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James K Christenson, Serina L Robinson, Tiffany A Engel, Jack E Richman, An N Kim, Larry P Wackett
OleB is an α/β-hydrolase found in bacteria that biosynthesize long-chain olefinic hydrocarbons, but its function has remained obscure. We report that OleB from the gram-negative bacterium Xanthomonas campestris performs an unprecedented β-lactone decarboxylation reaction, to complete cis-olefin biosynthesis. OleB reactions monitored by (1)H-NMR spectroscopy revealed a selectivity for decarboxylating cis-β-lactones and no discernable activity with trans-β-lactones, consistent with the known configuration of pathway intermediates...
September 19, 2017: Biochemistry
Rachel E Ashley, Tim R Blower, James M Berger, Neil Osheroff
Mycobacterium tuberculosis encodes only a single type II topoisomerase, gyrase. As a result, this enzyme likely carries out the cellular functions normally performed by canonical gyrase and topoisomerase IV, both in front of and behind the replication fork. In addition, it is the sole target for quinolone antibacterials in this species. Because quinolone-induced DNA strand breaks generated on positively supercoiled DNA ahead of replication forks and transcription complexes are most likely to result in permanent genomic damage, the actions of M...
September 18, 2017: Biochemistry
Matt J Jaremko, D John Lee, Ashay Patel, Victoria Winslow, Stanley J Opella, J Andrew McCammon, Michael D Burkart
In an effort to elucidate and engineer interactions in type II nonribosomal peptide synthetases, we analyzed biomolecular recognition between the essential peptidyl carrier proteins and adenylation domains using NMR spectroscopy, molecular dynamics, and mutational studies. Three peptidyl carrier proteins, PigG, PltL, and RedO, in addition to their cognate adenylation domains, PigI, PltF, and RedM, were investigated for their cross species activity. Of the three peptidyl carrier proteins, only PigG, showed substantial cross-pathway activity...
September 18, 2017: Biochemistry
Xun Sun, H Jane Dyson, Peter E Wright
Abnormal deposition of aggregated wild-type (WT) human transthyretin (TTR) and its pathogenic variants is responsible for cardiomyopathy and neuropathy related to TTR amyloidosis. The tryptophan (Trp) fluorescence measurements typically used to study structural changes of TTR do not yield site-specific information on the two Trp residues per TTR protomer. To obtain such information, tryptophan labeled with fluorine at the 5 and 6 positions (5FW and 6FW) was incorporated into TTR. Fluorescence of 5FW and 6FW-labeled WT-TTR (WT-5FW and WT-6FW) and a single-Trp mutant W41Y showed that the photophysics of incorporated fluoro-Trp is consistent with site-specific solvation of the indole ring of W41 and W79...
September 18, 2017: Biochemistry
Kalkena Sivanesam, Niels H Andersen
To date, fragments from within the amyloidogenic-patch region of human amylin (hAM) have been shown to aggregate independently of the full-length peptide. In this study, we show that under certain conditions, both oligomers of NFGAILSS and the monomeric form are capable of inhibiting the aggregation of the full-length hAM sequence. The inhibition, rather than aggregate seeding, observed with the soluble portion of aged NFGAILSS solutions was particularly striking occurring at far sub-stoichiometric levels. Apparently, the oligomer form of this fragment is responsible for inhibiting the transition from random coil to β-sheet or serves as a disaggregator of hAM β-oligomers...
September 18, 2017: Biochemistry
Sean T Smrt, Adrian W Draney, Indira Singaram, Justin L Lorieau
In vitro studies of protein structure, function and dynamics typically preclude the complex range of molecular interactions found in living tissues. In vivo studies elucidate these complex relationships, yet they are typically incompatible with the extensive and controlled biophysical experiments available in vitro. We present an alternative approach by extracting membranes from eukaryotic tissues to produce native bicelles to capture the rich and complex molecular environment of in vivo studies while retaining the advantages of in vitro experiments...
September 15, 2017: Biochemistry
Benjamin R Lichman, Altin Sula, Thomas Pesnot, Helen C Hailes, John Ward, Nicholas H Keep
Norcoclaurine synthase (NCS) is a Pictet-Spenglerase that catalyzes the first key step in plant benzylisoquinoline alkaloid metabolism, a compound family that includes bioactive natural products such as morphine. The enzyme has also shown great potential as a biocata-lyst for the formation of chiral isoquinolines. Here we present new high-resolution X-ray crystallography data describing Thalictrum flavum NCS bound to a mechanism inspired ligand. The structure supports two key features of the NCS 'dopamine-first' mechanism: the binding of dopamine catechol to Lys-122 and the position of the carbonyl substrate binding site at the active site entrance...
September 15, 2017: Biochemistry
Tsz-Leung To, Xiaokun Shu
No abstract text is available yet for this article.
September 15, 2017: Biochemistry
Eric Sheng-Wen Chen, Jui-Hung Weng, Yu-Hou Chen, Shun-Chang Wang, Xiao-Xia Liu, Wei-Cheng Huang, Tsutomu Matsui, Yoshiaki Kawano, Jiahn-Haur Liao, Liang-Hin Lim, Yoshitaka Bessho, Kai-Fa Huang, Wen-Jin Wu, Ming-Daw Tsai
The vast majority of in vitro structural and functional studies of the activation mechanism of protein kinases use the kinase domain alone. Well-demonstrated effects of regulatory domains or allosteric factors are scarce for serine/threonine kinases. Here we use a site-specifically phosphorylated SCD1-FHA1-kinase three-domain construct of the serine/threonine kinase Rad53 to show the effect of phospho-priming, an in vivo regulatory mechanism, on the autophosphorylation intermediate and specificity. Unphosphorylated Rad53 is a flexible monomer in solution but is captured in an asymmetric enzyme:substrate complex in crystal with the two FHA domains separated from each other...
September 15, 2017: Biochemistry
Betül Kitir, Alex R Maolanon, Ragnhild G Ohm, Ana R Colaço, Peter Fristrup, Andreas S Madsen, Christian A Olsen
Histone deacetylases (HDACs) are validated targets for treatment of certain cancer types and play numerous regulatory roles in biology, ranging from epigenetics to metabolism. Small molecules are highly important as tool compounds for probing these mechanisms as well as for the development of new medicines. Therefore, detailed mechanistic information and precise characterization of the chemical probes used to investigate the effects of HDAC enzymes are vital. We interrogated Nature's arsenal of macrocyclic nonribosomal peptide HDAC inhibitors by chemical synthesis and evaluation of more than 30 natural products and analogues...
September 15, 2017: Biochemistry
Luca Mazzei, Michele Cianci, Umberto Contaldo, Francesco Musiani, Stefano Ciurli
The nickel-dependent enzyme urease is a virulence factor for a large number of pathogenic and antibiotic-resistant bacteria, as well as a negative factor for the efficiency of soil nitrogen fertilization for crop production. The use of urease inhibitors to offset these effects requires knowledge, at a molecular level, of their mode of action. The 1.28 Å resolution structure of the enzyme-inhibitor complex obtained upon incubation of Sporosarcina pasteurii urease with N-(n-butyl)thiophosphoric triamide (NBPT), a molecule largely utilized in agriculture, reveals the presence of the monoamidothiophosphoric acid (MATP) moiety, obtained upon enzymatic hydrolysis of the diamide derivative of NBPT (NBPD) to yield n-butyl amine...
September 15, 2017: Biochemistry
Philipp Leippe, Julia Koehler Leman, Dirk Trauner
Genetics and pharmacology are often seen as two distinct approaches to interrogating, elucidating, and manipulating biological systems. The former is renowned for its precision whereas the latter for its fast kinetics, reversibility, and practicality. Here, we show that both can be joined as "tethered pharmacology", wherein a genetically programmed bioconjugation site provides selectivity and a tethered pharmacophore provides function. The speed of onset, and especially cessation, of pharmacological activity can be greatly enhanced by incorporating photoswitches and using light as the trigger ("tethered photopharmacology")...
September 14, 2017: Biochemistry
Mark Rance
No abstract text is available yet for this article.
September 13, 2017: Biochemistry
Yasuyuki Matoba, Shogo Kihara, Yoshimi Muraki, Naohiko Bando, Hironari Yoshitsu, Teruo Kuroda, Miyuki Sakaguchi, Kure'e Kayama, Hulin Tai, Shun Hirota, Takashi Ogura, Masanori Sugiyama
Tyrosinase (EC, which possesses two copper ions at the active center, catalyzes a rate-limiting reaction of melanogenesis: that is, the conversion of a phenol to the corresponding ortho-quinone. The enzyme from the genus Streptomyces is generated as a complex with a "caddie" protein that assists the transport of two copper ions into the active center. In this complex, the Tyr(98) residue in the caddie protein was found to be accommodated in the pocket of the active center of tyrosinase, probably in a manner similar to that of L-tyrosine as a genuine substrate of tyrosinase...
September 13, 2017: Biochemistry
Sarah Benabdi, François Peurois, Agata Nawrotek, Jahnavi Chikireddy, Tatiana Cañeque, Takao Yamori, Isamu Shiina, Yoshimi Ohashi, Shingo Dan, Raphaël Rodriguez, Jacqueline Cherfils, Mahel Zeghouf
Arf GTPases and their guanine nucleotide exchange factors (ArfGEFs) are major regulators of membrane traffic and organelle structure in cells. They are associated with a variety of diseases and are thus attractive therapeutic targets for inhibition by small molecules. Several inhibitors of unrelated chemical structures have been discovered, which have shown their potential in dissecting molecular pathways and blocking disease-related functions. However, their specificity across the ArfGEF family has remained elusive...
September 13, 2017: Biochemistry
Ling Wu, Paul Velander, Dongmin Liu, Bin Xu
Oleuropein, a natural product derived from olive leaves, has reported anti-diabetic functions. However, detailed molecular mechanisms for how it affects β-cell functions remain poorly understood. Here, we present evidence that oleuropein promotes glucose-stimulated insulin secretion (GSIS) in β-cells. The effect is dose-dependent and stimulates the ERK/MAPK signaling pathway. We further demonstrated that oleuropein inhibits the cytotoxicity induced by amylin amyloids, a hallmark feature of type 2 diabetes...
September 13, 2017: Biochemistry
Rong Liu, M Moazzem Hossain, Xuequn Chen, Jian-Ping Jin
SM22α, also named transgelin, is an actin filament-associated protein in smooth muscle and fibroblast. Three decades after discovery, the biological function of SM22α remains under investigation. Here we report a novel finding that the expression and degradation of SM22α/transgelin is regulated by mechanical tension. Following a mass spectrometry identification of SM22α degradation in isolated and tension-unloaded mouse aorta, we developed specific monoclonal antibodies to study the regulation of SM22α in human fetal lung myofibroblast line MRC-5 and primary cultures of neonatal mouse skin fibroblast...
September 12, 2017: Biochemistry
Marawan Ahmed, Khaled H Barakat
In the current study, we focused on the immune-checkpoints PD-1 pathway and in particular on the ligand, PD-L1. We studied the conformational dynamics of PD-L1 through principal component analysis (PCA) of existing crystal structures combined with classical and accelerated molecular dynamics simulations. We identified the maximum structural displacements that take place in all PD-L1 crystal structures and in the MD trajectories. We found that these displacements are attributed to specific flexible regions in the protein...
September 12, 2017: Biochemistry
Matthew R Hassett, Bryce E Riegel, Paul Samuel Callaghan, Paul David Roepe
Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum malaria is widespread and has limited the use of CQ in many regions of the globe. Malaria caused by the related human parasite P. vivax is as widespread as is P. falciparum malaria and has been treated with CQ as extensively as has P. falciparum, suggesting that P. vivax parasites have been selected with CQ as profoundly as have P. falciparum parasites. Indeed, a growing number of clinical reports have presented data suggesting increased P. vivax CQR...
September 12, 2017: Biochemistry
Lizzette M Gómez Ramos, Natalya N Degtyareva, Nicholas A Kovacs, Stefany Y Holguin, Liuwei Jiang, Anton S Petrov, Marcin Biesiada, Michael Y Hu, Katarzyna J Purzycka, Dev Priya Arya, Loren Dean Williams
Diversity in eukaryotic rRNA structure and function offers possibilities of novel therapeutic targets. Unlike ribosomes of prokaryotes, eukaryotic ribosomes contain species-specific rRNA expansion segments (ESs) with idiosyncratic structures and functions that are essential and specific to some organisms. Here we investigate expansion segment 7 (ES7), one of the largest and most variable expansions of the eukaryotic ribosome. We hypothesize that ES7 of the pathogenic fungi Candida albicans (ES7CA) could be a prototypic drug target...
September 12, 2017: Biochemistry
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