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Jacob M Goldberg, Stephen J Lippard
No abstract text is available yet for this article.
March 19, 2018: Biochemistry
Masha M Rosenberg, Alfred G Redfield, Mary Roberts, Lizbeth Hedstrom
The ability of enzymes to modulate the dynamics of bound substrates and cofactors is a critical feature of catalysis, but the role of dynamics has largely been approached from the perspective of the protein. Here we use an underappreciated NMR technique, subtesla high resolution field cycling31 P NMR relaxometry, to interrogate the dynamics of enzyme bound substrates and cofactors in guanosine-5'-monophosphate reductase (GMPR). These experiments reveal distinct binding modes and dynamic profiles associated with the31 P nuclei in the Michaelis complexes for the deamination and hydride transfer steps of the catalytic cycle...
March 16, 2018: Biochemistry
Nicolas Daffern, Zhonglei Chen, Yongbo Zhang, Leslie Pick, Ishwar Radhakrishnan
The ligand-binding domains (LBD) of the NR5A subfamily of nuclear receptors activate transcription via ligand-dependent and ligand-independent mechanisms. The Drosophila Ftz-F1 receptor (NR5A3) belongs to the latter category and its ligand-independence is attributed to a short helical segment (6) within the protein that resides in the canonical ligand-binding pocket (LBP) in the crystalline state. Here, we show that the 6 helix is dynamic in solution when Ftz-F1 is bound to the LxxLL motif of its cofactor Ftz, undergoing motions on the fast (picosecond-nanosecond) as well as slow (microsecond-millisecond) timescales...
March 16, 2018: Biochemistry
Evgenia N Nikolova, Robyn L Stanfield, Jane Dyson, Peter E Wright
Many eukaryotic transcription factors recognize the epigenetic marker 5-methylcytosine (mC) at CpG sites in DNA. Despite their structural diversity, methyl-CpG-binding proteins (MBPs) share a common mode of recognition of mC methyl groups that involves hydrophobic pockets and weak hydrogen bonds of the CH---O type. The zinc finger protein Kaiso possesses a remarkably high specificity for methylated over unmethylated CpG sites. A key contribution to this specificity is provided by glutamate 535 (E535), which is optimally positioned to form multiple interactions with mCpG, including direct CH---O hydrogen bonds...
March 16, 2018: Biochemistry
Caitlin M Davis, Martin Gruebele
Qualitative imaging of biomolecular localization and distribution inside cells has revolutionized cell biology. Most of these powerful techniques require modifications to the target biomolecule. Over the past 10 years, these techniques have been extended to quantitative measurements, from in-cell protein folding rates, to complex dissociation constants, to RNA lifetimes. Such measurements can be affected even when a target molecules is just mildly perturbed by its labels. Here, the impact of labeling on protein (and RNA) structure, stability, and function in cells are discussed via practical examples from recent literature...
March 16, 2018: Biochemistry
Paween Mahinthichaichan, Robert B Gennis, Emad Tajkhorshid
Cytochrome aa3 is the terminal respiratory enzyme of all eukaryotes and many bacteria and archaea, reducing O2 to water and harnessing the free energy from the reaction to generate the transmembrane electrochemical potential. The diffusion of O2 to the heme-copper catalytic site, which is buried deep inside the enzyme, is the initiation step of the reaction chemistry. Our previous molecular dynamics (MD) study with cytochrome ba3 , a homologous enzyme of cytochrome aa3 in Thermus thermophilus, demonstrated that O2 diffuses from the lipid bilayer to its reduction site through a 25-Å long tunnel inferred by Xe-binding sites detected by X-ray crystallography$ ...
March 16, 2018: Biochemistry
Juan Pan, Minakshi Bhardwaj, Bo Zhang, Wei-Chen Chang, Christopher Lewis Schardl, Carsten Krebs, Robert B Grossman, J Martin Bollinger
The core of the loline family of insecticidal alkaloids is the bicyclic pyrrolizidine unit with an additional strained ether bridge between carbons 2 and 7. Previously reported genetic and in vivo biochemical analyses showed that the presumptive iron- and 2-oxoglutarate-dependent (Fe/2OG) oxygenase, LolO, is required for installation of the ether bridge upon the pathway intermediate, 1- exo-acetamidopyrrolizidine (AcAP). Here we show that LolO is, in fact, solely responsible for this biosynthetic four-electron oxidation...
March 14, 2018: Biochemistry
Deepti Chaturvedi, Radhakrishnan Mahalakshmi
Transmembrane β-barrel proteins (OMPs) are highly robust structures for engineering and development of nanopore channels, surface biosensors, and display libraries. Expanding the applications of designed OMPs requires the identification of elements essential for β-barrel scaffold formation and stability. Here, we have designed chimeric 8-stranded OMPs composed of strand hybrids of Escherichia coli OmpX and Yersinia pestis Ail, and identified molecular motifs essential for β-barrel scaffold formation. For the OmpX/Ail chimeras, we find that the central hairpin strands β4-β5 in tandem are vital for β-barrel folding...
March 14, 2018: Biochemistry
Lisa Milazzo, Stefan Hofbauer, Barry D Howes, Thomas Gabler, Paul G G Furtmüller, Christian Obinger, Giulietta Smulevich
Coproheme decarboxylases (ChdC) catalyse the hydrogen peroxide-mediated conversion of coproheme to heme b. This work compares the structure and function of wild-type (WT) coproheme decarboxylase from Listeria monocytogenes and its M149A, Q187A, and M149A/Q187A mutants. The UV-vis, resonance Raman and electron paramagnetic resonance spectroscopies clearly show that the ferric form of the WT protein is a pentacoordinate quantum mechanically mixed-spin state, which is very unusual in biological systems. Exchange of the Met149 residue to Ala dramatically alters the heme coordination, which becomes a 6 coordinate low spin species with the amide nitrogen atom of the Q187 residue bound to the heme iron...
March 14, 2018: Biochemistry
Kenneth D Clevenger, Rosa Ye, Jin Woo Bok, Paul M Thomas, Md Nurul Islam, Galen P Miley, Matthew Robey, Cynthia Chen, KaHoua Yang, Michael Swyers, Edward Wu, Peng Gao, Chengcang Wu, Nancy P Keller, Neil L Kelleher
The benzodiazepine benzomalvin A/D is a fungal-derived specialized metabolite and inhibitor of the substance P receptor NK1, biosynthesized by a three-gene non-ribosomal peptide synthetase cluster. Here, we utilize <u>f</u>ungal <u>a</u>rtificial <u>c</u>hromosomes with <u>m</u>etabolomic <u>s</u>coring (FAC-MS) to carry out molecular genetic pathway dissection and targeted metabolomics analysis to assign the in vivo role of each domain in the benzomalvin biosynthetic pathway...
March 13, 2018: Biochemistry
Hanan L Messiha, Syed T Ahmed, Vijaykumar Karuppiah, Reynier Suardiaz, Gabriel A Ascue Avalos, Natalie Fey, Stephen Yeates, Helen S Toogood, Adrian J Mulholland, Nigel S Scrutton
Monoterpenoids offer potential as bio-derived monomer feedstocks for high performance renewable polymers. We describe a biocatalytic route to lactone monomers menthide and dihydrocarvide employing Baeyer-Villiger monooxygenases (BVMOs) from Pseudomonas sp. HI-70 (CPDMO) and Rhodococcus sp. Phi1 (CHMOPhi1) as an alternative to organic synthesis. The regio-selectivity of dihydrocarvide isomer formation was controlled by site-directed mutagenesis of three key active site residues in CHMOPhi1. A combination of crystal structure determination, molecular dynamics simulations and mechanistic modeling using density functional theory (DFT) on a range of models provides insight into the origins of discrimination of wild type (WT) and a variant CHMOPhi1 for producing different regio-isomers of the lactone product...
March 13, 2018: Biochemistry
Xian Cheng, Irina A Shkel, Cristen Molzahn, David Lambert, Rezwana Karim, M Thomas Record
Alkylureas display hydrocarbon and amide groups, the primary functional groups of proteins. To obtain thermodynamic information needed to analyze interactions of amides and proteins with nucleobases and nucleic acids, we quantify preferential interactions of alkylureas with nucleobases differing in amount and composition of water-accessible surface area (ASA) by solubility assays. Using an established additive ASA-based analysis, we interpret these thermodynamic results to determine interactions of each alkylurea with five types of nucleobase unified atoms (carbonyl sp2O, amino sp3N, ring sp2N, methyl sp3C, and ring sp2C)...
March 13, 2018: Biochemistry
Michael A Jensen, Ronald W Davis
There is a growing demand for sustainable methods in research and development, where instead of hazardous chemicals, an aqueous medium is chosen to perform biological reactions. In this Perspective, we examine the history and current methodology of using enzymes to generate artificial single-stranded DNA. By using traditional solid-phase phosphoramidite chemistry as a metric, we also explore criteria for the method of template-independent enzymatic oligonucleotide synthesis (TiEOS). As its key component, we delve into the biology of one of the most enigmatic enzymes, terminal deoxynucleotidyl transferase (TdT)...
March 13, 2018: Biochemistry
Stephen Shinsky, David W Christianson
Polyamines such as putrescine, spermidine, and spermine are small aliphatic cations that serve myriad biological functions in all forms of life. While polyamine biosynthesis and cellular trafficking pathways are generally well defined, it is only recently that the molecular basis of reversible polyamine acetylation has been established. In particular, enzymes that catalyze polyamine deacetylation reactions have been identified and structurally characterized: histone deacetylase 10 (HDAC10) from Homo sapiens and Danio rerio (zebrafish) is a highly specific N8-acetylspermidine deacetylase, and its prokaryotic counterpart, acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa, is a broad-specificity polyamine deacetylase...
March 13, 2018: Biochemistry
Chin-Yuan Chang, Jeremy R Lohman, Tingting Huang, Karolina Michalska, Lance Bigelow, Jeffrey D Rudolf, Robert Jedrzejczak, Xiaohui Yan, Ming Ma, Gyorgy Babnigg, Andrzej Joachimiak, George N Phillips, Ben Shen
C-1027 is a chromoprotein enediyne antitumor antibiotic, consisting of the CagA apo-protein and the C-1027 chromophore. The C-1027 chromophore features a nine-membered enediyne core appended with three peripheral moieties, including an (S)-3-chloro-5-hydroxy--tyrosine. In a convergent biosynthesis of the C-1027 chromophore, the (S)-3-chloro-5-hydroxy--tyrosine moiety is appended to the enediyne core by the free-standing condensation enzyme SgcC5. Unlike canonical condensation domains from the modular nonribosomal peptide synthetases that catalyze amide bond formation, SgcC5 catalyzes ester bond formation, as demonstrated in vitro, between SgcC2-tethered (S)-3-chloro-5-hydroxy-β-tyrosine and (R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core as an acceptor substrate...
March 13, 2018: Biochemistry
Guosong Hong, Robert D Viveros, Theodore J Zwang, Xiao Yang, Charles M Lieber
Electrophysiology tools have contributed substantially to understanding brain function, yet the capabilities of conventional electrophysiology probes have remained limited in key ways due to large structural and mechanical mismatches with respect to neural tissue. In this Perspective, we discuss how the general goal of probe design in biochemistry - that the probe or label has a minimal impact on the properties and function of the system being studied - can be realized by minimizing structural, mechanical and topological differences between neural probes and brain tissue, thus leading to a new paradigm of tissue-like mesh electronics...
March 12, 2018: Biochemistry
Laura J Marholz, Nicholas A Zeringo, Hua Jane Lou, Benjamin E Turk, Laurie L Parker
A majority of the 90 human protein tyrosine kinases (PTKs) are understudied "orphan" enzymes with few or no known substrates. Designing experiments aimed at assaying the catalytic activity of these PTKs has been a long-running problem. In the past, researchers have used polypeptides with a randomized 4:1 molar ratio of glutamic acid to tyrosine as general PTK substrates. However, these substrates are inefficient and perform poorly for many applications. In this work, we apply the KINATEST-ID pipeline for artificial kinase substrate discovery to design a set of candidate "universal" PTK peptide substrate sequences...
March 12, 2018: Biochemistry
Benjamin Levin, Emily P Balskus
Propanediol dehydratase (PD), a recently characterized member of the glycyl radical enzyme (GRE) family, uses protein-based radicals to catalyze the chemically challenging dehydration of (S)-1,2-propanediol. This transformation is also performed by the well-studied enzyme B12-dependent propanediol dehydratase (B12-PD) using an adenosylcobalamin cofactor. Despite the prominence of PD in anaerobic microorganisms, it remains unclear if the mechanism of this enzyme is similar to that of B12-PD. Here we report oxygen-18 labeling experiments that suggest PD and B12-PD employ distinct mechanisms...
March 12, 2018: Biochemistry
David Sychantha, Robert Chapman, Natalie C Bamford, Geert-Jan Boons, P Lynne Howell, Anthony John Clarke
Bacterial surface (S)-layers are paracrystalline arrays of protein assembled on the bacterial cell wall which serve as protective barriers and scaffolds for housekeeping enzymes and virulence factors. The attachment of S-layer proteins to the cell walls of the Bacillus cereus sensu lato, which includes the pathogen Bacillus anthracis, occurs through non-covalent interactions between their S-layer homology domains and secondary cell wall polysaccharides. To promote recognition for these interactions, it is presumed that the terminal N-acetylmannosamine (ManNAc) residues of the secondary cell wall polysaccharides must be ketal-pyruvylated...
March 9, 2018: Biochemistry
Kyle S Cole, Julia M D Grandjean, Kenny Chen, Collin H Witt, Johanna O'Day, Matthew D Shoulders, R Luke Wiseman, Eranthie Weerapana
Protein disulfide isomerase A1 (PDIA1) is an endoplasmic reticulum (ER)-localized thiol-disulfide oxidoreductase that is an important folding catalyst for secretory pathway proteins. PDIA1 contains two active-site domains (a and a'), each containing a Cys-Gly-His-Cys (CGHC) active-site motif. The two active-site domains share 37% sequence identity, and function independently to perform disulfide-bond reduction, oxidation and isomerization. Numerous inhibitors for PDIA1 have been reported, yet the selectivity of these inhibitors toward the a and a' sites are poorly characterized...
March 9, 2018: Biochemistry
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