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Ene-Reductases in Pharmaceutical Chemistry
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
In situ recycling of NAD(P)+ via the coupled enzyme approach is a commonly used strategy in ERED-catalyzed biotransformations allowing for the use of catalytic levels of NAD(P)H. In this set-up, the addition of a sacrificial co-substrate is required, which is added in excess amounts to overcome thermodynamic limitations. Typically considered systems are a combination of (a) glucose dehydrogenase and glucose, (b) formate dehydrogenase and formate, (c) glucose-6-phosphate dehydrogenase and glucose 6-phosphate or (d) phosphite dehydrogenase and phosphite. When using the metal-dependent enzymes glucose dehydrogenase, glucose-6-phosphate dehydrogenase and formate dehydrogenase, the nature of the target substrate needs to be considered. In the presence of cis-configurated α,β -unsaturated dicarboxylic acids, which act as chelating agent, the addition of metal ions (e.g., Ca2+, Mg2+, or Zn2+) to the reaction medium is required to maintain activity (Hall et al., 2007).
Preclinical developments of enzyme-loaded red blood cells
Published in Expert Opinion on Drug Delivery, 2021
Luigia Rossi, Francesca Pierigè, Alessandro Bregalda, Mauro Magnani
Alcohol oxidase (AlOx) from Pichia pastoris (a methylotrophic yeast) has a much higher affinity for methanol than for ethanol. Based on this observation, we investigate the potential use of this enzyme for the treatment of methanol intoxication [77]. In fact, in humans, methanol is metabolized to formaldehyde by alcohol dehydrogenase and formaldehyde is metabolized to formic acid by acetaldehyde dehydrogenase, leading to cytochrome C oxidase inhibition. AlOx was encapsulated into human and murine erythrocytes up to 2 units/ml of packed cells. Enzyme‐loaded erythrocytes showed an increased rate of the hexose‐monophosphate‐shunt activity and a significant methemoglobin production resulting from the intracellular generation of H2O2. However, the in vivo survival of these cells did not seem to be significantly affected by methanol catabolism. In vivo, mice receiving AlOx‐loaded erythrocytes were able to keep the blood methanol concentrations below values that were about 50% of those found in control mice who received similar amounts of methanol. Thus, AlOx‐loaded erythrocytes may add an important contribution to the detoxification protocol against methanol poisoning. Formic acid can eventually be further degraded by encapsulate formate dehydrogenase [78].
Bile acid oxidation by Eggerthella lenta strains C592 and DSM 2243T
Published in Gut Microbes, 2018
Spencer C. Harris, Saravanan Devendran, Celia Méndez- García, Sean M. Mythen, Chris L. Wright, Christopher J. Fields, Alvaro G. Hernandez, Isaac Cann, Phillip B. Hylemon, Jason M. Ridlon
Genes encoding enzymes in the methyl branch of the WLP were also identified in the genomes of E. lenta DSM 2243 and E. lenta sp. strain C592 including formate dehydrogenase (fdh) (Elen_3031; CAB18_RS01995), which flanks the ACS/CODH cluster, formyl-tetrahydrofolate synthase (fsh) (Elen_2864; CAB18_RS01970), methylene-tetrahydrofolate dehydrogenase/cyclohydrolase (folD) (Elen_2861; CAB18_RS01985), bifunctional homocysteine S-methyltransferase/5,10-methylene-tetrahydrofolate reductase (yitJ) (Elen_2573; CAB18_RS03325). These results provide a plausible explanation for why E. lenta oxidizes bile acids in a reducing environment: oxidation of bile acids provides reducing equivalents for the fixation of CO2 to acetate. Genes encoding enzymes involved in the energy conservation by substrate-level phosphorylation resulting in the conversion of acetyl-CoA to acetyl-PO4 (eutD) (Elen_1728, and acetate kinase (ackA) (Elen_1729; CAB18_RS07170) were also identified. We also located pyruvate:ferrodoxin oxidoreductase (PFOR) in both E. lenta DSM 2243 (Elen_2140) and several annotated genes for PFOR in E. lenta C592 (CAB18_RS00220; CAB18_RS05160; CAB18_RS07295; CAB18_RS07920; CAB18_RS13765). PFOR links the Wood-Ljungdahl pathway to the reductive tricarboxylic acid cycle, allowing autotrophic biosynthesis of complex macromolecules.44
sesA, sesB, sesC, sesD, sesE, sesG, sesH, and embp genes are genetic markers that differentiate commensal isolates of Staphylococcus epidermidis from isolates that cause prosthetic joint infection
Published in Infectious Diseases, 2019
Silvestre Ortega-Peña, Carlos F. Vargas-Mendoza, Rafael Franco-Cendejas, Alejandra Aquino-Andrade, Guillermo J. Vazquez-Rosas, Gabriel Betanzos-Cabrera, Claudia Guerrero-Barajas, Janet Jan-Roblero, Sandra Rodríguez-Martínez, Mario E. Cancino-Diaz, Juan C. Cancino Diaz
Studies on the distribution and the presence of ses genes in S. epidermidis clinical isolates from pre-term infants and healthy skin isolates [18], from various sources of isolation [37] and from patients with orthopedic-device-related infections [33] show that the genes ses are highly distributed. Our results on the presence of ses genes in PJI and HS isolates showed that HS isolates have higher proportions of sesA, sesB, sesC, sesD, sesE, sesG, and sesH genes than PJI isolates (p < .05). This result suggests that ses genes can be considered as biomarkers for differentiating between commensal and PJI isolates. The high proportion of ses genes in HS isolates can be contrary to what was expected, because PJI isolates were high biofilm producers and Ses proteins are associated to the biofilm formation. We did not find a relationship between sesA, sesB, sesC, sesD, sesE, sesG, and sesH genes and the biofilm production; however, aap (sesF) gene was highly prevalent in the biofilm-producer PJI isolates suggesting that PJIs biofilm is of ica-independent type. Rohde et al. reported that PJI S. epidermidis isolates are high biofilm producers and they are aap gene positives [10]. On the other hand, it is commonly found that the differential biomarkers are more associated with clinical isolates than commensal isolates, there are scarce works that report the contrary, e.g. a high proportion in the commensal isolates of the arginine catabolic mobile element (ACME) [38] and the formate dehydrogenase gene [6] has been reported. The sesB gene is slightly more common among invasive isolates than contaminants [39]; however, the presence of the sesB gene was similar between hospital airborne S. epidermidis isolates (77.8%) and the patient isolates (88.5%) [40]. In this study, we found that the sesI gene is present only in biofilm-producer PJI isolates belonging to the B PFGE profile.