Structures of methane and ammonia monooxygenases in native membranes.

Methane- and ammonia-oxidizing bacteria play key roles in the global carbon and nitrogen cycles, respectively. These bacteria use homologous copper membrane monooxygenases to accomplish the defining chemical transformations of their metabolisms: the oxidations of methane to methanol by particulate methane monooxygenase (pMMO) and ammonia to hydroxylamine by ammonia monooxygenase (AMO), enzymes of prime interest for applications in mitigating climate change. However, investigations of these enzymes have been hindered by the need for disruptive detergent solubilization prior to structure determination, confounding studies of pMMO and precluding studies of AMO.

Translating metabolic and cardiovascular research into effective treatments: What's next?

The future of healthcare for cardiovascular diseases holds immense promise, not only based in new discoveries in cardiac metabolism but also in translating them to solutions for critical challenges faced by society. Here, ten scientists share their insights, shedding light on the future that lies ahead for this field.

A multi-iron enzyme installs copper-binding oxazolone/thioamide pairs on a nontypeable virulence factor.

The multinuclear nonheme iron-dependent oxidases (MNIOs) are a rapidly growing family of enzymes involved in the biosynthesis of ribosomally synthesized, posttranslationally modified peptide natural products (RiPPs). Recently, a secreted virulence factor from nontypeable (NTHi) was found to be expressed from an operon, which we designate the operon, that also encodes an MNIO. Here, we show by Mössbauer spectroscopy that the MNIO HvfB contains a triiron cofactor.

Cardiac aging: from hallmarks to therapeutic opportunities.

Cardiac aging is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular and functional changes associated with cardiac aging and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of aging, with particular attention to promising therapeutic candidates.

Cinnamosyn, a Cinnamoylated Synthetic-Bioinformatic Natural Product with Cytotoxic Activity.

Most biosynthetic gene clusters (BGCs) are functionally inaccessible by using fermentation methods. Bioinformatic-coupled total synthesis provides an alternative approach for accessing BGC-encoded bioactivities. To date, synthetic bioinformatic natural product (synBNP) methods have focused on lipopeptides containing simple lipids.

Identification of an Optimized Clinical Development Candidate from Cilagicin, an Antibiotic That Evades Resistance by Dual Polyprenyl Phosphate Binding.

Cilagicin is a dual polyprenyl phosphate binding lipodepsipeptide antibiotic with strong activity against clinically relevant Gram-positive pathogens while evading antibiotic resistance. Cilagicin showed high serum binding that reduced its in vivo efficacy. Cilagicin-BP, which contains a biphenyl moiety in place of the N-terminal myristic acid found on cilagicin, showed reduced serum binding and increased in vivo efficacy but decreased potency against some pathogens.

Initial Steps in Methanobactin Biosynthesis: Substrate Binding by the Mixed-Valent Diiron Enzyme MbnBC.

The MbnBC enzyme complex converts cysteine residues in a peptide substrate, MbnA, to oxazolone/thioamide groups during the biosynthesis of copper chelator methanobactin (Mbn). MbnBC belongs to the mixed-valent diiron oxygenase (MVDO) family, of which members use an Fe(II)Fe(III) cofactor to react with dioxygen for substrate modification. Several crystal structures of the inactive Fe(III)Fe(III) form of MbnBC alone and in complex with MbnA have been reported, but a mechanistic understanding requires determination of the oxidation states of the crystallographically observed Fe ions in the catalytically active Fe(II)Fe(III) state, along with the site of MbnA binding.

Direct Methane Oxidation by Copper- and Iron-Dependent Methane Monooxygenases.

Methane is a potent greenhouse gas that contributes significantly to climate change and is primarily regulated in Nature by methanotrophic bacteria, which consume methane gas as their source of energy and carbon, first by oxidizing it to methanol. The direct oxidation of methane to methanol is a chemically difficult transformation, accomplished in methanotrophs by complex methane monooxygenase (MMO) enzyme systems. These enzymes use iron or copper metallocofactors and have been the subject of detailed investigation.

Product analog binding identifies the copper active site of particulate methane monooxygenase.

Nature's primary methane-oxidizing enzyme, the membrane-bound particulate methane monooxygenase (pMMO), catalyzes the oxidation of methane to methanol. pMMO activity requires copper, and decades of structural and spectroscopic studies have sought to identify the active site among three candidates: the Cu, Cu, and Cu sites. Challenges associated with the isolation of active pMMO have hindered progress toward locating its catalytic center.

miR-222 inhibits pathological cardiac hypertrophy and heart failure.

Aims: Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct.

A Family of Antibiotics That Evades Resistance by Binding Polyprenyl Phosphates.

Cilagicin is a Gram-positive active antibiotic that has a dual polyprenyl phosphate binding mechanism that impedes resistance development. Here we bioinformatically screened predicted non-ribosomal polypeptide synthetase encoded structures to search for antibiotics that might similarly avoid resistance development. Synthesis and bioactivity screening of the predicted structures that we identified led to three antibiotics that are active against multidrug-resistant Gram-positive pathogens, two of which, paenilagicin and virgilagicin, did not lead to resistance even after prolonged antibiotic exposure.

Roles of Activin A and Gpnmb in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as nonalcoholic fatty liver disease [NAFLD]) and metabolic dysfunction-associated steatohepatitis (MASH, formerly known as nonalcoholic steatohepatitis [NASH]) are leading chronic liver diseases, driving cirrhosis, hepatocellular carcinoma, and mortality. MASLD/MASH is associated with increased senescence proteins, including Activin A, and senolytics have been proposed as a therapeutic approach. To test the role of Activin A, we induced hepatic expression of Activin A in a murine MASLD/MASH model.

Predictability of Pediatric Sepsis Outcome Using SEPSIS-3 Definition in a Single Tertiary Pediatric Institution.

Sepsis is a syndrome of dysregulated response to infection and is associated with high morbidity and mortality. Sepsis was initially defined as a host's systemic inflammatory response syndrome (SIRS) to infection. In 2016, the importance of dysregulated response was incorporated into the definition of sepsis; adult sepsis was redefined as a life-threatening organ dysfunction caused by a dysregulated host response to infection, with organ function being evaluated by the Sequential Organ Failure Assessment (SOFA) score (Sepsis-3 definition).

Present and future outlooks on environmental DNA-based methods for antibiotic discovery.

Novel antibiotics are in constant demand to combat a global increase in antibiotic-resistant infections. Bacterial natural products have been a long-standing source of antibiotic compounds, and metagenomic mining of environmental DNA (eDNA) has increasingly provided new antibiotic leads. The metagenomic small-molecule discovery pipeline can be divided into three main steps: surveying eDNA, retrieving a sequence of interest, and accessing the encoded natural product.

Ketone ester supplementation suppresses cardiac inflammation and improves cardiac energetics in a swine model of acute myocardial infarction.

Background: Myocardial infarction (MI) is a major risk factor for the development of heart failure with reduce ejection fraction (HFrEF). While previous studies have focused on HFrEF, the cardiovascular effects of ketone bodies in acute MI are unclear. We examined the effects of oral ketone supplementation as a potential treatment strategy in a swine acute MI model.

Management of Patients With Pancreatic Cancer Using the "Right Track" Model.

Pancreatic cancer is one of the few cancer types in the US with incidence and death rates continuing to rise. As the disease threatens to become the second leading cause of cancer-related deaths in the country, it is imperative to review the best practices currently available to extend and improve patient lives. To provide a roadmap for healthcare professionals detecting, diagnosing, and caring for patients with pancreatic cancer as a supplement to national guidelines focused on recommended treatment regimens, the Pancreatic Cancer Action Network (PanCAN)'s Scientific and Medical Affairs staff and expert Scientific and Medical Advisory Board have created a series of position statements.