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Academic literature on the topic 'Enzyme mutations'

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Published: 4 June 2021

Last updated: 4 February 2022

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Journal articles on the topic "Enzyme mutations"

Coates, Talmage L., Naomi Young, Austin J. Jarrett, Connor J. Morris, James D. Moody, and Dennis Della Corte. "Current computational methods for enzyme design." Modern Physics Letters B 35, no. 09 (February 12, 2021): 2150155. http://dx.doi.org/10.1142/s0217984921501554.

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Computational enzyme design has made great strides over the last five years. Traditional methods of enzyme design require synthesis and evaluation of many mutations. Computational enzyme design has emerged as a powerful tool to predict how specific mutations modify a protein’s activity, stability, and/or selectivity. Such computational approaches can evaluate many mutations and reduce the load of in vitro work by identifying mutations likely to accomplish design objectives. Computational approaches can explore mutational spaces inaccessible in traditional mutagenesis. Computational methods reduce cost and time compared with experimental approaches. We review the efficacy and key differences of computational enzyme design methods as published in recent studies. The included articles used computational methods to design enzymes, were published no earlier than 2015, met design objectives, and verified results in vitro.

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Perutz, M. F. "Mutations make enzyme polymerize." Nature 385, no. 6619 (February 1997): 773–75. http://dx.doi.org/10.1038/385773a0.

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Klesmith, Justin R., John-Paul Bacik, Emily E. Wrenbeck, Ryszard Michalczyk, and Timothy A. Whitehead. "Trade-offs between enzyme fitness and solubility illuminated by deep mutational scanning." Proceedings of the National Academy of Sciences 114, no. 9 (February 14, 2017): 2265–70. http://dx.doi.org/10.1073/pnas.1614437114.

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Proteins are marginally stable, and an understanding of the sequence determinants for improved protein solubility is highly desired. For enzymes, it is well known that many mutations that increase protein solubility decrease catalytic activity. These competing effects frustrate efforts to design and engineer stable, active enzymes without laborious high-throughput activity screens. To address the trade-off between enzyme solubility and activity, we performed deep mutational scanning using two different screens/selections that purport to gauge protein solubility for two full-length enzymes. We assayed a TEM-1 beta-lactamase variant and levoglucosan kinase (LGK) using yeast surface display (YSD) screening and a twin-arginine translocation pathway selection. We then compared these scans with published experimental fitness landscapes. Results from the YSD screen could explain 37% of the variance in the fitness landscapes for one enzyme. Five percent to 10% of all single missense mutations improve solubility, matching theoretical predictions of global protein stability. For a given solubility-enhancing mutation, the probability that it would retain wild-type fitness was correlated with evolutionary conservation and distance to active site, and anticorrelated with contact number. Hybrid classification models were developed that could predict solubility-enhancing mutations that maintain wild-type fitness with an accuracy of 90%. The downside of using such classification models is the removal of rare mutations that improve both fitness and solubility. To reveal the biophysical basis of enhanced protein solubility and function, we determined the crystallographic structure of one such LGK mutant. Beyond fundamental insights into trade-offs between stability and activity, these results have potential biotechnological applications.

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Salverda, Merijn L. M., Jeroen Koomen, Bertha Koopmanschap, Mark P. Zwart, and J. Arjan G. M. de Visser. "Adaptive benefits from small mutation supplies in an antibiotic resistance enzyme." Proceedings of the National Academy of Sciences 114, no. 48 (November 13, 2017): 12773–78. http://dx.doi.org/10.1073/pnas.1712999114.

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Populations with large mutation supplies adapt via the “greedy” substitution of the fittest genotype available, leading to fast and repeatable short-term responses. At longer time scales, smaller mutation supplies may in theory lead to larger improvements when distant high-fitness genotypes more readily evolve from lower-fitness intermediates. Here we test for long-term adaptive benefits from small mutation supplies using in vitro evolution of an antibiotic-degrading enzyme in the presence of a novel antibiotic. Consistent with predictions, large mutant libraries cause rapid initial adaptation via the substitution of cohorts of mutations, but show later deceleration and convergence. Smaller libraries show on average smaller initial, but also more variable, improvements, with two lines yielding alleles with exceptionally high resistance levels. These two alleles share three mutations with the large-library alleles, which are known from previous work, but also have unique mutations. Replay evolution experiments and analyses of the adaptive landscape of the enzyme suggest that the benefit resulted from a combination of avoiding mutational cohorts leading to local peaks and chance. Our results demonstrate adaptive benefits from limited mutation supplies on a rugged fitness landscape, which has implications for artificial selection protocols in biotechnology and argues for a better understanding of mutation supplies in clinical settings.

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Puranen, T. J., M. H. Poutanen, H. E. Peltoketo, P. T. Vihko, and R. K. Vihko. "Site-directed mutagenesis of the putative active site of human 17β-hydroxysteroid dehydrogenase type 1." Biochemical Journal 304, no. 1 (November 15, 1994): 289–93. http://dx.doi.org/10.1042/bj3040289.

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Several amino acid residues (Cys54, Tyr155, His210, His213 and His221) at a putative catalytic site of human 17 beta-hydroxysteroid dehydrogenase type 1 were mutated to Ala. Replacement of His221 by Ala remarkably reduced the catalytic activity, which resulted from a change of both the Km and the Vmax. values of the enzyme. Compared with the wild-type enzyme, the catalytic efficiency of the His221-->Ala mutant was reduced 20-fold for the oxidative reaction and 11-fold for the reductive reaction. With similar mutations at His210 or His213, no notable effects on the catalytic properties of the enzyme were detected. However, a simultaneous mutation of these amino acid residues decreased the Vmax. values of both oxidation and reduction by about 50% from those measured for the wild-type enzyme. Although Cys54 has been localized in the cofactor-binding region of the enzyme, a Cys54-->Ala mutation did not lead to changes in the enzymic activity. The most dramatic effects on the catalytic properties of the enzyme were achieved by mutating Tyr155, which resulted in an almost completely inactivation of the enzyme. The decreased enzymic activities of the Tyr155-->Ala, His210-->Ala + His213-->Ala and His221-->Ala mutations were also reflected in a reduced immunoreactivity of the enzymes. The results thus suggest that the lower catalytic efficiency of the mutant enzymes is due to an exchange of catalytically important amino acid residues and/or remarkable alterations in the three-dimensional structure of the enzyme. The recently detected polymorphisms (Ala237<-->Val and Ser312<-->Gly) were not found to affect either the catalytic or the immunological properties of the type 1 enzyme.

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NJÅLSSON, Runa, Katarina CARLSSON, Vikas BHANSALI, Jia-Li LUO, Lennart NILSSON, Rudolf LADENSTEIN, Mary ANDERSON, Agne LARSSON, and Svante NORGREN. "Human hereditary glutathione synthetase deficiency: kinetic properties of mutant enzymes." Biochemical Journal 381, no. 2 (July 6, 2004): 489–94. http://dx.doi.org/10.1042/bj20040114.

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Patients with hereditary glutathione synthetase deficiency suffer from haemolytic anaemia, 5-oxoprolinuria, metabolic acidosis, recurrent bacterial infections and various degrees of central nervous system dysfunction. To investigate the molecular basis of the mutations associated with this disease, seven naturally occurring missense mutations [L188P (Leu188→Pro), D219A, D219G, Y270C, Y270H, R283C and P314L] were expressed using a His-tagged, Escherichia coli-based expression system. Effects of the mutations on kinetic properties, including negative co-operative binding of γ-glutamyl substrate, were evaluated. The mutation P314L did not have any major effect on these parameters and was classified as a neutral mutation. The remaining mutations decreased Vmax to 2–27% of wild-type activity. Negative co-operativity for γ-gluABA (L-γ-glutamyl-L-α-aminobutyric acid) was abolished in five mutant recombinant enzymes, whereas for one mutant enzyme, this co-operativity changed from negative to positive. The structural consequences of the mutations were interpreted on the basis of the known structure of the wild-type enzyme.

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Yanase, Michiyo, Hiroki Takata, Kazutoshi Fujii, Takeshi Takaha, and Takashi Kuriki. "Cumulative Effect of Amino Acid Replacements Results in Enhanced Thermostability of Potato Type L α-Glucan Phosphorylase." Applied and Environmental Microbiology 71, no. 9 (September 2005): 5433–39. http://dx.doi.org/10.1128/aem.71.9.5433-5439.2005.

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ABSTRACT The thermostability of potato type L α-glucan phosphorylase (EC 2.4.1.1) was enhanced by random and site-directed mutagenesis. We obtained three single-residue mutations—Phe39→Leu (F39L), Asn135→Ser (N135S), and Thr706→Ile (T706I)—by random mutagenesis. Although the wild-type enzyme was completely inactivated, these mutant enzymes retained their activity even after heat treatment at 60°C for 2 h. Combinations of these mutations were introduced by site-directed mutagenesis. The simultaneous mutation of two (F39L/N135S, F39L/T706I, and N135S/T706I) or three (F39L/N135S/T706I) residues further increased the thermostability of the enzyme, indicating that the effect of the replacement of the residues was cumulative. The triple-mutant enzyme, F39L/N135S/T706I, retained 50% of its original activity after heat treatment at 65°C for 20 min. Further analysis indicated that enzymes with a F39L or T706I mutation were resistant to possible proteolytic degradation.

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Bebenek, Anna, Geraldine T. Carver, Holly Kloos Dressman, Farid A. Kadyrov, Joseph K. Haseman, Vasiliy Petrov, William H. Konigsberg, Jim D. Karam, and John W. Drake. "Dissecting the Fidelity of Bacteriophage RB69 DNA Polymerase: Site-Specific Modulation of Fidelity by Polymerase Accessory Proteins." Genetics 162, no. 3 (November 1, 2002): 1003–18. http://dx.doi.org/10.1093/genetics/162.3.1003.

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Abstract Bacteriophage RB69 encodes a replicative B-family DNA polymerase (RB69 gp43) with an associated proofreading 3′ exonuclease. Crystal structures have been determined for this enzyme with and without DNA substrates. We previously described the mutation rates and kinds of mutations produced in vivo by the wild-type (Pol+ Exo+) enzyme, an exonuclease-deficient mutator variant (Pol+ Exo-), mutator variants with substitutions at Tyr567 in the polymerase active site (PolM Exo+), and the double mutator PolM Exo-. Comparing the mutational spectra of the Pol+ Exo- and Pol+ Exo+ enzymes revealed the patterns and efficiencies of proofreading, while Tyr567 was identified as an important determinant of base-selection fidelity. Here, we sought to determine how well the fidelities of the same enzymes are reflected in vitro. Compared to their behavior in vivo, the three mutator polymerases exhibited modestly higher mutation rates in vitro and their mutational predilections were also somewhat different. Although the RB69 gp43 accessory proteins exerted little or no effect on total mutation rates in vitro, they strongly affected mutation rates at many specific sites, increasing some rates and decreasing others.

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Patel, Meha P., Bartlomiej G. Fryszczyn, and Timothy Palzkill. "Characterization of the Global Stabilizing Substitution A77V and Its Role in the Evolution of CTX-M β-Lactamases." Antimicrobial Agents and Chemotherapy 59, no. 11 (August 17, 2015): 6741–48. http://dx.doi.org/10.1128/aac.00618-15.

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ABSTRACTThe widespread use of oxyimino-cephalosporin antibiotics drives the evolution of the CTX-M family of β-lactamases that hydrolyze these drugs and confer antibiotic resistance. Clinically isolated CTX-M enzymes carrying the P167S or D240G active site-associated adaptive mutation have a broadened substrate profile that includes the oxyimino-cephalosporin antibiotic ceftazidime. The D240G substitution is known to reduce the stability of CTX-M-14 β-lactamase, and the P167S substitution is shown here to also destabilize the enzyme. Proteins are marginally stable entities, and second-site mutations that stabilize the enzyme can offset a loss in stability caused by mutations that enhance enzyme activity. Therefore, the evolution of antibiotic resistance enzymes can be dependent on the acquisition of stabilizing mutations. The A77V substitution is present in CTX-M extended-spectrum β-lactamases (ESBLs) from a number of clinical isolates, suggesting that it may be important in the evolution of antibiotic resistance in this family of β-lactamases. In this study, the effects of the A77V substitution in the CTX-M-14 model enzyme were characterized with regard to the kinetic parameters for antibiotic hydrolysis as well as enzyme expression levelsin vivoand protein stabilityin vitro. The A77V substitution has little effect on the kinetics of oxyimino-cephalosporin hydrolysis, but it stabilizes the CTX-M enzyme and compensates for the loss of stability resulting from the P167S and D240G mutations. The acquisition of global stabilizing mutations, such as A77V, is an important feature in β-lactamase evolution and a common mechanism in protein evolution.

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Kapoor, Ritika R., Sarah E. Flanagan, Piers Fulton, Anupam Chakrapani, Bernadette Chadefaux, Tawfeg Ben-Omran, Indraneel Banerjee, Julian P. Shield, Sian Ellard, and Khalid Hussain. "Hyperinsulinism–hyperammonaemia syndrome: novel mutations in the GLUD1 gene and genotype–phenotype correlations." European Journal of Endocrinology 161, no. 5 (November 2009): 731–35. http://dx.doi.org/10.1530/eje-09-0615.

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BackgroundActivating mutations in the GLUD1 gene (which encodes for the intra-mitochondrial enzyme glutamate dehydrogenase, GDH) cause the hyperinsulinism–hyperammonaemia (HI/HA) syndrome. Patients present with HA and leucine-sensitive hypoglycaemia. GDH is regulated by another intra-mitochondrial enzyme sirtuin 4 (SIRT4). Sirt4 knockout mice demonstrate activation of GDH with increased amino acid-stimulated insulin secretion.ObjectivesTo study the genotype–phenotype correlations in patients with GLUD1 mutations. To report the phenotype and functional analysis of a novel mutation (P436L) in the GLUD1 gene associated with the absence of HA.Patients and methodsTwenty patients with HI from 16 families had mutational analysis of the GLUD1 gene in view of HA (n=19) or leucine sensitivity (n=1). Patients negative for a GLUD1 mutation had sequence analysis of the SIRT4 gene. Functional analysis of the novel P436L GLUD1 mutation was performed.ResultsHeterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). In addition, a patient with a normal serum ammonia concentration (21 μmol/l) was heterozygous for a novel missense mutation P436L. Functional analysis of this mutation confirms that it is associated with a loss of GTP inhibition. Seizure disorder was common (43%) in our cohort of patients with a GLUD1 mutation. No mutations in the SIRT4 gene were identified.ConclusionPatients with HI due to mutations in the GLUD1 gene may have normal serum ammonia concentrations. Hence, GLUD1 mutational analysis may be indicated in patients with leucine sensitivity; even in the absence of HA. A high frequency of epilepsy (43%) was observed in our patients with GLUD1 mutations.

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Dissertations / Theses on the topic "Enzyme mutations"

Chen, Wei 1965. "Site Directed Mutagenesis Of Dienelactone Hydrolase." Thesis, University of North Texas, 1992. https://digital.library.unt.edu/ark:/67531/metadc500900/.

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The role of individual amino acid residues of the enzyme dienelactone hydrolase was investigated. Using the polymerase chain reaction (PCR), a 1.9 kbp clcD fragment was amplified and subcloned yielding a 821 bp BamHI to EcoRI clcD subclone in the plasmid pUC19. Site-specific mutants of dienelactone hydrolase were created using mismatched oligonucleotides to prime DNA synthesis. Specifically modified proteins from mutated clcD genes (Arg 81 to alanine, Tyr 85 to phenylalanine and Arg 206 to alanine), were encoded by the mutant clones. Enzyme assays showed that dienelactone hydrolase activity of the mutants Arg 81 and Arg 206 was totally abolished. The DLHase enzyme activity of mutant Tyr 85 is greatly decreased by approximately two thirds.

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Hira, Asuka. "Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi Anemia." Kyoto University, 2015. http://hdl.handle.net/2433/202672.

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Daar, Shahina Firdos. "Haemoglobinopathies in the Sultanate of Oman : a study of clinically significant beta globin gene mutations." Thesis, University of Bristol, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340440.

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Velusamy, Mahesh. "New computational approaches for investigating the impact of mutations on the transglucosylation activity of sucrose phosphorylase enzyme." Thesis, La Réunion, 2018. http://www.theses.fr/2018LARE0045.

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Comprendre comment les mutations impactent l’activité d’une protéine reste un défi dans le domaine des sciences protéiques. Les méthodes biochimiques traditionnellement utilisées pour résoudre ce type de questionnement sont très puissantes mais sont laborieuses à mettre en œuvre. Des approches bioinformatiques ont été développées à cet égard pour surmonter ces contraintes. Dans cette thèse, nous explorons l'utilisation d'approches bioinformatiques pour comprendre le lien entre mutations et changements d'activité. Notre modèle d'étude est une enzyme bactérienne, la sucrose phosphorylase de Bifidobacterium adolescentis (BaSP). Cette glycosyl-hydrolase de la famille 13 (GH13) suscite l’intérêt de l'industrie en raison de sa capacité à synthétiser des disaccharides et des glycoconjugués originaux. Son activité consiste à transférer un glucose d'un donneur, le saccharose, à un accepteur qui peut être un monosaccharide ou un aglycone hydroxylé. La réaction enzymatique se déroule selon un mécanisme dit « double déplacement avec rétention de configuration », ce qui nécessite la formation d'un intermédiaire covalent dit glucosyl-enzyme. Cependant, la possibilité de contrôler la régiosélectivité de ce transfert pour qu'il soit applicable au niveau industriel est un enjeumajeur. Cette thèse vise d’une part, à fournir une explication rationnelle quant aux modifications de la régiosélectivité de BaSP apportées par des mutations et d’autre part à proposer un canevas pour le contrôle de la régiosélectivité de couplage en vue de la synthèse de disaccharides pré-biotiques rares comme le kojibiose et le nigerose. Dans notre approche, nous avons émis l'hypothèse que les orientations préférées de l'accepteur dans le site catalytique après formation du glycosyl-enzyme déterminent la régiosélectivité de l'enzyme. Nous avons utilisé des approches computationnelles pour étudier l'impact des mutations sur la liaison de l'accepteur à l'intermédiaire covalent, le glucosylenzyme. À cette fin, nous avons construit des modèles à l’échelle atomique du glucosyl-enzyme pour un ensemble de variants de la BaSP pour lesquels des données expérimentales étaient disponibles. Pour y parvenir, nous avons paramétré le glucosyl-aspartyle en tant que nouveau résidu et les avons intégré dans des outils de modélisation tels que Modeller et Gromacs. Nous avons évalué la pertinence de ces paramètres et les avons ensuite appliqués à la vérification de notre hypothèse de travail par le biais d’expériences d'ancrage moléculaire. La méthodologie utilisée dans ce travail ouvre la perspective de l'utilisation d'approches bioinformatiques pour l'ingénierie de la régiosélectivité de la sucrose phosphorylase et plus généralement des glycosylhydrolases possédant un mécanisme similaire. À cet égard, un pipeline de modélisation moléculaire et d'amarrage de molécules accepteurs sur des intermédiaires covalents des enzymes de cette famille (ENZO pour Optimisation d’ENZyme) a été développé au cours de cette thèse. Son application à l’ingénierie d’autres variants de BaSP est en cours
In this thesis, we explore the usage of computational approaches for understanding the link between mutations and changes in protein activity. Our study model is a bacterial sucrose phosphorylase enzyme from Bifidobacterium adolescentis (BaSP). This glycosyl hydrolase from family 13 (GH13) has been a focus in the industry due to its ability to synthesize original disaccharides and glycoconjugates. In fact, its activity is to transfer a glucose moiety from a donor sucrose to an acceptor which can be a monosaccharide or a hydroxylated aglycone. The enzymatic reaction proceeds by a double displacement with retention of configuration mechanism whereby a covalent glucosyl-enzyme intermediate is formed. However, it is at stake to control the regioselectivity of this transfer for it to be applicable at industrial level. This thesis aimed at providing a rational explanation for the observed impact of mutations on the regioselectivity of BaSP in view of controlling the synthesis of rare pre-biotic disaccharides like kojibiose and nigerose. We hypothesized that the preferred orientations of the acceptor determines the regioselectivity of the enzyme. In that respect, we used computational approaches to investigate the impact of mutations on the binding of the acceptor to the glucosyl-enzyme intermediate. The methodology used in this work opens the perspective of using computational approaches for engineering the regioselectivity of of glycosyl hydrolases with similar mechanism

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Al-Dbass, Abeer M. "Structural basis of acute intermittent porphyria and the relationship between mutations in human porphobilinogen deaminase and enzyme activity." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390590.

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Hammed, Abdessalem. "Résistance de cible aux antivitamines KR : analyse des conséquences catalytiques de différentes mutations de VKORC1 et, : étude du rôle d’une nouvelle enzyme, la VKORC1L1." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10025/document.

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Les anticoagulants antivitamine K (AVK) sont destinées à limiter la coagulation du sang. Ils sont donc susceptibles de provoquer des saignements. Les AVK ralentissent le cycle de la vitamine K qui est indispensable à la gamma-carboxylation de certaines protéines (PVKD). Les AVK inhibent l'activité vitamine K époxide reductase (VKOR), principalement catalysée par VKORC1. Ce sont des médicaments anticoagulants utilisés chez l'homme. Chez les rongeurs, ils servent de rodonticides. Une résistance aux AVK est observé tant chez l'homme que chez le rongeur.Chez des patients résistants aux AVK, 26 mutations ont été décrites dans la zone codante de VKORC1. L'expression hétérologue de ces enzymes mutées n'a permis de trouver que 6 mutations impliquées dans la résistance. Repérer ces mutations avant le début d'un traitement permettra une mise en place du traitement plus rapide. Les autres mutations ne seraient pas responsables du phénotype observé.La VKORC1L1 a été décrite comme une protéine agissant contre le stress oxydatif. Notre travail confirme que l'enzyme catalyse la réaction VKOR. Si sa participation dans la réduction de la vitamine K époxide est insignifiante dans le foie, il en est tout autrement dans les autres tissus testés. De plus, la VKORC1L1 apparait plus résistante aux AVK par rapport à la VKORC1. Ces propriétés catalytiques de la VKORC1L1 permettent d'expliquer l'absence d'effets des AVK sur les PVKD d'origine extra-hépatiques.Enfin, un travail de mutagénèse dirigée a permis d'abaisser ou d'augmenter considérablement la sensibilité de VKORC1L1 aux AVK. Ces résultats nous permettent de décrire l'implication de différents acides aminés dans l'interaction avec les AVK
Anticoagulant vitamin K antagonists (VKA) are molecules designed to prevent or delay blood clotting. They cause bleeding by slowing the recycling of vitamin K, an essential micronutrient for posttranslational modification of specific proteins (VKDP). It has been shown that VKA specifically inhibit VKORC1 enzyme which catalyze the VKOR reaction. VKA are used as rodenticides to control the proliferation of populations of pest rodents. In humans, they are used in the treatment and prevention of the occurrence of thromboembolic events. Due to the widespread use of these VKA, it was observed a phenomenon of resistance which is essential to better understand for economic, ecological or public health interests. In humans, 25 of 26 mutations were characterized. While these changes have been observed in patients resistant to VKA, the causality of these mutations has been demonstrated for 6 mutations. The ability to detect these changes before the start of treatment will allow the future implementation of the much faster and less expensive. Other mutations are not responsible for the observed phenotype.Moreover, VKORC1L1 has been described as an enzyme whose function is to act against oxidative stress. This study confirms that the enzyme catalyzes the VKOR reaction. If it appears that the liver in its participation in the reduction of vitamin K epoxide is insignificant, it is quite different in other tissues tested. In addition, VKORC1L1 appears more resistant to VKA over the VKORC1. Finally, directed mutagenesis of these residues lead to the decrease or the increase of VKORC1L1 sensitivity to VKA. These data result to the implication of residues in their interaction with VKA

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Nord, Emilia. "Optimization of a Multiplex PCR-RFLP Method Used for Detection of Three Primary Mutations in Leber’s Hereditary Optic Neuropathy Patients." Thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-412744.

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Leber’s hereditary optic neuropathy (LHON) is the most commonly inherited disease that causes blindness in one or both eyes, with a minimum prevalence of 1 in 31 000 in the northeast of England. What causes LHON is not fully known but three mitochondrial mutations, G3460A, G11778A, and T14484C, have been identified in over 95 % of all LHON patients. To diagnose LHON, detection methods like sequencing, allele specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) are used to identify these three mutations. The methods are now evolving into multiplex ones to increase efficiency, the aim of this study was therefore to optimize one of them, a multiplex PCR-RFLP method developed in 2015. This study was however not completed, due to the COVID-19 pandemic, but a series of preparatory steps were performed before its termination. DNA extraction was performed, both genomic and plasmid, using a kit and in-house protocols. The DNA was then used for polymerase chain reactions (PCRs), for both the human β-globin gene and for the three mutations, where magnesium concentration and annealing temperature was optimized. This study resulted in clear, high quality extractions, with the kit as the preferable method. It also indicated that a 3 mM magnesium concentration and an annealing temperature of 59 °C was optimal for all mutations when using so called LHON primers. The conditions for the PCR using the multiplex primers might be different, therefore a new study is required to evaluate the multiplex PCR-RFLP method further.
Bakgrund: Lebers hereditära optikusneuropati (LHON) är en vanlig ärftlig sjukdom som orsakar blindhet. LHON orsakas i över 95 % av fallen av en av tre mitokondriella mutationer, där en byggsten i mitokondriens DNA felaktigt bytts ut mot en annan. Dessa mutationer heter G3460A, G11778A och T14484C. För att diagnostisera sjukdomen detekteras mutationerna, bland annat genom att extrahera DNA från blod, DNA som man sedan skapar otaliga kopior av genom en metod som heter ”polymerase chain reaction” (PCR). Dessa kopior kan sedan klyvas i bitar med hjälp av enzym och baserat på fragmentens storlek kan det avgöras om personen har mutationen eller inte, detta kallas för ”restriction fragment length polymorphism” (RFLP). I nuläget letar man efter en mutation i taget men det har utvecklats några metoder där man kan hitta alla mutationer på en gång och den här studiens syfte var att undersöka hur man på bästa sätt kan utföra en av dessa metoder, en så kallad multiplex PCR-RFLP. Metod: Studien avbröts i förtid på grund av ett pandemiskt utbrott av COVID-19 men hann omfatta DNA-extraktion från humant blod och bakterier med hjälp av ett kommersiellt kit och laboratoriets egna protokoll. Även PCR utfördes för en normal genuppsättning och de tre mutationerna. Resultat och slutsats: Extraktionen gav bra resultat med alla metoder men det kommersiella kitet gav bäst resultat. PCR med det DNA som extraherats fungerade bara ibland vilket gjorde det svårt att dra några större slutsatser, oavsett krävs fler studier för att undersöka metoden eftersom arbetet inte kunde slutföras.

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Lalève, Anaïs. "Impacts biochimiques et biologiques de mutations dans le gène sdhB codant la sous-unité B de la succinate déshydrogénase chez le champignon phytopathogène Botrytis cinerea." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112077.

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La succinate déshydrogénase (SDH) est à la fois une enzyme clé du cycle de Krebs oxydant le succinate en fumarate et le complexe II de la chaîne respiratoire mitochondriale impliqué dans le transfert des électrons et la réduction de l’ubiquinone. Des inhibiteurs de cette enzyme (SDHI) ont été développés ou sont en cours de développement comme antifongiques. Cette famille de fongicides est notamment utilisée pour lutter contre Botrytis cinerea, champignon phytopathogène responsable de la pourriture grise sur de nombreuses cultures dont la vigne. Des souches résistantes aux SDHI ont été isolées chez B. cinerea et d’autres champignons phytopathogènes. Chez ces isolats résistants, des mutations ont été identifiées dans les gènes codant la SDH. Au cours de cette thèse, nous avons étudié l’impact de mutations affectant la sous-unité B (SdhB) de la succinate déshydrogénase sur l’activité de l’enzyme, la biologie du champignon B. cinerea et la résistance aux inhibiteurs ciblant cette enzyme. Par mutagénèse dirigée du gène sdhB, nous avons obtenu des mutants dits « isogéniques » qui ont permis de confirmer l’implication de ces mutations dans la résistance aux différentes molécules SDHI. Par ailleurs, nos résultats montrent que les modifications de la sous-unité SdhB affectent l’affinité des SDHI pour la SDH et les niveaux d’inhibition de l’activité SDH par les molécules inhibitrices ; ce qui explique - in fine - les spectres de résistance des mutants aux SDHI. Actuellement, tous les mutants sont résistants au boscalid et les mutants les plus fréquemment retrouvés au vignoble, sdhBH272R/Y, sont sensibles au fluopyram. Les travaux réalisés sur les mutants sdhB montrent que les mutations étudiées ont également un impact sur l’activité de l’enzyme et sur le développement du champignon, conséquences dépendantes du résidu substitué et de la substitution. En particulier, les mutations sdhBH272L/R affectent fortement l’activité de l’enzyme et la fitness du champignon alors que le mutant sdhBH272Y est peu affecté. Enfin, l’analyse de populations de pourriture grise de différentes origines (région, plantes hôtes) par rapport à la résistance aux SDHI réalisée sur les années 2009/2010 montre que les mutants sdhBH272R/Y sont toujours les plus fréquents mais leurs fréquences varient en fonction des situations agronomiques. Notamment la fréquence du mutant sdhBH272R augmente avec la pression de sélection exercée par les fongicides. Ce mutant attire particulièrement notre attention du fait de sa relation non linéaire entre fitness et fréquence au champ
Succinate dehydrogenase is both a key enzyme of the TCA cycle, oxidizing succinate into fumarate and complex II of the mitochondrial respiratory chain involved in electron transfer and ubiquinone reduction. Inhibitors of this enzyme (SDHIs) have been developed or are in the developmental process as fungicides. Actually, SDHIs are registered to deal with Botrytis cinerea, a phytopathogenic fungus responsible for grey mold on many crops including grapevine. Strains of B. cinerea and other pathogenic fungi have been isolated for their resistance to SDHI. They mainly harbor mutations in genes encoding SDH subunits. During this thesis, we studied the impact of mutations modifying subunit B of succinate dehydrogenase on enzyme activity, fungal biology and resistance to SDHIs. “Isogenic” mutants obtained through site-directed mutagenesis and homologous recombination allowed us to confirm the role of sdhB mutations in SDHIs resistance. Our results also show that the substitutions in the SdhB subunit impact respectively the affinity of SDHIs to SDH and the inhibition levels of SDH activity by inhibitors, which explain – in fine – the resistance spectra observed for the mutants. Up to now, all sdhB mutants are resistant to boscalid and the most frequent mutants observed in grapevines, sdhBH272R/Y, are susceptible to fluopyram. Studies on sdhB mutants reveal that the mutations also impact the enzymatic activity and the fungal development depending on the substitution. In particular, sdhBH272L/R mutations have the strongest impact on enzyme activity and the fitness of the fungus, whereas these parameters are almost not altered in the sdhBH272Y mutant. Finally, grey mold populations from different origins (country, plant host) were analyzed for their SDHI resistance pheno- and genotypes. Yet, the sdhBH272R/Y mutants were the most frequent, but these frequencies varied according to the agronomical situation. Interestingly, the frequencies of the sdhBH272R mutant seem to increase with the selective pressure exerted by fungicides. This mutant is of particular interest because of the absence of correlation between the fitness we measured and the frequencies we observed in natura

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Sheikh, Qaiser Iftikhar. "Exploring the structure and function of bacterial cytosine specific DNA methyltransferases using site-directed mutagenesis." Thesis, University of Sheffield, 2001. http://etheses.whiterose.ac.uk/10258/.

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Point mutations were engineered into the sequence of the multispecific DNA methyltransferase (Mtase) M. SPRI in motif IX, in order to mimic the corresponding motif IX of mono-specific Mtase. A similar approach was adopted to modify the sequence of the monospecific enzyme M. HhaI in motifs IX and X based on the available structure and as a consequence the enzyme regained methylation potential. It was thought that these changes might be sufficient to enable functional exchange of the target recognition domains (TRDs) between a mono- and a multispecific enzyme. However, insertion of various segments of TRD region from M. SPRI into the M. HhaI was not successful (Chapter 4). To establish whether mono- and multispecific Mtases are incompatible in terms of sequence exchanges, a systematic "swapping" of motifs was carried out (Chapter 5). These experiments suggested that there are some enzyme-specific structural interactions between different subunits within each class of Mtases. In second half of this thesis a bacterial two-hybrid system based on the reversible assembly of an engineered form of M. SPRI was developed (Chapter 6). However the Mtase protein does not assemble into an active species until a DNA segment encoding a leucine zipper motif is fused to each of the two halves. Co-transformation of E. coli with the plasmids expressing the C-terminal and N-terminal domains respectively resulted in the abolition of colonies on double antibiotic plates, when an mcr strain was used as host. High performance liquid chromatography was used to estimate the extent of modification of plasmids indirectly. The extent of methylation at specific sequences within a plasmid molecule was readily detected by the corresponding differential susceptibility to digestion by specific restriction enzymes. Using this approach it proved possible to detect different levels of activity produced by wild type and mutant recombinant DNA Methyltransferases with sensitivity and in a semi quantitative manner. In order to analyse the biochemical properties of Mtase, I have developed an in vitro translation-modification assay. Binary studies with the mutants (from Chapter 3 and 5) showed that there were no detectable sequence-specific recognition differences between these enzymes. Taken together, these results suggest that motif IX plays a role in general stabilisation of the enzyme core structure and has a less significant role in DNA recognition.

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Chitpinityol, Supannee. "Heterologous expression and site-directed mutagenesis of the enzyme chymosin." Thesis, University of Reading, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320101.

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Books on the topic "Enzyme mutations"

Building expert systems: Cognitive emulation. Chichester, West Sussex, England: E. Horwood, 1987.

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Brahm, Amanda J., and Robert A. Hegele. Monogenic Chylomicronemia: Deficiency of Lipoprotein Lipase and Related Factors. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0033.

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Monogenic chylomicronemia is an autosomal recessive condition characterized by severely elevated fasting triglyceride that carries lifelong elevated risk of developing pancreatitis. The majority of cases are caused by mutations in the LPL gene encoding lipoprotein lipase, the enzyme primarily responsible for chylomicron clearance. Mutations in genes encoding associated proteins (APOC2, APOA5, GPIHBP1 and LMF1) may also present with a very similar phenotype. Current management, which includes restriction of dietary fat intake and standard pharmacologic interventions, has met with limited success, but new therapies under development may prove to be more effective.

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Jadon, Deepak R., Tehseen Ahmed, and Ashok K. Bhalla. Disorders of bone mineralization—osteomalacia. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199642489.003.0146_update_001.

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Disorders of bone mineralization cause rickets in children and osteomalacia in adults. Both remain common in developing countries. Incidence in Western countries had declined since the fortification of foodstuffs, but appears to be increasing again. Calcium and inorganic phosphate are the key precursors for bone mineralization and growth. The commonest aetiology of osteomalacia is vitamin D deficiency, primarily due to low dietary intake and inadequate sun exposure. In the last decade gene mutations have been identified that are responsible for inherited rickets and osteomalacia, particularly those that result in phosphate deficiency, hypophosphatasia, and vitamin D receptor or metabolizing enzyme mutations. Additionally, the pathogenesis of tumour-induced osteomalacia is becoming better understood. Osteomalacia may present as bone pain and tenderness, muscle pain and weakness, and skeletal deformity or fracture. Key investigations include biochemical assessment and plain radiographs. Radioisotope bone scans and bone biopsy may be considered in selected cases. Differential diagnoses include osteoporosis, seronegative arthritides, and localized soft tissue disorders. Treatment, guided by the underlying aetiology, aims to reduce symptoms, fracture risk, bone deformity and sequelae. Vitamin D deficient patients require vitamin D and calcium replacement.

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Jadon, Deepak R., Tehseen Ahmed, and Ashok K. Bhalla. Disorders of bone mineralization—osteomalacia. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0146.

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Frenkel, Joost, and Hans R. Waterham. Mevalonate Kinase Deficiency. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0039.

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Mevalonate kinase deficiency (MKD) is an autosomal recessive inborn error of isoprenoid biosynthesis, a pathway yielding sterols and nonsterol isoprenoids.In patients, the enzyme activity of mevalonate kinase is severely reduced due to mutations in the encoding gene, MVK. The substrate, mevalonate, accumulates and is elevated in blood and urine. Shortage of certain downstream products of the pathway, nonsterol isoprenoids, leads to dysregulation of the innate immune system, activation of inflammasomes, and interleukin (IL)-1 mediated inflammation.Symptoms start in early childhood with recurrent attacks of fever, vomiting, diarrhea, headache, sore throat, abdominal pain, arthralgias, painful lymphadenopathy, hepatosplenomegaly, skin rash, and mucosal ulcers. Severely affected patients have additional symptoms, such as intellectual impairment, progressive cerebellar ataxia, and tapetoretinal degeneration. Complications include intestinal obstruction, AA-amyloidosis, hemophagocytosis, and severe infection.Management of MKD is directed at controlling inflammation.

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Hall, Andrew, and Shamima Rahman. Mitochondrial diseases and the kidney. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0340.

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Mitochondrial disease can affect any organ in the body including the kidney. As increasing numbers of patients with mitochondrial disease are either surviving beyond childhood or being diagnosed in adulthood, it is important for all nephrologists to have some understanding of the common renal complications that can occur in these individuals. Mitochondrial proteins are encoded by either mitochondrial or nuclear DNA (mtDNA and nDNA, respectively); therefore, disease causing mutations may be inherited maternally (mtDNA) or autosomally (nDNA), or can arise spontaneously. The commonest renal phenotype in mitochondrial disease is proximal tubulopathy (Fanconi syndrome in the severest cases); however, as all regions of the nephron can be affected, from the glomerulus to the collecting duct, patients may also present with proteinuria, decreased glomerular filtration rate, nephrotic syndrome, water and electrolyte disorders, and renal tubular acidosis. Understanding of the relationship between underlying genotype and clinical phenotype remains incomplete in mitochondrial disease. Proximal tubulopathy typically occurs in children with severe multisystem disease due to mtDNA deletion or mutations in nDNA affecting mitochondrial function. In contrast, glomerular disease (focal segmental glomerulosclerosis) has been reported more commonly in adults, mainly in association with the m.3243A<G point mutation. Co-enzyme Q10 (CoQ10) deficiency has been particularly associated with podocyte dysfunction and nephrotic syndrome in children. Underlying mitochondrial disease should be considered as a potential cause of unexplained renal dysfunction; clinical clues include lack of response to conventional therapy, abnormal mitochondrial morphology on kidney biopsy, involvement of other organs (e.g. diabetes, cardiomyopathy, and deafness) and a maternal family history, although none of these features are specific. The diagnostic approach involves acquiring tissue (typically skeletal muscle) for histological analysis, mtDNA screening and oxidative phosphorylation (OXPHOS) complex function tests. A number of nDNA mutations causing mitochondrial disease have now been identified and can also be screened for if clinically indicated. Management of mitochondrial disease requires a multidisciplinary approach, and treatment is largely supportive as there are currently very few evidence-based interventions. Electrolyte deficiencies should be corrected in patients with urinary wasting due to tubulopathy, and CoQ10 supplementation may be of benefit in individuals with CoQ10 deficiency. Nephrotic syndrome in mitochondrial disease is not typically responsive to steroid therapy. Transplantation has been performed in patients with end-stage kidney disease; however, immunosuppressive agents such as steroids and tacrolimus should be used with care given the high incidence of diabetes in mitochondrial disease.

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Ng, Dominic S. Familial Lecithin Cholesterol Acyl Transferase Deficiency Syndromes. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0034.

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Lecithin cholesterol ester transferase (LCAT) is the sole enzyme in the circulation that mediates the esterification of free cholesterol (FC) to cholesterol ester (CE) in lipoproteins. Mutations in the LCAT gene result in one of two clinical syndromes: complete LCAT deficiency syndrome, and “fish eye disease.” The former is characterized by a broad spectrum of clinical features, including profound high-density lipoprotein (HDL) deficiency, hypertriglyceridemia, corneal opacities, anemia, neuropathies, and nephropathy. In contrast, fish eye disease patients develop severe HDL deficiency and severe corneal opacities, but the nervous system and kidneys are typically unaffected. Whether there is a predisposition to accelerated coronary heart disease with LCAT deficiency remains controversial. Currently, severe corneal opacities may be treated with corneal transplant. Only anecdotal evidence is available for preventive measures of progressive renal complications. LCAT replacement therapies are under investigation.

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Heidet, Laurence, Bertrand Knebelmann, and Marie Claire Gubler. Alport syndrome. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0324.

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Management of Alport syndrome has in the past been expectant and supportive. Modern hearing aids have substantially improved the function of affected individuals. However, animal data and more recently observational data from Alport registries strongly suggest a protective effect of angiotensin-converting enzyme inhibitors. There is a suggestion that early commencement of treatment may slow progression substantially. These should now be recommended for all with proteinuria, and possibly even before then for those known to harbour mutations certain to cause end-stage renal failure. A very small minority develop the difficult post-transplant complication of Alport anti-glomerular basement membrane disease. This can rarely be treated successfully and leaves some patients on long-term dialysis. However, overall, patients with Alport syndrome have better than average survival and other outcomes than other patients with end-stage renal failure. Most are successfully transplanted. The question of risk to heterozygous carriers from donating kidneys to their affected relatives arises frequently. The risks may be felt acceptable in some circumstances. Additional therapies are under investigation.

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Krueger, Darcy A., and Jamie Capal. Familial CNS Tumor Syndromes. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0136.

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Tuberous sclerosis complex is an autosomal dominant multi-system disease that involves the skin, brain, heart, lungs, and kidneys and is associated with seizures including infantile spasms, intellectual disability, autism and pulmonary and heart disease. Skin lesions can be particularly disfiguring and infantile spasms can be associated with marked cognitive decline. The outlook for patients has improved markedly with the recognition that TSC is caused by upregulation of the mammalian target of rapamycin (mTOR) enzyme, which connects energy needs and supply with cellular and neuronal growth. mTOR is upregulated in TSC because of mutations in hamartin or tuberin, which normally serve as a brake on mTOR. The drug rapamycin is commonly used as an immunosuppressive for patients undergoing kidney transplants; it has also found a new use in patients with TSC. Although the drug is immunosuppressive for non-TSC patients, careful titration of the drug in TSC patients corrects its upregulation but is not particulary immunosuppressive. Additional mTOR inhibitors such as everolimus have been developed and have been shown to be effective for pulmonary disease associated with TSC. Rapamycin in ointment form is dramatically effective in suppressing skin lesions of TSC and studies are underway to test the effect of mTOR inhibitors on seizures, brain tubers, intellect, and features of autism. Infantile spasms associated with TSC are very responsive to vigabatrin.

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Alan, Wiseman, ed. Enzyme induction, mutagen activation, and carcinogen testing in yeast. Chichester, West Sussex, England: E. Horwood, 1987.

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Book chapters on the topic "Enzyme mutations"

Mitraki, Anna, Ben Fane, Cameron Haase-Pettingell, and Jonathan King. "Mutations Affecting Protein Folding and Misfolding in Vivo." In Applications of Enzyme Biotechnology, 129–36. Boston, MA: Springer US, 1991. http://dx.doi.org/10.1007/978-1-4757-9235-5_10.

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Sevag, M. G. "Enzyme Problems in Relation to Chemotherapy, “Adaptation,” Mutations, Resistance, and Immunity." In Advances in Enzymology - and Related Areas of Molecular Biology, 33–127. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2006. http://dx.doi.org/10.1002/9780470122518.ch2.

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Varfolomeev, Sergey, Bella Grigorenko, Sofya Lushchekina, Patrick Masson, Galina Mahaeva, Dana Novichkova, and Alexander Nemuchin. "Study and modeling of mechanisms of cholinesterasis reactions in order to improve their catalytic properties in the neutralization reactions of organophosphorus compounds." In ORGANOPHOSPHORUS NEUROTOXINS, 140–80. ru: Publishing Center RIOR, 2020. http://dx.doi.org/10.29039/23_140-180.

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“Biocleaners” or “bioscavengers” are biological objects (enzymes, catalytic antibodies) that are capable of binding and/or hydrolyzing organophosphorus compounds (OPC). Their use seems to be the most effective alternative to traditional antidotes to neutralize or detoxify OPC. The introduction of bioscavengers allows neutralizing toxicant molecules in the bloodstream before they reach their biological targets, thereby providing protection against poisoning. Bioscavengers of the first-generation neutralized OPC molecules by stoichiometrically binding to them. The safety and efficacy of human butyrylcholinesterase (BChE) for protecting against OPC poisoning has been shown. However, the stoichiometric neutralization of OPC requires the introduction of a huge amount of expensive biopharmaceuticals. Catalytic bioscavengers that hydrolytically neutralize OPC were introduced at a much lower dose to achieve the same degree of effectiveness. The most effective catalytic bioscavengers are enzymes. The most promising enzymes are artificial mammalian paraoxonase mutants and bacterial phosphotriesterases. However, studies of other enzymes, such as prolidases, oxidases, artificial mutants of cholinesterases and carboxyl esterases and catalytic antibodies are actively ongoing. Since OPC are pseudosubstrates of cholinesterases (ChEs), a detailed description of the mechanisms of inhibition, dealkylation, and spontaneous reactivation of phosphorylated ChEs is critical for the development of ChEs mutants with a high rate of hydrolysis of OPC. The review presents an analysis of different views on the mechanisms of interaction of ChEs with OPC, discusses the possible directions of creating effective catalytic biological traps based on BChE and changes in their mechanism of action as compared to the native enzyme. A separate section is devoted to the effect of mutations, both polymorphic and artificial, on the stability of the protein molecule of BChE.

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Varfolomeev, Sergey, Bella Grigorenko, Sofya Lushchekina, Patrick Masson, Galina Mahaeva, Dana Novichkova, and Alexander Nemuchin. "Study and modeling of mechanisms of cholinesterasis reactions in order to improve their catalytic properties in the neutralization reactions of organophosphorous compounds." In Organophosphorous Neurotoxins, 134–74. ru: Publishing Center RIOR, 2020. http://dx.doi.org/10.29039/chapter_5e4132b603bfc4.70818543.

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Medina, J. F., A. Wetterholm, O. RåDmark, R. Shapiro, J. Z. HaeggströM, B. L. Vallee, and B. Samuelsson. "Mutations of the Three Zinc-Ligands of Leukotriene A4 Hydrolase: Effects on Zinc Content and Enzyme Activities." In Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation and Radiation Injury, 43–46. Boston, MA: Springer US, 1993. http://dx.doi.org/10.1007/978-1-4615-3520-1_10.

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Panigrahi, Sunitha, Syed Rizwan Hasan Razvi, and Syeda Rabia Mariyam. "Insilico Characterization of the Mutational Hotspot Regions of the Enzyme Protease and an Insight to the Effect of These Mutations on the Stability of the Protein." In Next Generation DNA Led Technologies, 123–34. Singapore: Springer Singapore, 2015. http://dx.doi.org/10.1007/978-981-287-670-6_14.

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Kirby, Lorne T. "Probes, Allele Mutations, and Restriction Enzymes." In DNA Fingerprinting, 135–47. London: Palgrave Macmillan UK, 1990. http://dx.doi.org/10.1007/978-1-349-12040-6_7.

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Burkart-Waco, Diana, Isabelle M. Henry, Kathie Ngo, Luca Comai, and Thomas H. Tai. "Determining Mutation Density Using Restriction Enzyme Sequence Comparative Analysis (RESCAN)." In Biotechnologies for Plant Mutation Breeding, 305–21. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-45021-6_19.

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Bikker, Hennie, and Jan J. M. de Vijlder. "Severe Congenital Hypothyroidism Caused by Mutations in the Thyroid Peroxidase Gene." In The Peroxidase Multigene Family of Enzymes, 133–35. Berlin, Heidelberg: Springer Berlin Heidelberg, 2000. http://dx.doi.org/10.1007/978-3-642-58314-8_18.

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Petrides, Petro E., Susanne Bock, and Chuanbing Zang. "Mutation Analysis for Genotype-Phenotype Relationships in Myeloperoxidase Deficiency." In The Peroxidase Multigene Family of Enzymes, 166–72. Berlin, Heidelberg: Springer Berlin Heidelberg, 2000. http://dx.doi.org/10.1007/978-3-642-58314-8_23.

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Conference papers on the topic "Enzyme mutations"

Higuchi, M., L. Kochhan, R. Schwaab, H. H. Brackmann, H. Egli, and K. Olek. "DETECTION OF MUTATIONS IN HEMOPHILIA A." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644012.

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Hemophilia A (HA) is a x-linked bleeding disordercaused by lack or abnormality of factor VIII:C. Because of the heterogeneity of the clinical picture thedisease might result from many different molecular lesions.We examined 202 patients of HA from 160 families by restriction analysis with Taq I, Msp I and EcoR I using three subcloned cDNA fragments of factor VIII:C.We detected 13 mutations within the factor VI11:C gene. All of these patients suffer from the severe form of HA.Table I shows six deletions which we characterized. We also identified seven point mutations on four different exons using restriction enzyme Taq I. The results are shown in Table II.That means in approximately 3.8% of the patients we found deletions and in 4.4% we found point mutations.This confirms the results of Youssofian et al (1986):These authors consider the CpG-dimer as a mutation hotspot in the factor VI11:C gene.

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HOUK, KENDALL N. "COMPUTATIONAL ENZYME DESIGN AND METHODS TO PREDICT THE ROLE OF REMOTE MUTATIONS." In 23rd International Solvay Conference on Chemistry. WORLD SCIENTIFIC, 2014. http://dx.doi.org/10.1142/9789814603836_0011.

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Fabiano, Julia, Gabriela Chiaramida, Mira Magner, Meghan O'Connor, Joseph Stallone, Nicholas DiDuca, Kathryn Neville, Richard Tartarini, and Marla Tipping. "Abstract 1827: UsingDrosophilato study the role of metabolic enzyme mutations in glioblastoma and leukemia." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1827.

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Rabiet, M. J., B. C. Furie, and B. Furie. "MOLECULAR DEFECT IN PROTHROMBIN MADRID: SUBSTITUTION OF ARGININE 273 BY CYSTEINE PRECLUDES ACTIVATION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643936.

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Prothrombin Madrid, a mutant prothrombin, was detected in a patient with a excessive bleeding history. The defect was characterized by a low coagulant activity contrasting with a normal level of prothrombin antigen in plasma. Activation of the purified protein was impaired by the absence of one of the two factor Xa catalyzed cleavages, generating meizothrombin which expressed a thrombin-like activity but was inactive on fibrinogen (Guillin et al., Ann. N.Y. Acad. Sci. 370:414, 1981). Prothrombin and prothrombin Madrid were isolated directly from plasma, with high yield, by immunoaffinity chromatography using conformation specific antibodies immobilized on Sepharose. After reduction and alkylation, purified proteins were hydrolyzed by trypsin. Resulting peptides were separated by reverse phase HPLC. Comparison of the two peptide maps showed that the prothrombin Madrid digest contained an additional peptide, identified by automated Edman degradation as residues 269 to 287 in prothrombin with the substitution of cysteine for arginine at position 273. Peptide 274—287, present in the prothrombin digest, was missing in the prothrombin Madrid digest. The mutation, precluding cleavage by factor Xa and normal generation of thrombin, is identical to the one described for prothrombin Barcelona. The two patients families are not related, raising the possibility that the gene coding for the cysteine 273 mutation in prothrombin is more common than anticipated. Of the seven mutants of vitamin E-dependant blood clotting proteins structurally characterized to date, three are functionally defective due to the presence of the propeptide on the mature amino-ternfinus (factor IX Cambridge, Oxford 3 and San Dimas) and three are due to an alteration that precludes zymogen activation (faotor TX Chapel Hill, prothrombin Barcelona and Madrid). This sample remains too small to anticipate the different classes of point mutations seen in the human population but functional abnormalities of protein processing, metal and lipid binding, zymogen activation, substrate recognition and enzyme catalysis will likely be important phenotypes. However genetic defects may be limited to a discrete group of point mutations that have significant functional implication for the proteins

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Smith, Peter G., Michael Thomas, Tary Traore, Usha Narayanan, Jessica Riceberg, Ben Amidon, Neil Bence, et al. "Abstract C28: Treatment emergent mutations in NAEbeta confer resistance to the investigational NEDD8-activating enzyme inhibitor MLN4924." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1535-7163.targ-11-c28.

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Boikos, Sosipatros A., Paraskevi Xekouki, Fabio R. Faucz, Karel Pacak, Margarita Raygada, Karen Adams, Evan Szarek, et al. "Abstract 568: Few Carney's Triad patients have mutations in two subunits of the succinate dehydrogenase enzyme (SDHB, SDHC)." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-568.

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Reitsma, P. H., A. M. Riemens, R. M. Bertina, and E. Briít. "PROMOTOR MUTATIONS IN A PATIENT WITH HAEMOPHILIA B LEYDEN." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643870.

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Haemophilia B Leyden is characterized by low levels of factor IX antigen and activity before the age of 15, whereas after puberty factor IX levels rise at a rate of about 4-5% per year. To date such a genetic variant of factor IX synthesis has been reported in two (probably related) Dutch families, in a Greek and in an American family of Armenian descent. Laboratory and clinical investigations indicate that the factor IX protein is normal but that the regulation of factor IX synthesis has come under the control of the steroid hormone testosterone. We have started to investigate the factor IX gene in a patient from a Dutch family in an attempt to explain the aberrant regulation.Southern blotting revealed no gross deletions or insertions in the factor IX gene. Therefore the promotor region of the factor IX gene was cloned and subjected to a detailed restriction enzyme analysis. This also did not indicate that significant DNA deletions or insertions had occurred. Subsequently we established the nucleotide sequence of the DNA surrounding the first exon which encompassed about 600 basepairs of the promotor region. Two deviations from previously published sequence data were recorded. Firstly, an A T change was noted in the presumed "tata" box region 20 basepairs upstream from the start site of mRNA synthesis. Secondly, at position −423 a T C change was found which lies 13 basepairs upstream from a potential alternative "tata" box.The point mutation at position −20 might well explain the failure of gene expression during the prepuberal stage of the disease. Whether the same point mutation also leads to the testosterone effects or that a second sequence variation is a prerequisite for this phenomenon remains to be established from studies on the promotor region in representatives of the Greek and American families. Eventually the introduction of chaemeric genes, containing the various promotor regions, into testosterone responsive cells should delineate the promotor sequences responsible for the variations in factor IX gene expression.

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MALOSHENOK, L. G., and N. N. UGAROVA. "CATALYTIC PROPERTIES AND BIOLUMINESCENCE SPECTRA OF RECOMBINANT FIREFLY LUCIFERASE LUCIOLA MINGRELICA WITH POINT MUTATIONS OUT OF THE ENZYME ACTIVE SITE." In Bioluminescence and Chemiluminescence - Progress and Current Applications - 12th International Symposium on Bioluminescence (BL) and Chemiluminescence (CL). WORLD SCIENTIFIC, 2002. http://dx.doi.org/10.1142/9789812776624_0009.

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Bernaedi, F., V. Bertagnolo, S. Bartolai, L. Rossi, F. Panicucci, and F. Conconi. "A POINT MUTATION AND A GENE DELETION OF FVIII GENE IN SEVERE HAEMOPHILIA." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644047.

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Abstract:

The presence of Factor VIII (FVIII) gene lesions has been investigated in 100 haemophilia A patients using cDNA probes for the 3'part of FVIII gene (exons 14-26 ).In two related severe patients without inhibitor a deletion removesthe exon 26; the gene lesion has been confirmed with several restriction enzymes and has been shown by densitometry of the autoradiographic pattern in a woman of the same family. The complete deletionof the exon 26 has been described by Gitschier et al. in a patient with inhibitor. Thus the comparison of the end points of the two deletions could help to define the mechanism originating these gene lesions and the relation between gene lesions and the presence of antibody.In a patient with severe Haemophilia and without inhibitor a mutation removing the TaqI site in the exon 24 and originating an abnormal band of 4.2 Kb has been found. A C→T transition in this TaqI site, originating a nonsense codon and a new Hindlll site, has been reported by Gitschier et al in a patient presenting inhibitor. The DNA from our patient tested with Hindlll shows a normal pattern thus indicating a C→T transition in the antisense strand. This mutation should causean aminoacid change (CGA→CAA, Arg→Gln) possiblyresponsible for the FVIII inactivation but that does not remove theantigenic determinants present in the COOH terminal part of FVIII.In addition the same mutation has been observed in an unrelated (asdemonstrated by RFLPs analysis) Italian haemophilic patient confirming the observation of Youssoufian et al that TaqI sites are mutational hot spots in FVIII gene.

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Benslimane, Fatiha M., Hebah Al Khatib, Dana Albatesh, Ola Al-Jamal, Sonia Boughattas, Asmaa A. Althani, and Hadi M. Yassine. "Nanopore Sequencing SARS-CoV-2 Genome in Qatar." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2020. http://dx.doi.org/10.29117/quarfe.2020.0289.

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Background: The current pandemic, COVID-19, is cause by an RNA Coronavirus that was recently identified as SARS-CoV-2. RNA viruses tend to have a high mutation rate; the rate is around a million times greater than that of their hosts. The mutagenic potential of the virus depends on many factors, including the fidelity of nucleic acid-replicating viral enzymes, such as SARSCoV-2 RNA dependent RNA polymerase (RdRp). The rate of mutation drives viral evolution and genome variability, consequently allowing viruses to escape the immunity of the host and develop resistance to drugs. Therefore, the characterization of SARS-CoV-2 variants might lead to implement better therapeutics treatments, vaccines design and identify new diagnostics approaches. Aim: The aim of this study was to establish a fast sequencing method to identify SARS-CoV-2 mutations in Qatar. This will help to assess if there are new viral variants that are spreading in country. Methods: RNA was isolated from samples collected from Qatar COVID-19 positive patients. The Artic Network V3 primer scheme and Oxford Nanopore ligation sequencing kit were used to prepare the sequencing libraries. Libraries were loaded on to R9.4.1 flow cells and ran on a GridION. Bioinformatics analysis was done following the Artic Network SARA-CoV-2 bioinformatics tools. Results: Genome coverage of sequenced samples was >80% and the depth was average at 200x. The coverage was highly dependable on sample viral load; samples of CT value lower than 30 resulted in better sequence coverage. The sequenced genomes were deposited in GISAID and were mainly clustering with genomes deposited from the UK. Sequences were compared to Illumina and sanger sequences and they showed compatible results. Conclusion: The use of ONT to sequence SARA-CoV-2 is a quick, affordable, and reliable technique to determine viral mutation. Using this technique, the first sequences from Qatar were deposited in to GISAID. Up to date, 700 genomes have been sequenced from Qatari samples.

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Reports on the topic "Enzyme mutations"

Harris, Reuben S. Enzyme-Catalyzed Mutation in Breast Cancer. Fort Belvoir, VA: Defense Technical Information Center, August 2014. http://dx.doi.org/10.21236/ada613711.

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