Identification of Cysteine Metabolism Regulator (CymR)-Derived Pentapeptides as Nanomolar Inhibitors of -Acetyl-l-serine Sulfhydrylase (CysK).

The pathway of bacterial cysteine biosynthesis is gaining traction for the development of antibiotic adjuvants. Bacterial cysteine biosynthesis is generally facilitated by two enzymes possessing -acetyl-l-serine sulfhydrylases (OASS), CysK and CysM. In , there exists a single OASS homologue, CysK.

Fostering healthy cognitive ageing in people living with HIV.

Prevalence and incidence of HIV among people aged 50 years and older continue to rise worldwide, generating increasing awareness among care providers, scientists, and the HIV community about the importance of brain health in older adults with HIV. Many age-related factors that adversely affect brain health can occur earlier and more often among people with HIV, including epigenetic ageing, chronic medical conditions (eg, cardiovascular disease), and age-related syndromes (eg, frailty). Extensive dialogue between HIV community leaders, health-care providers, and scientists has led to the development of a multidimensional response strategy to protect and enhance brain health in people ageing with HIV that spans across public health, clinical spaces, and research spaces.

Neuroprotective effect of neuron-specific deletion of the C16 ceramide synthetic enzymes in an animal model of multiple sclerosis.

Ceramide C16 is a sphingolipid detected at high levels in several neurodegenerative disorders, including multiple sclerosis (MS). It can be generated de novo or from the hydrolysis of other sphingolipids, such as sphingomyelin or through the recycling of sphingosine, in what is known as the salvage pathway. While the myelin damage occurring in MS suggests the importance of the hydrolytic and salvage pathways, the growing interest on the importance of diet in demyelinating disorders, prompted us to investigate the involvement of de novo ceramide C16 synthesis on disease severity.

Astrocytic GLUT1 reduction paradoxically improves central and peripheral glucose homeostasis.

Astrocytes are considered an essential source of blood-borne glucose or its metabolites to neurons. Nonetheless, the necessity of the main astrocyte glucose transporter, i.e.

Identification of cysteine metabolism regulator (CymR)-derived pentapeptides as nanomolar inhibitors of O-acetyl-ʟ-serine sulfhydrylase (CysK).

Unlabelled: The conditionally essential pathway of bacterial cysteine biosynthesis is gaining traction for the development of antibiotic adjuvants. Bacterial cysteine biosynthesis is generally facilitated by two enzymes possessing O-acetyl-ʟ-serine sulfhydrylase (OASS) activity, CysK and CysM. CysK enzymes can also form functional complexes with other proteins that regulate cysteine metabolism.

NPY-mediated synaptic plasticity in the extended amygdala prioritizes feeding during starvation.

Efficient control of feeding behavior requires the coordinated adjustment of complex motivational and affective neurocircuits. Neuropeptides from energy-sensing hypothalamic neurons are potent feeding modulators, but how these endogenous signals shape relevant circuits remains unclear. Here, we examine how the orexigenic neuropeptide Y (NPY) adapts GABAergic inputs to the bed nucleus of the stria terminalis (BNST).

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release.

Nociceptin/orphanin-FQ (N/OFQ) is a recently appreciated critical opioid peptide with key regulatory functions in several central behavioral processes including motivation, stress, feeding, and sleep. The functional relevance of N/OFQ action in the mammalian brain remains unclear due to a lack of high-resolution approaches to detect this neuropeptide with appropriate spatial and temporal resolution. Here we develop and characterize NOPLight, a genetically encoded sensor that sensitively reports changes in endogenous N/OFQ release.

GABAergic disinhibition from the BNST to PNOC neurons promotes HFD-induced hyperphagia.

Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOC neurons can inhibit the anorexic response of proopiomelanocortin (POMC) neurons. Here, we validate the necessity of PNOC activity for HFD-induced inhibition of POMC neurons in mice and find that PNOC-neuron-dependent inhibition of POMC neurons is mediated by gamma-aminobutyric acid (GABA) release.

Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons.

Depletion of TBC1D4 Improves the Metabolic Exercise Response by Overcoming Genetically Induced Peripheral Insulin Resistance.

The Rab-GTPase-activating protein (RabGAP) TBC1D4 (AS160) represents a key component in the regulation of glucose transport into skeletal muscle and white adipose tissue (WAT) and is therefore crucial during the development of insulin resistance and type 2 diabetes. Increased daily activity has been shown to be associated with improved postprandial hyperglycemia in allele carriers of a loss-of-function variant in the human TBC1D4 gene. Using conventional Tbc1d4-deficient mice (D4KO) fed a high-fat diet, we show that moderate endurance exercise training leads to substantially improved glucose and insulin tolerance and enhanced expression levels of markers for mitochondrial activity and browning in WAT from D4KO animals.

Activation of GFRAL neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor.

GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment, and may mediate metformin effects by long-term GDF15-GFRAL agonism. Whether GFRAL neurons acutely regulate glucose and energy homeostasis is, however, underexplored. Here, we report that cell-specific activation of GFRAL neurons using a variety of techniques causes a torpor-like state, including hypothermia, the release of stress hormones, a shift from glucose to lipid oxidation, and impaired insulin sensitivity, glucose tolerance, and skeletal muscle glucose uptake but augmented glucose uptake in visceral fat.

A structural basis for the activation of peroxisome proliferator-activated receptor gamma (PPARγ) by perfluorooctanoic acid (PFOA).

Perfluorooctanoic acid (PFOA) is a widespread environmental pollutant of the perfluoroalkyl substance (PFAS) class that is extremely resistant to environmental and metabolic degradation, leading to bioaccumulation. PFOA exposure has been linked to many health effects including endocrine disruption and metabolic dysregulation, but our understanding of the molecular mechanisms resulting in these outcomes remains incomplete. One target affected by PFOA is the ligand regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) which plays a critical role in controlling metabolic homeostasis through regulating processes such as adipogenesis, glucose homeostasis, inflammation and osteogenesis.

Structural determination and characterisation of the CYP105Q4 cytochrome P450 enzyme from Mycobacterium marinum.

The cytochrome P450 family of heme metalloenzymes (CYPs) catalyse important biological monooxygenation reactions. Mycobacterium marinum contains a gene encoding a CYP105Q4 enzyme of unknown function. Other members of the CYP105 CYP family have key roles in bacterial metabolism including the synthesis of secondary metabolites.

Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism.

Agouti-related peptide (AgRP)-expressing and proopiomelanocortin (POMC)-expressing neurons reciprocally regulate food intake. Here, we combine non-interacting recombinases to simultaneously express functionally opposing chemogenetic receptors in AgRP and POMC neurons for comparing metabolic responses in male and female mice with simultaneous activation of AgRP and inhibition of POMC neurons with isolated activation of AgRP neurons or isolated inhibition of POMC neurons. We show that food intake is regulated by the additive effect of AgRP neuron activation and POMC neuron inhibition, while systemic insulin sensitivity and gluconeogenesis are differentially modulated by isolated-versus-simultaneous regulation of AgRP and POMC neurons.

Biochemical and characterization of glycosyltransferases from red sweet cherry ( L.) reveals their broad specificity toward phenolic substrates.

Polyphenolic compounds are a class of phytonutrients that play important roles in plants and contribute to human health when incorporated into our diet through fruit consumption. A large proportion occur as glycoconjugates but the enzymes responsible for their glycosylation are poorly characterized. Here, we report the biochemical and structural characterization of two glycosyltransferases from sweet cherry named UGT1 and UGT2.

An Approach to Intersectionally Target Mature Enteroendocrine Cells in the Small Intestine of Mice.

Enteroendocrine cells (EECs) constitute only a small proportion of -expressing intestinal epithelial cells (IECs) of the gastrointestinal tract; yet, in sum, they build the largest endocrine organ of the body, with each of them storing and releasing a distinct set of peptides for the control of feeding behavior, glucose metabolism, and gastrointestinal motility. Like all IEC types, EECs are continuously renewed from intestinal stem cells in the crypt base and terminally differentiate into mature subtypes while moving up the crypt-villus axis. Interestingly, EECs adjust their hormonal secretion according to their migration state as EECs receive altering differentiation signals along the crypt-villus axis and thus undergo functional readaptation.

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice.

Towards a High-Affinity Peptidomimetic Targeting Proliferating Cell Nuclear Antigen from .

Invasive fungal infections (IFIs) are prevalent in immunocompromised patients. Due to alarming levels of increasing resistance in clinical settings, new drugs targeting the major fungal pathogen are required. Attractive drug targets are those involved in essential processes like DNA replication, such as proliferating cell nuclear antigens (PCNAs).

CT-based comparison of porcine, ovine, and human pulmonary arterial morphometry.

To facilitate pre-clinical animal and in-silico clinical trials for implantable pulmonary artery pressure sensors, understanding the respective species pulmonary arteries (PA) anatomy is important. Thus, morphological parameters describing PA of pigs and sheep, which are common animal models, were compared with humans. Retrospective computed tomography data of 41 domestic pigs (82.

An In Crystallo Reaction with an Engineered Cytochrome P450 Peroxygenase.

The cytochrome P450 monooxygenases (CYPs) are a class of heme-thiolate enzymes that insert oxygen into unactivated C-H bonds. These enzymes can be converted into peroxygenases via protein engineering, which enables their activity to occur using hydrogen peroxide (H O ) without the requirement for additional nicotinamide co-factors or partner proteins. Here, we demonstrate that soaking crystals of an engineered P450 peroxygenase with H O enables the enzymatic reaction to occur within the crystal.

Generation of synthetic aortic valve stenosis geometries for in silico trials.

In silico trials are a promising way to increase the efficiency of the development, and the time to market of cardiovascular implantable devices. The development of transcatheter aortic valve implantation (TAVI) devices, could benefit from in silico trials to overcome frequently occurring complications such as paravalvular leakage and conduction problems. To be able to perform in silico TAVI trials virtual cohorts of TAVI patients are required.

Structure-guided design and synthesis of ATP-competitive N-acyl-substituted sulfamide d-alanine-d-alanine ligase inhibitors.

d-Alanine-d-alanine ligase (Ddl) catalyses the ATP-dependent formation of d-Ala-d-Ala, a critical component in bacterial cell wall biosynthesis and is a validated target for new antimicrobial agents. Here, we describe the structure-guided design, synthesis, and evaluation of ATP-competitive N-acyl-substituted sulfamides 27-36, 42, 46, 47 as inhibitors of Staphylococcus aureus Ddl (SaDdl). A crystal structure of SaDdl complexed with ATP and d-Ala-d-Ala (PDB: 7U9K) identified ATP-mimetic 8 as an initial scaffold for further inhibitor design.

Characterisation of the heme aqua-ligand coordination environment in an engineered peroxygenase cytochrome P450 variant.

The cytochrome P450 enzymes (CYPs) are heme-thiolate monooxygenases that catalyse the insertion of an oxygen atom into the C-H bonds of organic molecules. In most CYPs, the activation of dioxygen by the heme is aided by an acid-alcohol pair of residues located in the I-helix of the enzyme. Mutation of the threonine residue of this acid-alcohol pair of CYP199A4, from the bacterium Rhodospeudomonas palustris HaA2, to a glutamate residue induces peroxygenase activity.