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radical sam

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 deami- nation reaction during the biosynthesis of desosamine in Strep- tomyces venezuelae. Competing mechanistic hypotheses for this radical-mediated reaction are differentiated according to whether or not a 1,2-migration takes place and the timing of proton abstraction following generation of a substrate α- hydroxyalkyl radical intermediate. In the present study, the deuterated C4-epimer of the natural substrate, TDP-4-amino-4- deoxy-d-[3-2H]fucose, was prepared and shown to be a substrate for DesII undergoing deamination alone with a specific activity that is only marginally reduced (ca...
February 23, 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 6, 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...
January 13, 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...
January 11, 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 crosslink. Three radical SAM enzymes, StrB, AgaB, and SuiB from different Streptococci, have been shown to install this modification onto their respective precursor peptides in a leader-dependent fashion. Herein we conduct detailed investigations to differentiate between several plausible mechanistic proposals, specifically addressing radical versus electrophilic addition to the indole during crosslink 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 10, 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...
January 5, 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 4, 2018: Journal of the American Chemical Society
Nicholas Lanz, Anthony J Blaszczyk, Erin McCarthy, Bo Wang, Roy Wang, Brianne 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, B, C, and D. Class B radical SAM (RS) methylases require a cobalamin cofactor in addition to the [4Fe-¬4S] cluster that is characteristic of RS enzymes...
January 3, 2018: Biochemistry
Vera Haskamp, Simone Karrie, Toni Mingers, Stefan Barthels, François Alberge, Axel Magalon, Katrin Müller, Eckard 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...
December 27, 2017: Journal of Biological Chemistry
Mahir Maruf, Abhinav Sidana, Stephanie Purnell, Amit L Jain, Sam J Brancato, Piyush K Agarwal
PURPOSE: Population studies of patients undergoing radical cystectomy (RC) for bladder cancer (BC) suggest that a more extended lymph node dissection (LND) increases survival. However, information regarding LNDs of patients undergoing RC with a history of radiation therapy for BC is largely unknown. This study aims to define the lymph node yield (LNY) in patients undergoing RC for BC following radiation of the bladder using the surveillance epidemiology and end results (SEER) database...
December 23, 2017: International Urology and Nephrology
James E Thompson, Sam Egger, Maret Böhm, Amila R Siriwardana, Anne-Maree Haynes, Jayne Matthews, Matthijs J Scheltema, Phillip D Stricker
BACKGROUND: Our earlier analysis suggested that robot-assisted radical prostatectomy (RARP) achieved superiority over open radical prostatectomy (ORP) in terms of positive surgical margin (PSM) rates and functional outcomes. OBJECTIVE: With larger sample size and longer follow-up, the objective of this study update is to assess whether our previous findings are upheld and whether the improved PSM rates for RARP after an initial learning curve compared with ORP-as observed in our earlier analysis-ultimately resulted in improved biochemical control...
December 19, 2017: European Urology
Simon Arragain, Emilio Jiménez-Vicente, Alessandro A Scandurra, Stefan Burén, Luis M Rubio, Carlos Echavarri-Erasun
One of the main hurdles to engineer nitrogenase in a non-diazotrophic host is achieving NifB activity. NifB is an extremely unstable and oxygen sensitive protein that catalyzes a low-potential SAM-radical dependent reaction. The product of NifB activity is called NifB-co, a complex [8Fe-9S-C] cluster that serves as obligate intermediate in the biosyntheses of the active-site cofactors of all known nitrogenases. Here we study the diversity and phylogeny of naturally occurring NifB proteins, their protein architecture and the functions of the distinct NifB domains in order to understand what defines a catalytically active NifB...
2017: Frontiers in Plant Science
Christopher T Walsh, Yi Tang
Enzymes in biosynthetic pathways, especially in plant and microbial metabolism, generate structural and functional group complexity in small molecules by conversion of acyclic frameworks to cyclic scaffolds in short, efficient routes. The distinct chemical logic used by several distinct classes of cyclases, oxidative and non-oxidative, has recently been elucidated by genome mining, heterologous expression, and genetic and mechanistic analyses. These include enzymes carrying out pericyclic transformations, pyran synthases, tandem acting epoxygenases and epoxide "hydrolases", as well as oxygenases and radical SAM enzymes that involve rearrangements of substrate radicals under aerobic or anaerobic conditions, respectively...
December 13, 2017: Biochemistry
Dhananjay M Bhandari, Dmytro Fedoseyenko, Tadhg P Begley
Tryptophan lyase (NosL) catalyzes the formation of 3-methylindole-2-carboxylic acid and 3-methylindole from l-tryptophan. In this paper, we provide evidence supporting a formate radical intermediate and demonstrate that cyanide is a byproduct of the NosL-catalyzed reaction with l-tryptophan. These experiments require a major revision of the NosL mechanism and uncover an unanticipated connection between NosL and HydG, the radical SAM enzyme that forms cyanide and carbon monoxide from tyrosine during the biosynthesis of the metallo-cluster of the [Fe-Fe] hydrogenase...
January 17, 2018: Journal of the American Chemical Society
Natsaran Saichana, Katsuyuki Tanizawa, Hiroshi Ueno, Jiří Pechoušek, Petr Novák, Jitka Frébortová
PqqE is a radical S -adenosyl-l-methionine (SAM) enzyme that catalyzes the initial reaction of pyrroloquinoline quinone (PQQ) biosynthesis. PqqE belongs to the SPASM (subtilosin/PQQ/anaerobic sulfatase/mycofactocin maturating enzymes) subfamily of the radical SAM superfamily and contains multiple Fe - S clusters. To characterize the Fe - S clusters in PqqE from Methylobacterium extorquens AM1, Cys residues conserved in the N-terminal signature motif (CX3 CX2 C) and the C-terminal seven-cysteine motif (CX9-15 GX4 CX n CX2 CX5 CX3 CX n C; n  = an unspecified number) were individually or simultaneously mutated into Ser...
December 2017: FEBS Open Bio
Hui Li, Yingyu Wang, Qin Fu, Yang Wang, Xiaowei Li, Congming Wu, Zhangqi Shen, Qijing Zhang, Peibin Qin, Jianzhong Shen, Xi Xia
Campylobacter jejuni is a major zoonotic pathogen, and its resistance to antibiotics is of great concern for public health. However, few studies have investigated the global changes of the entire organism with respect to antibiotic resistance. Here, we provide mechanistic insights into high-level resistance to chloramphenicol in C. jejuni, using integrated genomic and proteomic analyses. We identified 27 single nucleotide polymorphisms (SNPs) as well as an efflux pump cmeB mutation that conferred modest resistance...
December 5, 2017: Scientific Reports
Catarina Veiga, David Landau, Jamie R McClelland, Jonathan A Ledermann, David Hawkes, Sam M Janes, Anand Devaraj
PURPOSE: To describe the radiological findings of radiation-induced lung damage (RILD) present on CT imaging of lung cancer patients 12 months after radical chemoradiation. MATERIAL AND METHODS: Baseline and 12-month CT scans of 33 patients were reviewed from a phase I/II clinical trial of isotoxic chemoradiation (IDEAL CRT). CT findings were scored in three categories derived from eleven sub-categories: (1) parenchymal change, defined as the presence of consolidation, ground-glass opacities (GGOs), traction bronchiectasis and/or reticulation; (2) lung volume reduction, identified through reduction in lung height and/or distortions in fissures, diaphragm, anterior junction line and major airways anatomy, and (3) pleural changes, either thickening and/or effusion...
November 27, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
Zhengan Zhang, Nilkamal Mahanta, Graham A Hudson, Douglas A Mitchell, Wilfred A van der Donk
The past decade has seen the discovery of four different classes of radical S-adenosylmethionine (rSAM) methyltransferases that methylate unactivated carbon centers. Whereas the mechanism of class A is well understood, the molecular details of methylation by classes B-D are not. In this study, we present detailed mechanistic investigations of the class C rSAM methyltransferase TbtI involved in the biosynthesis of the potent thiopeptide antibiotic thiomuracin. TbtI C-methylates a Cys-derived thiazole during posttranslational maturation...
December 27, 2017: Journal of the American Chemical Society
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