Modeling the structural origins of drug resistance to isoniazid via key mutations in Mycobacterium tuberculosis catalase-peroxidase, KatG.

WHO reported 10.4 million new tuberculosis (TB) cases and 1.8 million deaths in 2015, making M.

Structure-based analysis of Bacilli and plasmid dihydrofolate reductase evolution.

Dihydrofolate reductase (DHFR), a key enzyme in tetrahydrofolate-mediated biosynthetic pathways, has a structural motif known to be highly conserved over a wide range of organisms. Given its critical role in purine and amino acid synthesis, DHFR is a well established therapeutic target for treating a wide range of prokaryotic and eukaryotic infections as well as certain types of cancer. Here we present a structural-based computer analysis of bacterial (Bacilli) and plasmid DHFR evolution.

The conformation of acetylated virginiamycin M1 and virginiamycin M1 in explicit solvents.

The three-dimensional structure of acetylated virginiamycin M(1) (acetylated VM1) in chloroform and in a water/acetonitrile mixture (83:17 v/v) have been established through 2D high resolution NMR experiments and molecular dynamics modeling and the results compared with the conformation of the antibiotic VM1 in the same and other solvents. The results indicated that acetylation of the C-14 OH group of VM1 caused it to rotate about 90 degrees from the position it assumed in non-acetylated VM1. The conformation of both VM1 and acetylated VM1 appear to flatten in moving from a nonpolar to polar solvent.

Thoughts on the teaching of metabolism.

Systems biology, metabolomics, metabolic engineering, and other recent developments in biochemistry suggest that future biochemists will require a detailed familiarity with the compounds and pathways of intermediary metabolism and their biochemical control. The challenge to the biochemistry instructor is the presentation of metabolic pathways in a manner that allows student creativity in learning the pathways and their components. One approach that does permit the use of problem solving for the study of metabolic pathways involves following the fate of (13) C, (14) C, or (15) N labels, presented originally in the structure of an important metabolic starting compound, through relevant metabolic pathways.

Cytotoxicity of xanthopterin and isoxanthopterin in MCF-7 cells.

Human mammary carcinoma MCF-7 cell line responsiveness to the pteridines xanthopterin and isoxanthopterin was studied using the MTS assay for measurement of cell viability. The pteridines were tested at concentrations ranging from 7.8 to 500 microM singly and in 11 isoxanthopterin:xanthopterin ratios.

The conformational flexibility of the antibiotic virginiamycin M(1).

The antibiotic virginiamycin is a combination of two molecules, virginiamycin M(1) (VM1) and virginiamycin S(1) (VS1) or analogues, which function synergistically by binding to bacterial ribosomes and inhibiting bacterial protein synthesis. Both VM1 and VS1 dissolve poorly in water and are soluble in more hydrophobic solvents. We have recently reported that the 3D conformation of VM1 in CDCl(3) solution differs markedly from the conformation bound to a VM1 binding enzyme and to 50S ribosomes as found by X-ray crystallographic studies.

Solvent affects the conformation of virginiamycin M1 (pristinamycin IIA, streptogramin A).

The streptogramins are antibiotics which act by binding two different components at separate nearby sites on the bacterial 50S ribosome, inhibiting protein synthesis. The first component, a macrolactone, is common to many of the streptogramin antibiotics and, thus, is referred to by many names including virginiamycin M1(VM1), pristinamycin IIA, ostreogrycin A and streptogramin A. X-Ray crystallographic studies of VM1 bound to ribosomes and to a deactivating enzyme show a different conformation to that of VM1 in chloroform solution.