The effect of protease supplementation in broiler chicken diets containing maize from different batches on growth performance and nutrient digestibility.

Maize is the primary energy source in poultry diets. Nutritional and physical traits related to maize composition can affect nutrient utilization, as well as the efficacy of exogenous enzymes. A study was conducted to evaluate the effect of maize from different batches and protease supplementation on growth performance and ileal nutrient digestibility of broiler chickens from 1 to 40 days of age.

Isofagomine Inhibits Multiple TcdB Variants and Protects Mice from -Induced Mortality.

causes life-threatening diarrhea and is one of the leading causes of nosocomial infections. During infection, releases two gut-damaging toxins, TcdA and TcdB, which are the primary determinants of disease pathogenesis and are important therapeutic targets. Once in the cytosol of mammalian cells, TcdA and TcdB use UDP-glucose to glucosylate host Rho GTPases, which leads to cytoskeletal changes that result in a loss of intestinal integrity.

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition.

Homozygous 5'-methylthioadenosine phosphorylase (MTAP) deletions occur in approximately 15% of human cancers. Co-deletion of MTAP and methionine adenosyltransferase 2 alpha (MAT2a) induces a synthetic lethal phenotype involving protein arginine methyltransferase 5 (PRMT5) inhibition. MAT2a inhibitors are now in clinical trials for genotypic MTAP cancers, however the MTAP genotype represents fewer than 2% of human colorectal cancers (CRCs), limiting the utility of MAT2a inhibitors in these and other MTAP cancers.

Phosphate Binding in PNP Alters Transition-State Analogue Affinity and Subunit Cooperativity.

Purine nucleoside phosphorylases (PNPs) catalyze the phosphorolysis of 6-oxypurine nucleosides with an HPO dianion nucleophile. Nucleosides and phosphate occupy distinct pockets in the PNP active site. Evaluation of the HPO site by mutagenesis, cooperative binding studies, and thermodynamic and structural analysis demonstrate that alterations in the HPO binding site can render PNP inactive and significantly impact subunit cooperativity and binding to transition-state analogue inhibitors.

Decreased Transition-State Analogue Affinity in Isotopically Heavy MTAN with Increased Catalysis.

5'-Methylthioadenosine/-adenosylhomocysteine nucleosidase from (MTAN) demonstrated faster chemistry when expressed as an isotopically heavy protein, with H, C, and N replacing the bulk of normal isotopes. The inverse heavy enzyme isotope effect has been attributed to improved enzyme-reactant interactions causing more frequent transition-state formation ( 2021, 118, e2109118118). Transition-state analogues stabilize the transient dynamic geometry of the transition state and inform on transition-state dynamics.

Isofagomine inhibits multiple TcdB variants and protects mice from induced mortality.

causes life-threatening diarrhea and is the leading cause of healthcare associated bacterial infections in the United States. During infection, releases the gut-damaging toxins, TcdA and TcdB, the primary determinants of disease pathogenesis and are therefore therapeutic targets. TcdA and TcdB contain a glycosyltransferase domain that uses UDP-glucose to glycosylate host Rho GTPases, causing cytoskeletal changes that result in a loss of intestinal integrity.

Cell-Effective Transition-State Analogue of Phenylethanolamine -Methyltransferase.

Phenylethanolamine -methyltransferase (PNMT) catalyzes the -adenosyl-l-methionine (SAM)-dependent methylation of norepinephrine to form epinephrine. Epinephrine is implicated in the regulation of blood pressure, respiration, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Transition-state (TS) analogues bind their target enzymes orders of magnitude more tightly than their substrates.

Phosphoinositide and redox dysregulation by the anticancer methylthioadenosine phosphorylase transition state inhibitor.

Methylthio-DADMe-immucillin-A (MTDIA) is an 86 picomolar inhibitor of 5'-methylthioadenosine phosphorylase (MTAP) with potent and specific anti-cancer efficacy. MTAP salvages S-adenosylmethionine (SAM) from 5'-methylthioadenosine (MTA), a toxic metabolite produced during polyamine biosynthesis. Changes in MTAP expression are implicated in cancer growth and development, making MTAP an appealing target for anti-cancer therapeutics.

Residence Times for Femtomolar and Picomolar Inhibitors of MTANs.

5'-Methylthioadenosine nucleosidases (MTANs) catalyze the hydrolysis of 5'-substituted adenosines to form adenine and 5-substituted ribose. MTAN (MTAN) and MTAN (MTAN) form late and early transition states, respectively. Transition state analogues designed for the late transition state bind with fM to pM affinity to both classes of MTANs.

An enzyme-coupled microplate assay for activity and inhibition of hmdUMP hydrolysis by DNPH1.

2'-Deoxynucleoside 5'-monophosphate N-glycosidase 1 (DNPH1) hydrolyzes the epigenetically modified nucleotide 5-hydroxymethyl 2'-deoxyuridine 5'-monophosphate (hmdUMP) derived from DNA metabolism. Published assays of DNPH1 activity are low throughput, use high concentrations of DNPH1, and have not incorporated or characterized reactivity with the natural substrate. We describe the enzymatic synthesis of hmdUMP from commercially available materials and define its steady-state kinetics with DNPH1 using a sensitive, two-pathway enzyme coupled assay.

MAT Gain of Activity Mutation in Is Associated with Resistance to MTAN Transition State Analogues.

is found in the gut lining of more than half of the world's population, causes gastric ulcers, and contributes to stomach cancers. Menaquinone synthesis in relies on the rare futalosine pathway, where 5'-methylthioadenosine nucleosidase (MTAN) is proposed to play an essential role. Transition state analogues of MTAN, including BuT-DADMe-ImmA (BTDIA) and MeT-DADMe-ImmA (MTDIA), exhibit bacteriostatic action against numerous diverse clinical isolates of with minimum inhibitory concentrations (MIC's) of <2 ng/mL.

Inhibition and Mechanism of Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase.

hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine salvage of hypoxanthine into parasite purine nucleotides. Transition state analogue inhibitors of HGXPRT are characterized by kinetic analysis, thermodynamic parameters, and X-ray crystal structures. Compound , 9-deazaguanine linked to an acyclic ribocation phosphonate mimic, shows a kinetic of 0.

The design of protozoan phosphoribosyltransferase inhibitors containing non-charged phosphate mimic residues.

Phosphate groups play essential roles in biological processes, including retention inside biological membranes. Phosphodiesters link nucleic acids, and the reversible transfer of phosphate groups is essential in energy metabolism and cell-signalling processes. Phosphorylated metabolic intermediates are known targets for metabolic and disease-related disorders, and the enzymes involved in these pathways recognize phosphate groups in their catalytic sites.

Kinetic Characterization and Inhibition of Hypoxanthine-Guanine Phosphoribosyltransferases.

Chagas disease, caused by the parasitic protozoan , affects over 8 million people worldwide. Current antiparasitic treatments for Chagas disease are ineffective in treating advanced, chronic stages of the disease, and are noted for their toxicity. Like most parasitic protozoa, is unable to synthesize purines , and relies on the salvage of preformed purines from the host.

TcdB Toxin Glucosylates Rho GTPase by an S Mechanism and Ion Pair Transition State.

Toxins TcdA and TcdB from glucosylate human colon Rho GTPases. TcdA and TcdB glucosylation of RhoGTPases results in cytoskeletal changes, causing cell rounding and loss of intestinal integrity. Clostridial toxins TcdA and TcdB are proposed to catalyze glucosylation of Rho GTPases with retention of stereochemistry from UDP-glucose.

Recall Bias in Retrospective Assessment of Preoperative American Shoulder and Elbow Surgeons Scores After Reverse Total Shoulder Arthroplasty.

Introduction: Although reverse total shoulder arthroplasty (RTSA) has been shown to be effective for the treatment of cuff tear arthropathy (CTA), the patient's inability to accurately recall their preoperative shoulder condition could skew their perception of the effectiveness of the procedure. Identifying patients who are susceptible to notable recall bias before surgery can help surgeons counsel patients regarding expectations after surgery. The purpose of this study was to evaluate whether patients who undergo RTSA are susceptible to recall bias and, if so, which factors are associated with poor recollection.

Synthesis and Characterization of Transition-State Analogue Inhibitors against Human DNA Methyltransferase 1.

Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of -adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics.

The effect of alkyl substitution on the oxidative metabolism and mutagenicity of phenanthrene.

Alkyl-substituted PAHs may be present in certain petroleum-derived products and in the environment and may eventually end up in consumer products, such as foodstuffs, cosmetics and pharmaceuticals. Safety concerns over possible exposure to alkylated PAHs have emerged. Bioactivation is a prerequisite for the mutagenicity and carcinogenicity of PAHs and has been extensively studied for non-substituted PAHs, while data on the bioactivation of alkyl-substituted PAHs are scarce.

Inhibition of Clostridium difficile TcdA and TcdB toxins with transition state analogues.

Clostridium difficile causes life-threatening diarrhea and is the leading cause of healthcare-associated bacterial infections in the United States. TcdA and TcdB bacterial toxins are primary determinants of disease pathogenesis and are attractive therapeutic targets. TcdA and TcdB contain domains that use UDP-glucose to glucosylate and inactivate host Rho GTPases, resulting in cytoskeletal changes causing cell rounding and loss of intestinal integrity.

Mechanism of Triphosphate Hydrolysis by Human MAT2A at 1.07 Å Resolution.

Human methionine adenosyltransferase MAT2A provides -adenosyl-l-methionine (AdoMet) for methyl-transfer reactions. Epigenetic methylations influence expression patterns in development and in cancer. Transition-state analysis and kinetic studies have described the mechanism of AdoMet and triphosphate formation at the catalytic site.

Inverse heavy enzyme isotope effects in methylthioadenosine nucleosidases.

Heavy enzyme isotope effects occur in proteins substituted with H-, C-, and N-enriched amino acids. Mass alterations perturb femtosecond protein motions and have been used to study the linkage between fast motions and transition-state barrier crossing. Heavy enzymes typically show slower rates for their chemical steps.

Aminofutalosine Deaminase in the Menaquinone Pathway of .

is a Gram-negative bacterium that is responsible for gastric and duodenal ulcers. uses the unusual pathway with aminofutalosine (AFL) as an intermediate for menaquinone biosynthesis. Previous reports indicate that hydrolysis of AFL by 5'-methylthioadenosine nucleosidase (MTAN) is the direct path for producing downstream metabolites in the pathway.

Does preoperative disease severity influence outcomes in reverse shoulder arthroplasty for cuff tear arthropathy?

Background: The degree of symptomatic disease and functional burden has been demonstrated to influence patient results and satisfaction in total hip and knee arthroplasty. Although the relationship between preoperative diagnosis and patient outcomes has been an area of study for reverse total shoulder arthroplasty (RTSA), the influence of the progression of cuff tear arthropathy (CTA) has not yet been examined. The purpose of this study was to evaluate whether preoperative radiographic disease burden and scapular geometry impact patient outcomes and satisfaction in a cohort of patients with CTA treated with RTSA.

Transition state analogue of MTAP extends lifespan of APC mice.

A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5'-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5'-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathways.

Exogenous α-amylase improves the digestibility of corn and corn-soybean meal diets for broilers.

Starch is the main energy source in broiler diets. However, endogenous amylase secretion in young broilers is suboptimal to completely digest dietary starch, so exogenous α-amylase supplementation may help increase starch digestibility. The objective of this study was to assess the supplementation of increasing doses of an exogenous α-amylase (0, 40, 80, 120, and 160 kilo-novo α-amylase units (KNU)/kg) on corn and on a complete corn-soybean meal diet for 25-day-old broilers.