ABSTRACT
The Aspergillus fumigatus old yellow enzyme (OYE) EasA reduces chanoclavine-I aldehyde to dihydrochanoclavine aldehyde and works in conjunction with festuclavine synthase at the branchpoint for ergot alkaloid pathways. The crystal structure of the FMN-loaded EasA was determined to 1.8â Å resolution. The active-site amino acids of OYE are conserved, supporting a similar mechanism for reduction of the α/ß-unsaturated aldehyde. The C-terminal tail of one monomer packs into the active site of a monomer in the next asymmetric unit, which is most likely to be a crystallization artifact and not a mechanism of self-regulation.
Subject(s)
Aspergillus fumigatus/enzymology , Ergot Alkaloids/biosynthesis , Fungal Proteins/chemistry , NADPH Dehydrogenase/chemistry , Catalytic Domain , Crystallography, X-Ray , Flavin Mononucleotide/chemistry , Models, Molecular , Protein Structure, SecondaryABSTRACT
OBJECTIVE: We hypothesized that nebulized iloprost would improve ventilation-perfusion matching in patients with pulmonary hypertension and ARDS as reflected by an improved Pao2/Fio2 ratio and Pao2 without adversely affecting lung mechanics or systemic hemodynamics. METHODS: Patients with ARDS and pulmonary hypertension were enrolled. With constant ventilator settings, hemodynamics, airway pressures, and gas exchange measured at baseline were compared with values 30 min after administration of 10 µg nebulized iloprost, and again 30 min after a second, larger, 20 µg dose of iloprost, and then a final measurement 2 h after the second dose. The primary outcome variable was Pao2; secondary outcomes were Pao2/Fio2 ratio, mean arterial BP, and lung-compliance ventilatory equivalents for oxygen and CO2. RESULTS: After informed consent was obtained, 20 patients (nine men, 11 women; median age, 59 years [interquartile range, 44-66 years]) with ARDS were enrolled. Baseline PaO2 improved from a mean (±SD) of 82 (13) mm Hg to 100 (25) mm Hg after both the first and second doses of iloprost, and the baseline mean (±SD) PaO2/FIO2 ratio of 177 (60) improved to 213 (67) and 212 (70) (all P<.01). PaCO2, peak and plateau airway pressures, systemic BP, and heart rate were not significantly changed after iloprost. CONCLUSIONS: The improvement in gas exchange without any detrimental effects on pulmonary mechanics or systemic hemodynamics suggests nebulized iloprost may be a useful therapeutic agent to improve oxygenation in patients with ARDS. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01274481; URL: www.clinicaltrials.gov.
