Hydrolases (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Listed in this section are hydrolases not accumulated in other parts of the Concise Guide, such as monoacylglycerol lipase and acetylcholinesterase. Pancreatic lipase is the predominant mechanism of fat digestion in the alimentary system; its inhibition is associated with decreased fat absorption. CES1 is present at lower levels in the gut than CES2 (P23141), but predominates in the liver, where it is responsible for the hydrolysis of many aliphatic, aromatic and steroid esters. Hormone-sensitive lipase is also a relatively non-selective esterase associated with steroid ester hydrolysis and triglyceride metabolism, particularly in adipose tissue. Endothelial lipase is secreted from endothelial cells and regulates circulating cholesterol in high density lipoproteins

Harmonic radar tracking reveals that honeybee drones navigate between multiple aerial leks

Male honeybees (drones) are thought to congregate in large numbers in particular “drone congregation areas” to mate. We used harmonic radar to record the flight paths of individual drones and found that drones favored certain locations within the landscape which were stable over two years. Drones often visit multiple potential lekking sites within a single flight and take shared flight paths between them. Flights between such sites are relatively straight and begin as early as the drone's second flight, indicating familiarity with the sites acquired during initial learning flights. Arriving at congregation areas, drones display convoluted, looping flight patterns. We found a correlation between a drone's distance from the center of each area and its acceleration toward the center, a signature of collective behavior leading to congregation in these areas. Our study reveals the behavior of individual drones as they navigate between and within multiple aerial leks

Mapping photodissociation and shocks in the vicinity of Sgr A*

We have obtained maps of the molecular emission within the central five arcminutes (12 pc) of the Galactic center (GC) in selected molecular tracers: SiO(2-1), HNCO(5_{0,5}-4_{0,4}), and the J=1-->0 transition of H^{13}CO+, HN^{13}C, and C^{18}O at an angular resolution of 30" (1.2 pc). The mapped region includes the circumnuclear disk (CND) and the two surrounding giant molecular clouds (GMCs) of the Sgr A complex, known as the 20 and 50 km s^{-1} molecular clouds.Additionally, we simultaneously observed the J=2-1 and 3-2 transitions of SiO toward selected positions to estimate the physical conditions of the molecular gas. The SiO(2-1) and H^{13}CO+(1-0) emission covers the same velocity range and presents a similar distribution. In contrast, HNCO(5-4) emission appears in a narrow velocity range mostly concentrated in the 20 and 50 km s^{-1} GMCs. The HNCO column densities and fractional abundances present the highest contrast, with difference factors of $\geq$60 and 28, respectively. Their highest values are found toward the cores of the GMCs, whereas the lowest ones are measured at the CND. SiO abundances do not follow this trend, with high values found toward the CND, as well as the GMCs. By comparing our abundances with those of prototypical Galactic sources we conclude that HNCO, similar to SiO, is ejected from grain mantles into gas-phase by nondissociative C-shocks. This results in the high abundances measured toward the CND and the GMCs. However, the strong UV radiation from the Central cluster utterly photodissociates HNCO as we get closer to the center, whereas SiO seems to be more resistant against UV-photons or it is produced more efficiently by the strong shocks in the CND. Finally, we discuss the possible connections between the molecular gas at the CND and the GMCs using the HNCO/SiO, SiO/CS, and HNCO/CS intensity ratios as probes of distance to the Central cluster.Comment: 26 pages plus 2 appendixes with additional figures. 17 figures in total. Accepted for publication in A&

Rational Redesign of Glucose Oxidase for Improved Catalytic Function and Stability

Glucose oxidase (GOx) is an enzymatic workhorse used in the food and wine industries to combat microbial contamination, to produce wines with lowered alcohol content, as the recognition element in amperometric glucose sensors, and as an anodic catalyst in biofuel cells. It is naturally produced by several species of fungi, and genetic variants are known to differ considerably in both stability and activity. Two of the more widely studied glucose oxidases come from the species Aspergillus niger (A. niger) and Penicillium amagasakiense (P. amag.), which have both had their respective genes isolated and sequenced. GOx from A. niger is known to be more stable than GOx from P. amag., while GOx from P. amag. has a six-fold superior substrate affinity (KM) and nearly four-fold greater catalytic rate (kcat). Here we sought to combine genetic elements from these two varieties to produce an enzyme displaying both superior catalytic capacity and stability. A comparison of the genes from the two organisms revealed 17 residues that differ between their active sites and cofactor binding regions. Fifteen of these residues in a parental A. niger GOx were altered to either mirror the corresponding residues in P. amag. GOx, or mutated into all possible amino acids via saturation mutagenesis. Ultimately, four mutants were identified with significantly improved catalytic activity. A single point mutation from threonine to serine at amino acid 132 (mutant T132S, numbering includes leader peptide) led to a three-fold improvement in kcat at the expense of a 3% loss of substrate affinity (increase in apparent KM for glucose) resulting in a specify constant (kcat/KM) of 23.8 (mM−1 · s−1) compared to 8.39 for the parental (A. niger) GOx and 170 for the P. amag. GOx. Three other mutant enzymes were also identified that had improvements in overall catalysis: V42Y, and the double mutants T132S/T56V and T132S/V42Y, with specificity constants of 31.5, 32.2, and 31.8 mM−1 · s−1, respectively. The thermal stability of these mutants was also measured and showed moderate improvement over the parental strain

SARS-CoV-2 evolution during treatment of chronic infection

SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE21, and is a major 54 antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising 55 antibodies in an immune suppressed individual treated with convalescent plasma, generating 56 whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was 57 observed in the overall viral population structure following two courses of remdesivir over the 58 first 57 days. However, following convalescent plasma therapy we observed large, dynamic 59 virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and 60 H69/V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred 61 serum antibodies diminished, viruses with the escape genotype diminished in frequency, before 62 returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape 63 double mutant bearing H69/V70 and D796H conferred modestly decreased sensitivity to 64 convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be 65 the main contributor to decreased susceptibility but incurred an infectivity defect. The 66 H69/V70 single mutant had two-fold higher infectivity compared to wild type, possibly 67 compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS68 CoV-2 during convalescent plasma therapy associated with emergence of viral variants with 69 evidence of reduced susceptibility to neutralising antibodies.COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute

Assessing the functional coherence of modules found in multiple-evidence networks from Arabidopsis

<p>Abstract</p> <p>Background</p> <p>Combining multiple evidence-types from different information sources has the potential to reveal new relationships in biological systems. The integrated information can be represented as a relationship network, and clustering the network can suggest possible functional modules. The value of such modules for gaining insight into the underlying biological processes depends on their functional coherence. The challenges that we wish to address are to define and quantify the functional coherence of modules in relationship networks, so that they can be used to infer function of as yet unannotated proteins, to discover previously unknown roles of proteins in diseases as well as for better understanding of the regulation and interrelationship between different elements of complex biological systems.</p> <p>Results</p> <p>We have defined the functional coherence of modules with respect to the Gene Ontology (GO) by considering two complementary aspects: (i) the fragmentation of the GO functional categories into the different modules and (ii) the most representative functions of the modules. We have proposed a set of metrics to evaluate these two aspects and demonstrated their utility in <it>Arabidopsis thaliana</it>. We selected 2355 proteins for which experimentally established protein-protein interaction (PPI) data were available. From these we have constructed five relationship networks, four based on single types of data: PPI, co-expression, co-occurrence of protein names in scientific literature abstracts and sequence similarity and a fifth one combining these four evidence types. The ability of these networks to suggest biologically meaningful grouping of proteins was explored by applying Markov clustering and then by measuring the functional coherence of the clusters.</p> <p>Conclusions</p> <p>Relationship networks integrating multiple evidence-types are biologically informative and allow more proteins to be assigned to a putative functional module. Using additional evidence types concentrates the functional annotations in a smaller number of modules without unduly compromising their consistency. These results indicate that integration of more data sources improves the ability to uncover functional association between proteins, both by allowing more proteins to be linked and producing a network where modular structure more closely reflects the hierarchy in the gene ontology.</p

Made-to-Measure Malaria Vector Control Strategies: Rational Design Based on Insecticide Properties and Coverage of Blood Resources for Mosquitoes.

Eliminating malaria from highly endemic settings will require unprecedented levels of vector control. To suppress mosquito populations, vector control products targeting their blood hosts must attain high biological coverage of all available sources, rather than merely high demographic coverage of a targeted resource subset, such as humans while asleep indoors. Beyond defining biological coverage in a measurable way, the proportion of blood meals obtained from humans and the proportion of bites upon unprotected humans occurring indoors also suggest optimal target product profiles for delivering insecticides to humans or livestock. For vectors that feed only occasionally upon humans, preferred animal hosts may be optimal targets for mosquito-toxic insecticides, and vapour-phase insecticides optimized to maximize repellency, rather than toxicity, may be ideal for directly protecting people against indoor and outdoor exposure. However, for vectors that primarily feed upon people, repellent vapour-phase insecticides may be inferior to toxic ones and may undermine the impact of contact insecticides applied to human sleeping spaces, houses or clothing if combined in the same time and place. These concepts are also applicable to other mosquito-borne anthroponoses so that diverse target species could be simultaneously controlled with integrated vector management programmes. Measurements of these two crucial mosquito behavioural parameters should now be integrated into programmatically funded, longitudinal, national-scale entomological monitoring systems to inform selection of available technologies and investment in developing new ones