The relationship between secondary metabolism and infection in pathogenic fungi has remained largely elusive. The genus Penicillium comprises a group of plant pathogens with varying host specificities and with the ability to produce a wide array of secondary metabolites. The genomes of three Penicillium expansum strains, the main postharvest pathogen of pome fruit, and one Pencillium italicum strain, a postharvest pathogen of citrus fruit, were sequenced and compared with 24 other fungal species. A genomic analysis of gene clusters responsible for the production of secondary metabolites was performed. Putative virulence factors in P. expansum were identified by means of a transcriptomic analysis of apple fruits during the course of infection. Despite a major genome contraction, P. expansum is the Penicillium species with the largest potential for the production of secondary metabolites. Results using knockout mutants clearly demonstrated that neither patulin nor citrinin are required by P. expansum to successfully infect apples. Li et al. ( MPMI-12-14-0398-FI ) reported similar results and conclusions in their recently accepted paper.
BACKGROUND: Mucus stasis in chronic obstructive pulmonary disease (COPD) is a significant contributor to morbidity and mortality. Potentiators of cystic fibrosis transmembrane conductance regulator (CFTR) activity pharmacologically enhance CFTR function; ivacaftor is one such agent approved to treat CF patients with the G551D-CFTR gating mutation. CFTR potentiators may also be useful for other diseases of mucus stasis, including COPD. METHODS AND FINDINGS: In primary human bronchial epithelial cells, exposure to cigarette smoke extract diminished CFTR-mediated anion transport (65.8+/-0.2% of control, P<0.005) and mucociliary transport (0.17+/-0.05 microm/sec vs. 2.4+/-0.47 microm/sec control, P<0.05) by reducing airway surface liquid depth (7.3+/-0.6 microm vs. 13.0+/-0.6 microm control, P<0.005) and augmenting mucus expression (by 64%, P<0.05) without altering transepithelial resistance. Smokers with or without COPD had reduced CFTR activity measured by nasal potential difference compared to age-matched non-smokers (-6.3+/-1.4 and -8.0+/-2.0 mV, respectively vs. -15.2+/-2.7 mV control, each P<0.005, n = 12-14/group); this CFTR decrement was associated with symptoms of chronic bronchitis as measured by the Breathlessness Cough and Sputum Score (r = 0.30, P<0.05) despite controlling for smoking (r = 0.31, P<0.05). Ivacaftor activated CFTR-dependent chloride transport in non-CF epithelia and ameliorated the functional CFTR defect induced by smoke to 185+/-36% of non-CF control (P<0.05), thereby increasing airway surface liquid (from 7.3+/-0.6 microm to 10.1+/-0.4 microm, P<0.005) and mucociliary transport (from 0.27+/-0.11 microm/s to 2.7+/-0.28 microm/s, P<0.005). CONCLUSIONS: Cigarette smoking reduces CFTR activity and is causally related to reduced mucus transport in smokers due to inhibition of CFTR dependent fluid transport. These effects are reversible by the CFTR potentiator ivacaftor, representing a potential therapeutic strategy to augment mucociliary clearance in patients with smoking related lung disease.
        
Title: Hydrolysis of 3H-bambuterol, a carbamate prodrug of terbutaline, in blood from humans and laboratory animals in vitro Tunek A, Levin E, Svensson LA Ref: Biochemical Pharmacology, 37:3867, 1988 : PubMed
Tritiated bambuterol, a bis-dimethylcarbamate prodrug of terbutaline, was incubated in vitro with blood from both sexes of the following species: man, guinea pig, rat, mouse, dog and rabbit. The rates of hydrolysis of bambuterol to its monocarbamate derivative and further to terbutaline were measured. Large species variations were observed, e.g. blood from two of the human subjects was 15-fold more active than blood from the male rats. The rate of terbutaline formation as a function of initial bambuterol concentration was investigated in human plasma, and was found to describe a bell-shaped curve. Several pieces of evidence indicated that butyrylcholinesterase (EC 3.1.1.8) is the blood enzyme predominantly responsible for hydrolysis of bambuterol, although minor contributions from other esterases cannot be excluded. An exception may be blood from the rabbit, where the kinetics of the hydrolysis was different than in blood from the other species. The kinetics of bambuterol hydrolysis is discussed on basis of the established mechanism of carbamate interactions with cholinesterases, and the high affinity of bambuterol for butyrylcholinesterase.