E487K-Induced Disorder in Functionally Relevant Dynamics of Mitochondrial Aldehyde Dehydrogenase 2.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2), which is a homotetramer assembled by two equivalent dimers, is an important enzyme that metabolizes ethanol-derived acetaldehyde to acetate in a coenzyme-dependent manner. The highly reactive acetaldehyde exhibits a toxic effect, indicating that the proper functioning of ALDH2 is essential to counteract aldehyde-associated diseases. It is known that the catalytic activity of ALDH2 is drastically impaired by a frequently observed mutation, E487K, in a dominant fashion.

Improvement in predicting drug sensitivity changes associated with protein mutations using a molecular dynamics based alchemical mutation method.

While molecular-targeted drugs have demonstrated strong therapeutic efficacy against diverse diseases such as cancer and infection, the appearance of drug resistance associated with genetic variations in individual patients or pathogens has severely limited their clinical efficacy. Therefore, precision medicine approaches based on the personal genomic background provide promising strategies to enhance the effectiveness of molecular-targeted therapies. However, identifying drug resistance mutations in individuals by combining DNA sequencing and in vitro analyses is generally time consuming and costly.

Author Correction: Mechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids.

In the original version of this Article, the abbreviation of 3,4-dihydroxyphenylacetaldehyde synthase presented in the first paragraph of the Discussion section was given incorrectly as DYPAA. The correct abbreviation for this enzyme is DHPAAS. This error has been corrected in both the PDF and HTML versions of the Article.

Mechanism-based tuning of insect 3,4-dihydroxyphenylacetaldehyde synthase for synthetic bioproduction of benzylisoquinoline alkaloids.

Previous studies have utilized monoamine oxidase (MAO) and L-3,4-dihydroxyphenylalanine decarboxylase (DDC) for microbe-based production of tetrahydropapaveroline (THP), a benzylisoquinoline alkaloid (BIA) precursor to opioid analgesics. In the current study, a phylogenetically distinct Bombyx mori 3,4-dihydroxyphenylacetaldehyde synthase (DHPAAS) is identified to bypass MAO and DDC for direct production of 3,4-dihydroxyphenylacetaldehyde (DHPAA) from L-3,4-dihydroxyphenylalanine (L-DOPA). Structure-based enzyme engineering of DHPAAS results in bifunctional switching between aldehyde synthase and decarboxylase activities.

Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare mutations.

Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of mutations outside mutational hotspots, consisting of >50 types, in nonsmall cell lung carcinoma (NSCLC) is largely unknown. In fact, our pan-nation screening of NSCLC without hotspot mutations ( = 3,779) revealed that the majority (>90%) of cases with rare mutations, accounting for 5.

Improving the Accuracy of Protein-Ligand Binding Mode Prediction Using a Molecular Dynamics-Based Pocket Generation Approach.

Protein-drug binding mode prediction from the apo-protein structure is challenging because drug binding often induces significant protein conformational changes. Here, the authors report a computational workflow that incorporates a novel pocket generation method. First, the closed protein pocket is expanded by repeatedly filling virtual atoms during molecular dynamics (MD) simulations.

Quantitative assessment of harmonic power doppler myocardial perfusion imaging with intravenous Levovist in patients with myocardial infarction: comparison with myocardial viability evaluated by coronary flow reserve and coronary flow pattern of infarct-related artery.

Background: Myocardial contrast echocardiography and coronary flow velocity pattern with a rapid diastolic deceleration time after percutaneous coronary intervention has been reported to be useful in assessing microvascular damage in patients with acute myocardial infarction.

Aim: To evaluate myocardial contrast echocardiography with harmonic power Doppler imaging, coronary flow velocity reserve and coronary artery flow pattern in predicting functional recovery by using transthoracic echocardiography.

Methods: Thirty patients with anterior acute myocardial infarction underwent myocardial contrast echocardiography at rest and during hyperemia and were quantitatively analyzed by the peak color pixel intensity ratio of the risk area to the control area (PIR).