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Rosanilins: indicator dyes for chloramphenicol-resistant enterobacteria containing chloramphenicol acetyltransferase.

Rosanilin dyes such as crystal violet and basic fuchsin have been used as indicator dyes in solid growth medium for chloramphenicol-resistant enterobacterial colonies containing the enterobacterial resistance enzyme chloramphenicol acetyltransferase (CAT). On certain media containing rosanilins, cells containing CAT formed darker colonies than cells not containing CAT. Contrast was affected by the types and concentrations of complex nutrients, sugars salts, and rosanilin dyes present. When crystal violet was used as the indicator dye, contrast could not be obtained for strains whose growth was

Choline acetyltransferase activity in postganglionic parasympathetic nerves after "pharmacological decentralization".

The ganglion blocking drug chlorisondamine given frequently and in gradually increasing doses over a period of time to adult rats causes the activity of choline acetyltransferase to fall in the postganglionic parasympathetic nerves of parotid glands. Such a "pharmacologically" decentralized gland was also found to have lost weight and to have developed a supersensitivity to chemical stimuli. All these phenomena are thought to be consequences of loss or reduction of secretory impulses from the central nervous system due to impaired ganglionic transmission.

Distinct roles of the JADE and BRPF scaffolding subunits of the acetyltransferase HBO1 complex.

The human acetyltransferase complex HBO1 is implicated in cancer and developmental diseases. Here, we report the chromatin association mechanisms for scaffolding subunits of the complex, the JADE and BRPF paralogs. Structural and biochemical studies reveal a distinct paralog-specific engagement of the PZP domains of JADE1/2/3 and BRPF1 with the nucleosome. We show that only JADE1's PZP domain possesses a strong intrinsic DNA binding activity and binds to an almost entire histone H3 tail, forming a tight complex with the nucleosome. In contrast, the BRPF1 PZP domain's association with the nucle

Mitigation of Injury from Myocardial Infarction by Pentamidine, an Inhibitor of the Acetyltransferase Tip60.

PURPOSE: There is an urgent unmet need for new pharmacologic approaches that promote re-muscularization and repair following myocardial infarction (MI). We previously reported that genetic depletion of the acetyltransferase Tip60 after MI in a mouse model activates the CM cell-cycle, reduces scarring, and restores cardiac function, and that these beneficial effects are mimicked by the Tip60-selective inhibitor TH1834. Here, we investigated whether the FDA-approved anti-microbial agent pentamidine, a Tip60 inhibitor from which TH1834 is derived, also protects from the damaging effects of MI. M

Biochemical Characterisation of the Short Isoform of Histone N-Terminal Acetyltransferase NAA40.

N-alpha-acetyltransferase 40 (NAA40) is an evolutionarily conserved N-terminal acetyltransferase (NAT) linked to oncogenesis and chemoresistance. A recent study reported the generation of a second, shorter NAA40 isoform (NAA40S) through alternative translation, which we proceeded to further characterise. Notably, recombinant NAA40S had a greater in vitro enzymatic activity and affinity towards its histone H2A/H4 substrates compared to full-length NAA40 (NAA40L). Within cells, NAA40S was enzymatically active, based on its ability to suppress the H2A/H4S1Ph antagonistic mark in CRISPR-generated

An essential endoplasmic reticulum-resident N-acetyltransferase ortholog in Plasmodium falciparum.

N-terminal acetylation is a common eukaryotic protein modification that involves the addition of an acetyl group to the N-terminus of a polypeptide. This modification is largely performed by cytosolic N-terminal acetyltransferases (NATs). Most associate with the ribosome, acetylating nascent polypeptides co-translationally. In the malaria parasite Plasmodium falciparum, exported effectors are thought to be translated into the endoplasmic reticulum (ER), processed by the aspartic protease plasmepsin V and then N-acetylated, despite having no clear access to cytosolic NATs. Here, we used inducib…

Expanded in vivo substrate profile of the yeast N-terminal acetyltransferase NatC.

N-terminal acetylation is a conserved protein modification among eukaryotes. The yeast Saccharomyces cerevisiae is a valuable model system for studying this modification. The bulk of protein N-terminal acetylation in S. cerevisiae is catalyzed by the N-terminal acetyltransferases NatA, NatB, and NatC. Thus far, proteome-wide identification of the in vivo protein substrates of yeast NatA and NatB has been performed by N-terminomics. Here, we used S. cerevisiae deleted for the NatC catalytic subunit Naa30 and identified 57 yeast NatC substrates by N-terminal combined fractional diagonal chromato…

Evolutionary Genomics Reveals Multiple Functions of Arylalkylamine N-Acetyltransferase in Fish.

As an important hormone, melatonin participates in endocrine regulation of diverse functions in vertebrates. Its biosynthesis is catalyzed by four cascaded enzymes, among them, arylalkylamine N-acetyltransferase (AANAT) is the most critical one. Although only single aanat gene has been identified in most groups of vertebrates, researchers including us have determined that fish have the most diverse of aanat genes (aanat1a, aanat1b, and aanat2), playing various potential roles such as seasonal migration, amphibious aerial vision, and cave or deep-sea adaptation. With the rapid development of ge

Histone acetyltransferase inhibition rescues differentiation of emerin-deficient myogenic progenitors.

INTRODUCTION: Emery-Dreifuss muscular dystrophy (EDMD) is a disease characterized by skeletal muscle wasting, major tendon contractures, and cardiac conduction defects. Mutations in the gene encoding emerin cause EDMD1. Our previous studies suggested that emerin activation of histone deacetylase 3 (HDAC3) to reduce histone 4-lysine 5 (H4K5) acetylation (ac) is important for myogenic differentiation. METHODS: Pharmacological inhibitors (Nu9056, L002) of histone acetyltransferases targeting acetylated H4K5 were used to test whether increased acetylated H4K5 was responsible for the impaired diff…

The histone acetyltransferase GcnE regulates conidiation and biofilm formation in Aspergillus fumigatus.

Histone modifications play a crucial role in eukaryotic gene regulation. The Spt-Ada-Gcn5-acetyltransferase (SAGA) complex controls histone acetylation, with Gcn5 (GcnE) acting as the acetyltransferase. In the Aspergillus species, GcnE has been shown to regulate asexual development and secondary metabolism. Apart from this, GcnE is required for pathogenicity in plant fungal pathogen A. flavus; however, the role of GcnE in the pathogenicity of human pathogenic fungus A. fumigatus is unknown. In this study, we uncovered the key roles of GcnE in A. fumigatus conidiation, stress responses, and bio

Crystal structure of the aminoglycosides N-acetyltransferase Eis2 from Mycobacterium abscessus.

Mycobacterium abscessus is an emerging human pathogen that is notorious for being one of the most drug-resistant species of Mycobacterium. It has developed numerous strategies to overcome the antibiotic stress response, limiting treatment options and leading to frequent therapeutic failure. The panel of aminoglycosides (AG) usually used in the treatment of M. abscessus pulmonary infections is restricted by chemical modification of the drugs by the N-acetyltransferase Eis2 protein (Mabs_Eis2). This enzyme acetylates the primary amine of AGs, preventing these antibiotics from binding ribosomal R

Effect of N-Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy.

Hydralazine, an antihypertensive agent used during pregnancy, undergoes N-acetylation primarily via N-acetyltransferase 2 (NAT2) to form 3-methyl-1,2,4-triazolo[3,4-a]phthalazine (MTP). To characterize the steady-state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5-25 mg every 6 hours) in mid- (n = 5) and/or late pregnancy (n = 8). Serial blood samples were collected over 1 dosing interval, and steady-state noncompartmental PK parameters were estimated.

A potential acetyltransferase involved in Leishmania major metacaspase-dependent cell death.

BACKGROUND: Currently, there is no satisfactory treatment for leishmaniases, owing to the cost, mode of administration, side effects and to the increasing emergence of drug resistance. As a consequence, the proteins involved in Leishmania apoptosis seem a target of choice for the development of new therapeutic tools against these neglected tropical diseases. Indeed, Leishmania cell death, while phenotypically similar to mammalian apoptosis, is very peculiar, involving no homologue of the key mammalian apoptotic proteins such as caspases and death receptors. Furthermore, very few proteins invol

Spermidine/spermine N1-acetyltransferase-1 as a diagnostic biomarker in human cancer.

AimSSAT-1 is an enzyme that plays a critical role in cell growth. Amantadine, a FDA-approved antiviral drug, is a substrate for SSAT-1. The utility of amantadine as an agent to demonstrate elevated SSAT-1 activity linked to cancer was conducted.ResultsHigh levels of SSAT-1 expression were measured in tumor human cell lines, and in breast, prostate and lung tumor tissue. An increase in the urinary levels of acetylated amantadine in cancer patients was observed.ConclusionIncreases in SSAT-1 contents in tumor tissue could be of value in targeting cancers with high SSAT-1 expression for confirmati

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… It has been assumed that the increased acetylation activity could be attributed to the acetyltransferases NAT1 and NAT2. … N1-acetyltransferase catalyzes amantadine acetylation Drug Metab. …

The acetyltransferase Tip60 is a critical regulator of the differentiation-dependent amplification of human papillomaviruses.

UNLABELLED: The life cycle of human papillomaviruses (HPVs) is dependent upon differentiation of the infected host epithelial cell as well as activation of the ataxia telangiectasia mutated (ATM) DNA repair pathway that in normal cells acts to repair double-strand DNA breaks. In normal cells, following DNA damage the acetyltransferase Tip60 must acetylate ATM proteins prior to their full activation by autophosphorylation. E6 proteins have been shown to induce the degradation of Tip60, suggesting that Tip60 action may not be required for activation of the ATM pathway in HPV-positive cells. We i

Identification of critical residues of the serotype modifying O-acetyltransferase of Shigella flexneri.

BACKGROUND: Thirteen serotypes of Shigella flexneri (S. flexneri) have been recognised, all of which are capable of causing bacillary dysent … isting of hydrophobic and hydrophilic components. Oac bears homology to several known and predicted acetyltransferases with most homology existing in the N-terminal transmembrane (TM) regions. RESULTS: In this study, the conserved motifs in the TM regions and in hydrophilic loops of S. flexneri Oac were targeted for mutagenesis with the aim of identifying the amino …

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site.

Treatment of latent tuberculosis infection remains an important goal of global TB eradication. To this end, targets that are essential for intracellular survival of Mycobacterium tuberculosis are particularly attractive. Arylamine N-acetyltransferase (NAT) represents such a target as it is, along with the enzymes encoded by the associated gene cluster, essential for mycobacterial survival inside macrophages and involved in cholesterol degradation. Cholesterol is likely to be the fuel for M. tuberculosis inside macrophages. Deleting the nat gene and inhibiting the NAT enzyme prevents survival o

Role of the N-acetyltransferase 2 detoxification system in thyroid cancer susceptibility.

PURPOSE: Genetic polymorphisms in genes encoding for enzymes involved in the biotransformation of carcinogens have been shown to be relevant as risk for cancer and may be of considerable importance from a public health point of view. Considering that N-acetyltransferase 2 (NAT2) polymorphisms modulate the response to ionizing radiation, the strongest risk factor recognized to cause differentiated thyroid cancer (DTC) thus far, we sought to determine the influence of NAT2 detoxification system on thyroid cancer susceptibility. EXPERIMENTAL DESIGN: We conducted a prospective case-control study,

Zebrafish arylalkylamine-N-acetyltransferase genes - targets for regulation of the circadian clock.

Daily rhythms of melatonin production are controlled by changes in the activity of arylalkylamine-N-acetyltransferase (AANAT). Zebrafish possess two aanats, aanat1 and aanat2; the former is expressed only in the retina and the latter is expressed in both the retina and the pineal gland. Here, their differential expression and regulation were studied using transcript quantification and transient and stable in vivo and in vitro transfection assays. In the pineal gland, the aanat2 promoter exhibited circadian clock-controlled activity, as indicated by circadian rhythms of Enhanced green fluoresce

Proteasomal proteolysis in the adrenergic induction of arylalkylamine-N-acetyltransferase in rat pinealocytes.

In this study, we investigated the effect of proteasomal inhibition on the induction of arylalkylamine-N-acetyltransferase (AA-NAT) enzyme in cultured rat pinealocytes, using two proteasome inhibitors, MG132 and clastolactacystin beta-lactone (c-lact). Addition of c-lact or MG132 3 h after norepinephrine (NE) stimulation produced a significant increase in AA-NAT protein level and enzyme activity. However, when the proteasome inhibitors were added before or together with NE, significant reductions of the NE-induced aa-nat mRNA, protein, and enzyme activity were observed. A similar inhibitory ef