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radical sam

Stefan Jungen, Peter Chen
Intramolecular, homolytic substitution reactions between iron (II) species and various trialkylsulfonium groups were directly observed in the gas phase upon collision induced dissociation. In spite of the notoriously low reduction potential of trialkylsulfonium species and the mismatched oxidation potential of iron (II), the reactions proceed at moderate collision energies, forming an alkyl radical as well as a thioether coordinated to the iron. In contrast to classical homolytic substitutions, the attacking radical is a "metalloradical", namely iron (II) that is oxidized to iron (III) during the reaction...
May 16, 2018: Chemistry: a European Journal
Darja Deobald, Lorenz Adrian, Christian Schöne, Michael Rother, Gunhild Layer
The biological formation of methane (methanogenesis) is a globally important process, which is exploited in biogas technology, but also contributes to global warming through the release of a potent greenhouse gas into the atmosphere. The last and methane-releasing step of methanogenesis is catalysed by the enzyme methyl-coenzyme M reductase (MCR), which carries several exceptional posttranslational amino acid modifications. Among these, a 5-C-(S)-methylarginine is located close to the active site of the enzyme...
May 9, 2018: Scientific Reports
Min Dong, Yugang Zhang, Hening Lin
Radical S-adenosylmethionine (SAM) enzymes are a superfamily of enzymes that use SAM and reduced [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical to catalyze numerous challenging reactions. We have reported a type of non-canonical radical SAM enzymes in the diphthamide biosynthesis pathway. These enzymes also use SAM and reduced [4Fe-4S] clusters, but generate a 3-amino-3-carboxypropyl (ACP) radical to modify the substrate protein, translation elongation factor 2. The regioselective cleavage of a different C-S bond of the sulfonium center of SAM in these enzymes comparing to canonical radical SAM enzymes is intriguing...
April 30, 2018: Biochemistry
Svetlana Avulova, Sam S Chang
Organ-sparing cystectomy remains an operation for a highly selected patient population that can offer similar oncologic outcomes but improved sexual function in men and women. Occult prostate cancer in men may occur even with screening but the majority is of clinical insignificance. Paramount to patient selection are oncologic concerns, but preoperative sexual function, age, performance status, and postoperative expectations must also be evaluated during patient selection. Improved diagnostic and surveillance tools may facilitate and improve patient selection in the future...
May 2018: Urologic Clinics of North America
Christina Dal Magro, Patrick Keller, Annika Kotter, Stephan Werner, Victor Duarte, Virginie Marchand, Michael Ignarski, Anja Freiwald, Roman-Ulrich Müller, Christoph Dieterich, Yuri Motorin, Falk Butter, Mohammed Atta, Mark Helm
Recently discovered new chemical entities in RNA modifications have provided surprises with respect to functional groups that enlarge the chemical space of RNA. Using LC-MS, we found over one hundred signals of RNA constituents that contained a ribose moiety in tRNAs from E. coli. Feeding experiments with variegated stable isotope labeled compounds identified 37 compounds, representing new structures of RNA modifications. One structure was elucidated by deuterium exchange and high resolution mass spectrometry...
April 6, 2018: Angewandte Chemie
Qi Zhang, Xinjian Ji, Dhanaraju Mandalapu, Jinduo Chen
The radical S-adenosylmethionine (SAM) superfamily enzymes cleave SAM reductively to generate a highly reactive 5'-deoxyadenosyl (dAdo) radical, which initiates remarkably diverse reactions. Unlike most radical SAM enzymes, the class C radical SAM methyltransferase NosN binds two SAMs in the active site, using one SAM to produce dAdo radical and the second as a methyl donor. Here we report a mechanistic investigation of NosN by using an allyl analogue of SAM (allyl-SAM). We show that NosN cleaves allyl-SAM efficiently and the resulting dAdo radical can be captured by the olefin moieties of allyl-SAM or 5'-allylthioadenosine (ATA), the latter is a derivative of allyl-SAM...
March 30, 2018: Angewandte Chemie
Min Dong, Venkatesan Kathiresan, Michael K Fenwick, Andrew T Torelli, Yang Zhang, Jonathan D Caranto, Boris Dzikovski, Ajay Sharma, Kyle M Lancaster, Jack H Freed, Steven E Ealick, Brian M Hoffman, Hening Lin
Diphthamide biosynthesis involves a carbon-carbon bond-forming reaction catalyzed by a radical S-adenosylmethionine (SAM) enzyme that cleaves a carbon-sulfur (C-S) bond in SAM to generate a 3-amino-3-carboxypropyl (ACP) radical. Using rapid freezing, we have captured an organometallic intermediate with an iron-carbon (Fe-C) bond between ACP and the enzyme's [4Fe-4S] cluster. In the presence of the substrate protein, elongation factor 2, this intermediate converts to an organic radical, formed by addition of the ACP radical to a histidine side chain...
March 16, 2018: Science
Anna Schweifer, Friedrich Hammerschmidt
The methyl groups of [ methyl-( S)]- and [ methyl-( R)]-[ methyl-D,T]-l-methionine fed to Streptomyces fradiae were incorporated into fosfomycin, which was chemically degraded to chiral AcONa. The enzymatic test gave the ( S)-configuration for the chiral AcONa derived from methionine with the ( S)-[D,T]methyl group ( F = 31.7) and ( R) for the one derived from methionine with the ( R)-[D,T]methyl group ( F = 83.0). The radical SAM methyltransferase transfers the methyl group of MeCbl to HEP-CMP with inversion of configuration...
March 26, 2018: Biochemistry
Kourosh Honarmand Ebrahimi
RSAD2 (cig-5), also known as viperin (virus inhibitory protein, endoplasmic reticulum associated, interferon inducible), is a member of the radical S-adenosylmethionine (SAM) superfamily of enzymes. Since the discovery of this enzyme more than a decade ago, numerous studies have shown that it exhibits antiviral activity against a wide range of viruses. However, there is no clear picture demonstrating the mechanism by which RSAD2 restricts the replication process of different viruses, largely because there is no direct evidence describing its in vivo enzymatic activity...
March 23, 2018: Metallomics: Integrated Biometal Science
Mark W Ruszczycky, Aoshu Zhong, Hung-Wen Liu
Radical SAM enzymes use S-adenosyl-l-methionine as an oxidant to initiate radical-mediated transformations that would otherwise not be possible with Lewis acid/base chemistry alone. These reactions are either redox neutral or oxidative leading to certain expectations regarding the role of SAM as either a reusable cofactor or the ultimate electron acceptor during each turnover. However, these expectations are frequently not realized resulting in fundamental questions regarding the redox handling and movement of electrons associated with these biological catalysts...
February 27, 2018: Natural Product Reports
Yeonjin Ko, Geng-Min Lin, Mark W Ruszczycky, Hung-Wen Liu
DesII is a radical SAM lyase that catalyzes a deamination reaction during the biosynthesis of desosamine in Streptomyces venezuelae. Competing mechanistic hypotheses for this radical-mediated reaction are differentiated according to whether a 1,2-migration takes place and the timing of proton abstraction following generation of a substrate α-hydroxyalkyl radical intermediate. In this study, the deuterated C4 epimer of the natural substrate, TDP-4-amino-4-deoxy-d-[3-2 H]fucose, was prepared and shown to be a substrate for DesII undergoing deamination alone with a specific activity that is only marginally reduced (∼3-fold) with respect to that of deamination of the natural substrate...
February 28, 2018: Biochemistry
Ian Barr, Troy A Stich, Anthony S Gizzi, Tyler L Grove, Jeffrey B Bonanno, John A Latham, Tyler Chung, Carrie M Wilmot, R David Britt, Steven C Almo, Judith P Klinman
The Radical SAM (RS) enzyme PqqE catalyzes the first step in the biosynthesis of the bacterial cofactor pyrroloquinoline quinone, forming a new carbon-carbon bond between two side chains within the ribosomally synthesized peptide substrate PqqA. In addition to the active site RS 4Fe-4S cluster, PqqE is predicted to have two auxiliary Fe-S clusters, like the other members of the SPASM domain family. Here we identify these sites and examine their structure using a combination of X-ray crystallography and Mössbauer and electron paramagnetic resonance (EPR) spectroscopies...
February 27, 2018: Biochemistry
Shreyas S Joshi, Laura L Quast, Sam S Chang, Sanjay G Patel
Introduction: Upper Tract Urothelial Carcinoma (UTUC) is a rare disease with few prognostic determinants. We sought to evaluate the impact of tumor size and location on patient survival following nephroureterectomy for UTUC. Materials and Methods: Data on 8284 patients treated with radical nephroureterectomy for UTUC in the United States between 1998 and 2011 were analyzed from the National Cancer Data Base. Univariable survivorship curves were generated based on pT stage, pN stage, grade, tumor size, and tumor site (renal pelvis vs...
January 2018: Indian Journal of Urology: IJU: Journal of the Urological Society of India
Udit Dalwadi, Calvin K Yip
Conserved from yeast to humans, Elongator is a protein complex implicated in multiple processes including transcription regulation, α-tubulin acetylation, and tRNA modification, and its defects have been shown to cause human diseases such as familial dysautonomia. Elongator consists of two copies of six core subunits (Elp1, Elp2, Elp3, Elp4, Elp5, and Elp6) that are organized into two subcomplexes: Elp1/2/3 and Elp4/5/6 and form a stable assembly of ~ 850 kDa in size. Although the catalytic subunit of Elongator is Elp3, which contains a radical S-adenosyl-L-methionine (SAM) domain and a putative histone acetyltransferase domain, the Elp4/5/6 subcomplex also possesses ATP-modulated tRNA binding activity...
May 2018: Cellular and Molecular Life Sciences: CMLS
Sam Rowlands, Jean-Jacques Amy
BACKGROUND: The bodies of some transgender and intersex people have been mutilated and their minds subjected to immense distress. Their gender has often been determined by others. Loss of fertility used to be considered an inevitable consequence of treatment. OBJECTIVE: To review the issue of preserving the reproductive potential of transgender and intersex people. METHODS: A narrative review based on a wide-ranging search of the literature in multiple disciplines...
February 2018: European Journal of Contraception & Reproductive Health Care
Kelsey R Schramma, Clarissa C Forneris, Alessio Caruso, Mohammad R Seyedsayamdost
Streptide is a ribosomally synthesized and post-translationally modified peptide with a unique cyclization motif consisting of an intramolecular lysine-tryptophan cross-link. Three radical S-adenosylmethionine enzymes, StrB, AgaB, and SuiB from different species of Streptococcus, have been shown to install this modification onto their respective precursor peptides in a leader-dependent fashion. Herein, we conduct detailed investigations to differentiate among several plausible mechanistic proposals, specifically addressing radical versus electrophilic addition to the indole during cross-link formation, the role of substrate side chains in binding in the enzyme active site, and the identity of the catalytic base in the reaction cycle...
January 30, 2018: Biochemistry
Jarett Wilcoxen, Nathan A Bruender, Vahe Bandarian, R David Britt
7-Carboxy-7-deazaguanine (CDG) synthase (QueE), a member of the radical S-deoxyadenosyl-l-methionine (SAM) superfamily of enzymes, catalyzes a radical-mediated ring rearrangement required to convert 6-carboxy-5,6,7,8-tetrahydropterin (CPH4 ) into CDG, forming the 7-dezapurine precursor to all pyrrolopyrimidine metabolites. Members of the radical SAM superfamily bind SAM to a [4Fe-4S] cluster, leveraging the reductive cleavage of SAM by the cluster to produce a highly reactive 5'-deoxyadenosyl radical which initiates chemistry by H atom abstraction from the substrate...
February 7, 2018: Journal of the American Chemical Society
Wan-Qiu Liu, Patricia Amara, Jean-Marie Mouesca, Xinjian Ji, Oriane Renoux, Lydie Martin, Chen Zhang, Qi Zhang, Yvain Nicolet
Regiospecific dehydration of vicinal diols by enzymes is a difficult reaction that usually requires activation by dedicated organic cofactors. The enzymatic use of radical-based chemistry is an effective but challenging alternative as radical intermediates are difficult to control. Here we report the X-ray structure of the radical S-adenosyl-l-methionine (SAM) dehydratase AprD4 involved in the biosynthesis of the aminoglycoside (AG) antibiotic apramycin. Using in vitro characterizations and theoretical calculations based on our crystal structure, we have been able to propose a detailed mechanism of AprD4 catalysis, which involves a complex partially substrate-induced proton relay network in the enzyme active site and highlights the key role of the protein matrix in driving high-energy intermediates...
January 31, 2018: Journal of the American Chemical Society
Nicholas D Lanz, Anthony J Blaszczyk, Erin L McCarthy, Bo Wang, Roy X Wang, Brianne S Jones, Squire J Booker
The methylation of unactivated carbon and phosphorus centers is a burgeoning area of biological chemistry, especially given that such reactions constitute key steps in the biosynthesis of numerous enzyme cofactors, antibiotics, and other natural products of clinical value. These kinetically challenging reactions are catalyzed exclusively by enzymes in the radical S-adenosylmethionine (SAM) superfamily and have been grouped into four classes (A-D). Class B radical SAM (RS) methylases require a cobalamin cofactor in addition to the [4Fe-4S] cluster that is characteristic of RS enzymes...
March 6, 2018: Biochemistry
Vera Haskamp, Simone Karrie, Toni Mingers, Stefan Barthels, François Alberge, Axel Magalon, Katrin Müller, Eckhard Bill, Wolfgang Lubitz, Kirstin Kleeberg, Peter Schweyen, Martin Bröring, Martina Jahn, Dieter Jahn
Radical S -adenosylmethionine (SAM) enzymes exist in organisms from all kingdoms of life, and all of these proteins generate an adenosyl radical via the homolytic cleavage of the S-C(5') bond of SAM. Of particular interest are radical SAM enzymes, such as heme chaperones, that insert heme into respiratory enzymes. For example, heme chaperones insert heme into target proteins but have been studied only for the formation of cytochrome c -type hemoproteins. Here, we report that a radical SAM protein, the heme chaperone HemW from bacteria, is required for the insertion of heme b into respiratory chain enzymes...
February 16, 2018: Journal of Biological Chemistry
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