The cobalamin processing enzyme of Trichoplax adhaerens.

Cobalamin (Cbl) is an essential cofactor for methionine synthase (MS) and methylmalonyl-CoA mutase (MUT), but it must first undergo chemical processing for utilization in animals. In humans, this processing comprises β-axial ligand cleavage and Cbl reduction and is performed by the enzyme MMACHC (HsCblC). Although the functionality of CblC is well-understood in higher order organisms, little is known about the evolutionary origin of these enzymes and the reactivity of CblCs in lower-order organisms with unique environmental and cellular conditions.

Decarboxylation of the Catalytic Lysine Residue by the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the OXA-58 Carbapenemase.

Antibiotic resistance in bacteria is a major global health concern. The wide spread of carbapenemases, bacterial enzymes that degrade the last-resort carbapenem antibiotics, is responsible for multidrug resistance in bacterial pathogens and has further significantly exacerbated this problem. is one of the leading nosocomial pathogens due to the acquisition and wide dissemination of carbapenem-hydrolyzing class D β-lactamases, which have dramatically diminished available therapeutic options.

Restricted Rotational Flexibility of the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the GES-5 Carbapenemase.

Carbapenem antibiotics are used as a last-resort treatment for infections caused by multidrug-resistant bacteria. The wide spread of carbapenemases in Gram-negative bacteria has severely compromised the utility of these drugs and represents a serious public health threat. To combat carbapenemase-mediated resistance, new antimicrobials and inhibitors of these enzymes are urgently needed.

Novel sterol binding domains in bacteria.

Sterol lipids are widely present in eukaryotes and play essential roles in signaling and modulating membrane fluidity. Although rare, some bacteria also produce sterols, but their function in bacteria is not known. Moreover, many more species, including pathogens and commensal microbes, acquire or modify sterols from eukaryotic hosts through poorly understood molecular mechanisms.

Dirigent isoflavene-forming PsPTS2: 3D structure, stereochemical, and kinetic characterization comparison with pterocarpan-forming PsPTS1 homolog in pea.

Pea phytoalexins (-)-maackiain and (+)-pisatin have opposite C6a/C11a configurations, but biosynthetically how this occurs is unknown. Pea dirigent-protein (DP) PsPTS2 generates 7,2'-dihydroxy-4',5'-methylenedioxyisoflav-3-ene (DMDIF), and stereoselectivity toward four possible 7,2'-dihydroxy-4',5'-methylenedioxyisoflavan-4-ol (DMDI) stereoisomers was investigated. Stereoisomer configurations were determined using NMR spectroscopy, electronic circular dichroism, and molecular orbital analyses.

The C5α-Methyl-Substituted Carbapenem NA-1-157 Exhibits Potent Activity against spp. Isolates Producing OXA-48-Type Carbapenemases.

The wide spread of carbapenem-hydrolyzing β-lactamases in Gram-negative bacteria has diminished the utility of the last-resort carbapenem antibiotics, significantly narrowing the available therapeutic options. In the family, which includes many important clinical pathogens such as and , production of class D β-lactamases from the OXA-48-type family constitutes the major mechanism of resistance to carbapenems. To address the public health threat posed by these enzymes, novel, effective therapeutics are urgently needed.

Dirigent protein subfamily function and structure in terrestrial plant phenol metabolism.

Aquatic plant transition to land, and subsequent terrestrial plant species diversification, was accompanied by the emergence and massive elaboration of plant phenol chemo-diversity. Concomitantly, dirigent protein (DP) and dirigent-like protein subfamilies, derived from large multigene families, emerged and became extensively diversified. DP biochemical functions as gateway entry points into new and diverse plant phenol skeletal types then markedly expanded.

Implementation of a Regional Oxygen Saturation Thought Algorithm and Association with Clinical Outcomes in Pediatric Patients Following Cardiac Surgery.

Near infrared spectroscopy is routinely used in the noninvasive monitoring of cerebral and somatic regional oxygen saturation (rSO) in pediatric patients following surgery for congenital heart disease. We sought to evaluate the association of a bedside rSO thought algorithm with clinical outcomes in a cohort of pediatric patients following cardiac surgery. This was a single-center retrospective cohort study of patients admitted following cardiac surgery over a 42-month period.

Gastrostomy tube placement in congenital cardiac surgery: a multi-institutional database study.

Introduction: Neonates and infants who undergo congenital cardiac surgery frequently have difficulty with feeding. The factors that predispose these patients to require a gastrostomy tube have not been well defined. We aimed to report the incidence and describe hospital outcomes and characteristics in neonates and infants undergoing congenital cardiac surgery who required gastrostomy tube placement.

Structural characterization of a soil viral auxiliary metabolic gene product - a functional chitosanase.

Metagenomics is unearthing the previously hidden world of soil viruses. Many soil viral sequences in metagenomes contain putative auxiliary metabolic genes (AMGs) that are not associated with viral replication. Here, we establish that AMGs on soil viruses actually produce functional, active proteins.

The l,d-Transpeptidase Ldt from Is Poorly Inhibited by Carbapenems and Has a Unique Structural Architecture.

l,d-Transpeptidases (LDTs) are enzymes that catalyze reactions essential for biogenesis of the bacterial cell wall, including formation of 3-3 cross-linked peptidoglycan. Unlike the historically well-known bacterial transpeptidases, the penicillin-binding proteins (PBPs), LDTs are resistant to inhibition by the majority of β-lactam antibiotics, with the exception of carbapenems and penems, allowing bacteria to survive in the presence of these drugs. Here we report characterization of Ldt from the clinically important pathogen, .

Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: Insights into the cardiovascular risk of proton pump inhibitors.

Background: Proton pump inhibitors (PPIs) are widely prescribed drugs for the treatment of gastroesophageal reflux disease (GERD). Several meta-analysis studies have reported associations between prolonged use of PPIs and major adverse cardiovascular events. However, interaction of PPIs with biological molecules involved in cardiovascular health is incompletely characterized.

C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major Carbapenemase OXA-23 by Impeding Deacylation.

Acinetobacter baumannii has become a major nosocomial pathogen, as it is often multidrug-resistant, which results in infections characterized by high mortality rates. The bacterium achieves high levels of resistance to β-lactam antibiotics by producing β-lactamases, enzymes which destroy these valuable agents. Historically, the carbapenem family of β-lactam antibiotics have been the drugs of choice for treating A.

Making sense of SFX data: standards for data and structure validation for a non-standard experiment that has come of age.

SFX diffraction data collection at XFELs is becoming more accessible. To extract the most useful biological information from these non-standard experiments, standards for SFX data analysis and structure validation must be redefined.

Participatory Approaches to Addressing Missing COVID-19 Race and Ethnicity Data.

Varying dimensions of social, environmental, and economic vulnerability can lead to drastically different health outcomes. The novel coronavirus (SARS-CoV-19) pandemic exposes how the intersection of these vulnerabilities with individual behavior, healthcare access, and pre-existing conditions can lead to disproportionate risks of morbidity and mortality from the virus-induced illness, COVID-19. The available data shows that those who are black, indigenous, and people of color (BIPOC) bear the brunt of this risk; however, missing data on race/ethnicity from federal, state, and local agencies impedes nuanced understanding of health disparities.

Time-Resolved Interaction of the CDD-1 enzyme with Avibactam Provides New Insights into the Catalytic Mechanism of Class D β-lactamases.

Class D β-lactamases have risen to notoriety due to their wide spread in bacterial pathogens, propensity to inactivate clinically important β-lactam antibiotics, and ability to withstand inhibition by the majority of classical β-lactamase inhibitors. Understanding the catalytic mechanism of these enzymes is thus vitally important for the development of novel antibiotics and inhibitors active against infections caused by antibiotic-resistant bacteria. Here we report an time-resolved study of the interaction of the class D β-lactamase CDD-1 from with the diazobicyclooctane inhibitor, avibactam.

Closed-loop organic waste management systems for family farmers in Brazil.

Family farmers in Brazil could diversify their sources of income and improve agriculture practices by adopting circular economy principles on their farms. Closed-loop technological systems can be used to manage organic waste and produce fertiliser and biogas thereby generating revenue. Anaerobic Digestion (AD) is a proven technology that can produce digestate (i.

Inhibition of the Class D β-Lactamase CDD-1 by Avibactam.

Avibactam is a potent diazobicyclooctane inhibitor of class A and C β-lactamases. The inhibitor also exhibits variable activity against some class D enzymes from Gram-negative bacteria; however, its interaction with recently discovered class D β-lactamases from Gram-positive bacteria has not been studied. Here, we describe microbiological, kinetic, and mass spectrometry studies of the interaction of avibactam with CDD-1, a class D β-lactamase from the clinically important pathogen , and show that avibactam is a potent irreversible mechanism-based inhibitor of the enzyme.

Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking.

The SARS-CoV-2 macrodomain (Mac1) within the non-structural protein 3 (Nsp3) counteracts host-mediated antiviral ADP-ribosylation signalling. This enzyme is a promising antiviral target because catalytic mutations render viruses non-pathogenic. Here, we report a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain.

Crystal structures of glutathione- and inhibitor-bound human GGT1: critical interactions within the cysteinylglycine binding site.

Overexpression of γ-glutamyl transpeptidase (GGT1) has been implicated in an array of human diseases including asthma, reperfusion injury, and cancer. Inhibitors are needed for therapy, but development of potent, specific inhibitors of GGT1 has been hampered by a lack of structural information regarding substrate binding and cleavage. To enhance our understanding of the molecular mechanism of substrate cleavage, we have solved the crystal structures of human GGT1 (hGGT1) with glutathione (a substrate) and a phosphate-glutathione analog (an irreversible inhibitor) bound in the active site.

Development and Validation of a Seizure Prediction Model in Neonates After Cardiac Surgery.

Background: Electroencephalographic seizures (ESs) after neonatal cardiac surgery are often subclinical and have been associated with poor outcomes. An accurate ES prediction model could allow targeted continuous electroencephalographic monitoring (CEEG) for high-risk neonates.

Methods: ES prediction models were developed and validated in a multicenter prospective cohort where all postoperative neonates who underwent cardiopulmonary bypass (CPB) also underwent CEEG.

Pterocarpan synthase (PTS) structures suggest a common quinone methide-stabilizing function in dirigent proteins and proteins with dirigent-like domains.

The biochemical activities of dirigent proteins (DPs) give rise to distinct complex classes of plant phenolics. DPs apparently began to emerge during the aquatic-to-land transition, with phylogenetic analyses revealing the presence of numerous DP subfamilies in the plant kingdom. The vast majority (>95%) of DPs in these large multigene families still await discovery of their biochemical functions.

A surface loop modulates activity of the Bacillus class D β-lactamases.

The expression of β-lactamases is a major mechanism of bacterial resistance to the β-lactam antibiotics. Four molecular classes of β-lactamases have been described (A, B, C and D), however until recently the class D enzymes were thought to exist only in Gram-negative bacteria. In the last few years, class D enzymes have been discovered in several species of Gram-positive microorganisms, such as Bacillus and Clostridia, and an investigation of their kinetic and structural properties has begun in earnest.

Lucina pectinata oxyhemoglobin (II-III) heterodimer pH susceptibility.

Lucina pectinata live in high concentrations of hydrogen sulfide (HS) and contains one hemoglobin, Hemoglobin I (HbI), transporting HS and two hemoglobins, Hemoglobin II (HbII) and Hemoglobin (HbIII), transferring dioxygen to symbionts. HbII and HbIII contain B10 tyrosine (Tyr) and E7 glutamine (Gln) in the heme pocket generating an efficient hydrogen bonding network with the (HbII-HbIII)-O species, leading to very low ligand dissociation rates. The results indicate that the oxy-hemeprotein is susceptible to pH from 4 to 9, at acidic conditions, and as a function of the potassium ferricyanide concentration, 100% of the met-aquo derivative is produced.