianne L O'Connell, Suzanne K Chambers, Henry H Woo, David P Smith
BACKGROUND: Long-term psychological well-being and quality-of-life are important considerations when deciding whether to undergo active treatment for low-risk localised prostate cancer. OBJECTIVE: To assess the long-term effects of active surveillance (AS) and/or watchful waiting (WW) on psychological and quality-of-life outcomes for low-risk localised prostate cancer patients. DESIGN, SETTING, AND PARTICIPANTS: The Prostate Cancer Care and Outcome Study is a population-based prospective cohort study in New South Wales, Australia...
August 26, 2017: European Urology
https://www.readbyqxmd.com/read/28830931/at-the-confluence-of-ribosomally-synthesized-peptide-modification-and-radical-s-adenosylmethionine-sam-enzymology
#8
John A Latham, Ian Barr, Judith P Klinman
Radical SAM (RS) enzymology has emerged as a major biochemical strategy for the homolytic cleavage of unactivated C-H bonds. At the same time, the posttranslational modification of ribosomally encoded peptides is a rapidly expanding area of investigation, already shown to lead to a wide range of natural products that include a redox cofactor, antibiotics, quorum-sensing molecules, growth regulators, and mature proteins. In this mini-review, we discuss the cross-section of these two disciplines, highlighting the recently uncovered importance of protein-protein interactions, in particular, between the ribosomally-encoded peptide substrate and its chaperone, which functions either as a stand-alone protein or as an N-terminal domain to the Radical SAM enzyme in the peptide modification cascade...
August 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28819913/chemoradiation-and-local-excision-for-t2n0-rectal-cancer-offers-equivalent-overall-survival-compared-to-standard-resection-a-national-cancer-database-analysis
#9
Lawrence Lee, Justin Kelly, George J Nassif, Sam B Atallah, Matthew R Albert, Ravi Shridhar, John R T Monson
BACKGROUND: Local excision (LE) alone is associated with worse survival compared to radical surgery (RS) for T2 rectal cancer, but LE with additional chemoradiation (CRT) may improve outcomes. The objective of this study was to compare combined CRT and LE versus RS for T2 rectal cancer. METHODS: The 2004-2014 National Cancer Database was queried for patients with T2N0M0 rectal cancer undergoing LE with neoadjuvant(NA-CRT + LE) or adjuvant(LE + Adj-CRT) CRT, or RS...
August 17, 2017: Journal of Gastrointestinal Surgery: Official Journal of the Society for Surgery of the Alimentary Tract
https://www.readbyqxmd.com/read/28768413/monovalent-cation-activation-of-the-radical-sam-enzyme-pyruvate-formate-lyase-activating-enzyme
#10
Krista A Shisler, Rachel U Hutcheson, Masaki Horitani, Kaitlin S Duschene, Adam V Crain, Amanda S Byer, Eric M Shepard, Ashley Rasmussen, Jian Yang, William E Broderick, Jessica L Vey, Catherine L Drennan, Brian M Hoffman, Joan B Broderick
Pyruvate formate-lyase activating enzyme (PFL-AE) is a radical S-adenosyl-l-methionine (SAM) enzyme that installs a catalytically essential glycyl radical on pyruvate formate-lyase. We show that PFL-AE binds a catalytically essential monovalent cation at its active site, yet another parallel with B12 enzymes, and we characterize this cation site by a combination of structural, biochemical, and spectroscopic approaches. Refinement of the PFL-AE crystal structure reveals Na(+) as the most likely ion present in the solved structures, and pulsed electron nuclear double resonance (ENDOR) demonstrates that the same cation site is occupied by (23)Na in the solution state of the as-isolated enzyme...
August 30, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28747433/efficient-methylation-of-c2-in-l-tryptophan-by-the-cobalamin-dependent-radical-s-adenosylmethionine-methylase-tsrm-requires-an-unmodified-n1-amine
#11
Anthony J Blaszczyk, Bo Wang, Alexey Silakov, Jackson V Ho, Squire J Booker
TsrM catalyzes the methylation of C2 in Ltryptophan (Trp). This reaction is the first step in the biosynthesis of the quinaldic acid moiety of the thiopeptide antibiotic thiostrepton, which exhibits potent activity against Gram-positive pathogens. TsrM is a member of the radical S-adenosylmethionine (SAM) superfamily of enzymes, but does not catalyze formation of 5'-deoxyadenosin-5'-yl or any other SAM-derived radical. In addition to a [4Fe-4S] cluster, TsrM contains a cobalamin cofactor that serves as an intermediate methyl carrier in its reaction...
July 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28708394/human-viperin-causes-radical-sam-dependent-elongation-of-escherichia-coli-hinting-at-its-physiological-role
#12
Micah T Nelp, Anthony P Young, Branden M Stepanski, Vahe Bandarian
Viperin (virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible) is a widely distributed protein that is expressed in response to infection and causes antiviral effects against a broad spectrum of viruses. Viperin is a member of the radical S-adenosyl-l-methionine (SAM) superfamily of enzymes, which typically employ a 4Fe-4S cluster to reductively cleave SAM to initiate chemistry. Though the specific reaction catalyzed by viperin remains unknown, it has been shown that expression of viperin causes an increase in the fluidity of lipid membranes, which impedes the budding of nascent viral particles from the membrane inhibiting propagation of the infection...
August 1, 2017: Biochemistry
https://www.readbyqxmd.com/read/28704777/preinvasive-disease-of-the-airway
#13
REVIEW
Ricky M Thakrar, Adam Pennycuick, Elaine Borg, Sam M Janes
Squamous cell carcinoma of the lung arises from preinvasive progenitors in the central airways. The archetypal model appears to be a stepwise morphological progression until there is invasion of the basement membrane. However, not every lesion appears to follow this course and many individuals can have stable disease, or indeed regress to normal epithelium. From our increased understanding of the molecular pathology it is becoming apparent that the respiratory epithelium accumulates progressive genetic and epigenetic insults in response to carcinogens...
July 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28704043/structural-insights-into-thioether-bond-formation-in-the-biosynthesis-of-sactipeptides
#14
Tyler L Grove, Paul M Himes, Sungwon Hwang, Hayretin Yumerefendi, Jeffrey B Bonanno, Brian Kuhlman, Steven C Almo, Albert A Bowers
Sactipeptides are ribosomally synthesized peptides that contain a characteristic thioether bridge (sactionine bond) that is installed posttranslationally and is absolutely required for their antibiotic activity. Sactipeptide biosynthesis requires a unique family of radical SAM enzymes, which contain multiple [4Fe-4S] clusters, to form the requisite thioether bridge between a cysteine and the α-carbon of an opposing amino acid through radical-based chemistry. Here we present the structure of the sactionine bond-forming enzyme CteB, from Clostridium thermocellum ATCC 27405, with both SAM and an N-terminal fragment of its peptidyl-substrate at 2...
August 21, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28701039/aminofutalosine-synthase-evidence-for-captodative-and-aryl-radical-intermediates-using-%C3%AE-scission-and-srn1-trapping-reactions
#15
Sumedh Joshi, Nilkamal Mahanta, Dmytro Fedoseyenko, Howard Williams, Tadhg P Begley
Aminofutalosine synthase (MqnE) is a radical SAM enzyme involved in the menaquinone biosynthetic pathway. In this communication, we propose a novel mechanism for this reaction involving the addition of the adenosyl radical to the substrate double bond to form a captodative radical followed by rearrangement and decarboxylation to form an aryl radical anion which is then oxidized by the [4Fe-4S](+2) cluster. Consistent with this proposal, we describe the trapping of the captodative radical and the aryl radical anion using radical triggered C-Br fragmentation reactions...
August 16, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28678474/methylcobalamin-dependent-radical-sam-c-methyltransferase-fom3-recognizes-cytidylyl-2-hydroxyethylphosphonate-and-catalyzes-the-nonstereoselective-c-methylation-in-fosfomycin-biosynthesis
#16
Shusuke Sato, Fumitaka Kudo, Seung-Young Kim, Tomohisa Kuzuyama, Tadashi Eguchi
A methylcobalamin (MeCbl)-dependent radical S-adenosyl-l-methionine (SAM) methyltransferase Fom3 was found to catalyze the C-methylation of cytidylyl-2-hydroxyethylphosphonate (HEP-CMP) to give cytidylyl-2-hydroxypropylphosphonate (HPP-CMP), although it was originally proposed to catalyze the C-methylation of 2-hydroxyethylphosphonate to give 2-hydroxypropylphosphonate in the biosynthesis of a unique C-P bond containing antibiotic fosfomycin in Streptomyces. Unexpectedly, the Fom3 reaction product from HEP-CMP was almost a 1:1 diastereomeric mixture of HPP-CMP, indicating that the C-methylation is not stereoselective...
July 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28671210/a-mechanistic-study-of-the-non-oxidative-decarboxylation-catalyzed-by-the-radical-s-adenosyl-l-methionine-enzyme-blse-involved-in-blasticidin-s-biosynthesis
#17
Lei Liu, Xinjian Ji, Yongzhen Li, Wenjuan Ji, Tianlu Mo, Wei Ding, Qi Zhang
Decarboxylation is a fundamentally important reaction in biology and involves highly diverse mechanisms. Here we report a mechanistic study of the non-oxidative decarboxylation catalyzed by BlsE, a radical S-adenosyl-l-methionine (SAM) enzyme involved in blasticidin S biosynthesis. Through a series of biochemical analysis with isotopically labeled reagents, we show that the BlsE-catalyzed reaction is initiated by the 5'-deoxyadenosyl (dAdo) radical-mediated hydrogen abstraction from a sugar carbon of the substrate cytosylglucuronic acid (CGA), and does not involve a carboxyl radical as has been proposed for 4-hydroxyphenylacetate decarboxylase (HPAD)...
August 8, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28644475/post-translational-modification-of-ribosomally-synthesized-peptides-by-a-radical-sam-epimerase-in-bacillus-subtilis
#18
Alhosna Benjdia, Alain Guillot, Pauline Ruffié, Jérôme Leprince, Olivier Berteau
Ribosomally synthesized peptides are built out of L-amino acids, whereas D-amino acids are generally the hallmark of non-ribosomal synthetic processes. Here we show that the model bacterium Bacillus subtilis is able to produce a novel type of ribosomally synthesized and post-translationally modified peptide that contains D-amino acids, and which we propose to call epipeptides. We demonstrate that a two [4Fe-4S]-cluster radical S-adenosyl-L-methionine (SAM) enzyme converts L-amino acids into their D-counterparts by catalysing Cα-hydrogen-atom abstraction and using a critical cysteine residue as the hydrogen-atom donor...
July 2017: Nature Chemistry
https://www.readbyqxmd.com/read/28643349/a-qm-mm-study-of-the-catalytic-mechanism-of-sam-methyltransferase-rlmn-from-escherichia-coli
#19
Chenxiao Zhao, Lihua Dong, Yongjun Liu
RlmN is a radical S-adenosylmethionine (SAM) enzyme that catalyzes the C2 methylation of adenosine 2503 (A2503) in 23S rRNA and adenosine 37 (A37) in several Escherichia coli transfer RNAs (tRNA). The catalytic reaction of RlmN is distinctly different from that of typical SAM-dependent methyltransferases that employs an SN 2 mechanism, but follows a ping-pong mechanism which involves the intermediate methylation of a conserved cysteine residue. Recently, the x-ray structure of a key intermediate in the RlmN reaction has been reported, allowing us to perform combined quantum mechanics and molecular mechanics (QM/MM) calculations to delineate the reaction details of RlmN at atomic level...
June 23, 2017: Proteins
https://www.readbyqxmd.com/read/28640310/spectroscopic-evidence-for-cofactor-substrate-interaction-in-the-radical-sam-enzyme-tyw1
#20
Velavan Kathirvelu, Phanélie Perche-Letuvée, Jean-Marc Latour, Mohamed Atta, Farhad Forouhar, Serge Gambarelli, Ricardo Garcia-Serres
TYW1 is a metalloenzyme involved in the modifications of guanosine 37 of Phe-tRNA of Eukaryota and Archaea. It catalyzes the second step of Wybutosine biosynthesis, which consists of the formation of the tricyclic compound imG-14 from m(1)G using pyruvate and SAM (S-adenosyl-methionine) as co-substrates. Two [4Fe-4S] clusters are needed in the catalytic process. One effects the reductive binding of SAM, which initiates the radical reaction that inserts a C-C moiety into m(1)G. The other [4Fe-4S] cluster binds the pyruvate molecule that provides the C-C motif...
June 22, 2017: Dalton Transactions: An International Journal of Inorganic Chemistry
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