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Personalized biochemistry and biophysics.
Kroncke BM, Vanoye CG, Meiler J, George AL, Sanders CR
(2015) Biochemistry 54: 2551-9
MeSH Terms: Biochemistry, Biophysics, Genetic Linkage, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Nucleic Acid Conformation, Precision Medicine, Protein Conformation, RNA
Show Abstract · Added February 5, 2016
Whole human genome sequencing of individuals is becoming rapid and inexpensive, enabling new strategies for using personal genome information to help diagnose, treat, and even prevent human disorders for which genetic variations are causative or are known to be risk factors. Many of the exploding number of newly discovered genetic variations alter the structure, function, dynamics, stability, and/or interactions of specific proteins and RNA molecules. Accordingly, there are a host of opportunities for biochemists and biophysicists to participate in (1) developing tools to allow accurate and sometimes medically actionable assessment of the potential pathogenicity of individual variations and (2) establishing the mechanistic linkage between pathogenic variations and their physiological consequences, providing a rational basis for treatment or preventive care. In this review, we provide an overview of these opportunities and their associated challenges in light of the current status of genomic science and personalized medicine, the latter often termed precision medicine.
1 Communities
3 Members
0 Resources
11 MeSH Terms
Biotinylated probes for the analysis of protein modification by electrophiles.
Codreanu SG, Kim HY, Porter NA, Liebler DC
(2012) Methods Mol Biol 803: 77-95
MeSH Terms: Aldehydes, Amino Acid Sequence, Biochemistry, Biotin, Biotinylation, Blood Proteins, Blotting, Western, Cell Extracts, Cell Line, Tumor, Databases, Protein, Humans, Immunoblotting, Indicators and Reagents, Mass Spectrometry, Molecular Probes, Molecular Sequence Data, Peptides, Protein Processing, Post-Translational, Proteins, Streptavidin, Trypsin
Show Abstract · Added March 7, 2014
Formation of covalent protein adducts by lipid electrophiles contributes to diseases and toxicities linked to oxidative stress, but analysis of the adducts presents a challenging analytical problem. We describe selective adduct capture using biotin affinity probes to enrich protein and peptide adducts for analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS). One approach employs biotinamidohexanoic acid hydrazide to covalently label residual carbonyl groups on adducts. The other employs alkynyl analogs of lipid electrophiles, which form adducts that can be postlabeled with azidobiotin tags by Cu(+)-catalyzed cycloaddition (Click chemistry). To enhance the selectivity of adduct capture, we use an azidobiotin reagent with a photocleavable linker, which allows recovery of adducted proteins and peptides under mild conditions. This approach allows both the identification of protein targets of lipid electrophiles and sequence mapping of the adducts.
0 Communities
2 Members
0 Resources
21 MeSH Terms
Orphans in the human cytochrome P450 superfamily: approaches to discovering functions and relevance in pharmacology.
Guengerich FP, Cheng Q
(2011) Pharmacol Rev 63: 684-99
MeSH Terms: Animals, Biochemistry, Cytochrome P-450 Enzyme System, Humans, Isoenzymes, Organ Specificity, Pharmacology, Substrate Specificity
Show Abstract · Added March 7, 2014
As a result of technical advances in recombinant DNA technology and nucleotide sequencing, entire genome sequences have become available in the past decade and offer potential in understanding diseases. However, a central problem in the biochemical sciences is that the functions of only a fraction of the genes/proteins are known, and this is also an issue in pharmacology. This review is focused on issues related to the functions of cytochrome P450 (P450) enzymes. P450 functions can be categorized in several groups: 1) Some P450s have critical roles in the metabolism of endogenous substrates (e.g., sterols and fat-soluble vitamins). 2) Some P450s are not generally critical to normal physiology but function in relatively nonselective protection from the many xenobiotic chemicals to which mammals (including humans) are exposed in their diets [as well as more anthropomorphic chemicals (e.g., drugs, pesticides)]. 3) Some P450s have not been extensively studied and are termed "orphans" here. With regard to elucidation of any physiological functions of the orphan P450s, the major subject of this review, it is clear that simple trial-and-error approaches with individual substrate candidates will not be very productive in addressing questions about function. A series of liquid chromatography/mass spectrometry/informatics approaches are discussed, along with some successes with both human and bacterial P450s. Current information on what are still considered "orphan" P450s is presented. The potential for application of some of these approaches to other enzyme systems is also discussed.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Guest editor's introduction. Special issue on catalytic mechanisms.
Guengerich FP
(2011) Arch Biochem Biophys 507: 1-2
MeSH Terms: Biocatalysis, Biochemistry, Cytochrome P-450 Enzyme System, History, 20th Century
Added May 26, 2014
0 Communities
1 Members
0 Resources
4 MeSH Terms
Methods to evaluate alterations in polyamine metabolism caused by Helicobacter pylori infection.
Gobert AP, Chaturvedi R, Wilson KT
(2011) Methods Mol Biol 720: 409-25
MeSH Terms: Acetyltransferases, Animals, Apoptosis, Arginase, Arsenicals, Biochemistry, Cells, Cultured, Enzyme Assays, Helicobacter Infections, Helicobacter pylori, Humans, Immunoblotting, Luciferases, Macrophages, Mice, Nitrogen Dioxide, Ornithine Decarboxylase, Oxidoreductases Acting on CH-NH Group Donors, Polyamines, Promoter Regions, Genetic, RNA, Messenger, Transfection
Show Abstract · Added March 5, 2014
Helicobacter pylori is a Gram-negative bacteria that infects the human stomach of half of the world's -population. Colonization is followed by infiltration of the gastric mucosa by lymphocytes and myeloid cells. These cells are activated by various bacterial factors, causing them to produce immune/inflammatory mediators, including reactive nitrogen species and polyamines that contribute to cellular damage and the pathogenesis of H. pylori-associated gastric cancer. In vitro experiments have revealed that H. pylori induces macrophage polyamine production by upregulation of the arginase 2/ornithine decarboxylase (ODC) metabolic pathway and enhances hydrogen peroxide synthesis through the activity of spermidine oxidase (SMO). In this chapter, we present a survey of the methods used to analyze the induction and the role of the enzymes related to polyamine metabolism, i.e., arginase, ODC, and SMO in H. pylori-infected macrophages.
0 Communities
1 Members
0 Resources
22 MeSH Terms
Molecular morphology of the chick heart visualized by MALDI imaging mass spectrometry.
Grey AC, Gelasco AK, Section J, Moreno-Rodriguez RA, Krug EL, Schey KL
(2010) Anat Rec (Hoboken) 293: 821-8
MeSH Terms: Animals, Biochemistry, Biomarkers, Chickens, Coronary Vessels, Endocardium, Heart, Heart Septum, Heart Valves, Image Processing, Computer-Assisted, Myocardium, Paraffin Embedding, Proteins, Proteomics, Species Specificity, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tissue Fixation
Show Abstract · Added May 27, 2014
Utilization of MALDI-MS (matrix-assisted laser desorption/ionization mass spectrometry) for tissue imaging is a relatively new proteomic technique that simultaneously maps the spatial distribution of multiple proteins directly within a single frozen tissue section. Here, we report the development of a methodology to apply MALDI tissue imaging to chick heart tissue sections acquired from fixed and paraffin-embedded samples. This protocol produces molecular images that can be related to the high-quality histological tissue sections. Perfused term chick hearts were fixed in acidic ethanol and embedded in paraffin wax. Tissue sections (15 microm) were collected onto conductive slides, deparaffinized with xylene, and transitioned into water with graded ethanol washes and allowed to air dry. In separate experiments, three different MALDI matrices were applied to chick heart tissue sections through repeated cycles from a glass nebulizer. Tissue sections were then analyzed by MALDI mass spectrometry using a raster step-size of 75-100 microm, and molecular images for specific m/z ratios reconstituted. MALDI tissue imaging revealed spatially resolved protein signals within single heart sections that are specific to structures or regions of the heart, for example, vessels, valves, endocardium, myocardium, or septa. Moreover, no prior knowledge of protein expression is required as is the case for immunohistochemistry and in situ hybridization methodologies. The ability to simultaneously localize a large number of unique protein signals within a single tissue section, with good preservation of histological features, provides cardiovascular researchers a new tool to give insight into the molecular mechanisms underlying normal and pathological conditions.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Working towards an exegesis for lipids in biology.
Brown HA, Murphy RC
(2009) Nat Chem Biol 5: 602-6
MeSH Terms: Animals, Biochemistry, Brain, Cell Membrane, Lipid Metabolism, Lipids, Metabolomics, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Systems Biology
Show Abstract · Added March 19, 2013
As a field, lipidomics is in its infancy, yet it has already begun to influence lipid biochemistry in myriad ways. As with other omic technologies, the field is driven by advances in analytical chemistry, particularly by mass spectrometry. At the heart of a renaissance in lipid biochemistry, systems biology is being used to define the cellular lipome, build a comprehensive picture of metabolic interconnections, discover new molecular species and determine how lipids modulate biological functions.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Thematic minireview series: metals in biology.
Guengerich FP
(2009) J Biol Chem 284: 18557
MeSH Terms: Arsenic, Bacteria, Biochemistry, Iron, Metals, Nickel, Peroxidases, Vanadium, Zinc
Show Abstract · Added March 26, 2014
Metals have important roles in biochemistry ranging from essential to toxic. This prologue introduces the second of the Thematic Minireview Series on Metals in Biology, which includes minireviews on five metals: iron, zinc, nickel, vanadium, and arsenic. Three of the minireviews are focused on the roles of the metals in enzymes (iron, nickel, and vanadium). Zinc deficiency is discussed in another, and the arsenic minireview deals with the toxic and some potentially useful applications of the biological effects.
0 Communities
1 Members
0 Resources
9 MeSH Terms
Characterization of Novel Forms of Coagulation Factor XIa: independence of factor XIa subunits in factor IX activation.
Smith SB, Verhamme IM, Sun MF, Bock PE, Gailani D
(2008) J Biol Chem 283: 6696-705
MeSH Terms: Arginine, Binding Sites, Biochemistry, Catalysis, Catalytic Domain, Dimerization, Factor IX, Factor XIa, Hemostasis, Humans, Hydrolysis, Kinetics, Models, Biological, Peptides, Recombinant Proteins
Show Abstract · Added May 19, 2014
Factor XI is the zymogen of a dimeric plasma protease, factor XIa, with two active sites. In solution, and during contact activation in plasma, conversion of factor XI to factor XIa proceeds through an intermediate with one active site (1/2-FXIa). Factor XIa and 1/2-FXIa activate the substrate factor IX, with similar kinetic parameters in purified and plasma systems. During hemostasis, factor IX is activated by factors XIa or VIIa, by cleavage of the peptide bonds after Arg145 and Arg180. Factor VIIa cleaves these bonds sequentially, with accumulation of factor IX alpha, an intermediate cleaved after Arg145. Factor XIa also cleaves factor IX preferentially after Arg145, but little intermediate is detected. It has been postulated that the two factor XIa active sites cleave both factor IX peptide bonds prior to releasing factor IX abeta. To test this, we examined cleavage of factor IX by four single active site factor XIa proteases. Little intermediate formation was detected with 1/2-FXIa, factor XIa with one inhibited active site, or a recombinant factor XIa monomer. However, factor IX alpha accumulated during activation by the factor XIa catalytic domain, demonstrating the importance of the factor XIa heavy chain. Fluorescence titration of active site-labeled factor XIa revealed a binding stoichiometry of 1.9 +/- 0.4 mol of factor IX/mol of factor XIa (Kd = 70 +/- 40 nm). The results indicate that two forms of activated factor XI are generated during coagulation, and that each half of a factor XIa dimer behaves as an independent enzyme with respect to factor IX.
0 Communities
2 Members
0 Resources
15 MeSH Terms
Insights from crystallographic studies into the structural and pairing properties of nucleic acid analogs and chemically modified DNA and RNA oligonucleotides.
Egli M, Pallan PS
(2007) Annu Rev Biophys Biomol Struct 36: 281-305
MeSH Terms: Biochemistry, Biophysics, Carbohydrates, Cations, Crystallography, X-Ray, DNA, Macromolecular Substances, Models, Chemical, Molecular Conformation, Nucleic Acids, Oligonucleotides, Oligonucleotides, Antisense, Peptide Nucleic Acids, RNA, RNA Interference
Show Abstract · Added March 5, 2014
Chemically modified nucleic acids function as model systems for native DNA and RNA; as chemical probes in diagnostics or the analysis of protein-nucleic acid interactions and in high-throughput genomics and drug target validation; as potential antigene-, antisense-, or RNAi-based drugs; and as tools for structure determination (i.e., crystallographic phasing), just to name a few. Biophysical and structural investigations of chemically modified DNAs and RNAs, particularly of nucleic acid analogs with more significant alterations to the well-known base-sugar-phosphate framework (i.e., peptide or hexopyranose nucleic acids), can also provide insights into the properties of the natural nucleic acids that are beyond the reach of studies focusing on DNA or RNA alone. In this review we summarize results from crystallographic analyses of chemically modified DNAs and RNAs that are primarily of interest in the context of the discovery and development of oligonucleotide-based therapeutics. In addition, we re-examine recent structural data on nucleic acid analogs that are investigated as part of a systematic effort to rationalize nature's choice of pentose in the genetic system.
0 Communities
1 Members
0 Resources
15 MeSH Terms