Substrate flexibility of a 2,6-dideoxyglycosyltransferase

We report the first 2,6-dideoxysugar-O-glycosyltransferase with substrate flexibility at the 2 position, confirm the function of a putative NDP-hexose 2,3-dehydratase in the jadomycin B biosynthetic gene cluster and deduce the substrate flexibility of downstream enzymes in l-digitoxose assembly, enabling reprogramming of biosynthetic gene clusters to modify sugar substituents.     

Detecting functional magnetic resonance imaging activation in white matter: Interhemispheric transfer across the corpus callosum

Background  

It is generally believed that activation in functional magnetic resonance imaging (fMRI) is restricted to gray matter. Despite this, a number of studies have reported white matter activation, particularly when the corpus callosum is targeted using interhemispheric transfer tasks. These findings suggest that fMRI signals may not be neatly confined to gray matter tissue. In the current experiment, 4 T fMRI was employed to evaluate whether it is possible to detect white matter activation. We used an interhemispheric transfer task modelled after neurological studies of callosal disconnection. It was hypothesized that white matter activation could be detected using fMRI.     

Engineered synthesis of 7-oxo- and 15-deoxy-15-oxo-amphotericins: insights into structure-activity relationships in polyene antibiotics

Site-directed mutagenesis and gene replacement were used to inactivate two ketoreductase (KR) domains within the amphotericin polyketide synthase in Streptomyces nodosus. The KR12 domain was inactivated in the DeltaamphNM strain, which produces 16-descarboxyl-16-methyl-amphotericins. The resulting mutant produced low levels of the expected 15-deoxy-15-oxo analogs that retained antifungal activity. These compounds can be useful for further chemical modification. Inactivation of the KR16 domain in the wild-type strain led to production of 7-oxo-amphotericin A and 7-oxo-amphotericin B in good yield. 7-oxo-amphotericin B was isolated, purified, and characterized as the N-acetyl methyl ester derivative. 7-oxo-amphotericin B had good antifungal activity and was less hemolytic than amphotericin B. These results indicate that modification at the C-7 position can improve the therapeutic index of amphotericin B.     

Ring-opening dynamics of jadomycin A and B and dalomycin T

[structure: see text] A novel oxazolone ring-opening and interconversion process between the two jadomycin diastereomeric forms has been characterized by NMR spectroscopy. An analogue, dalomycin T, has been isolated for the first time and does not undergo interconversion.     

Adenophostin A and analogues modified at the adenine moiety: synthesis, conformational analysis and biological activity

The synthesis of adenophostin A (2) and two analogues [etheno adenophostin (4) and 8-bromo adenophostin (5)] modified at the adenine moiety, is reported. A combination of NMR analysis and molecular modelling was used to compare their structures in solution and determined that they all adopt very similar conformations. The analogues were tested for their ability to mobilise Ca(2+) from DT40 cells expressing recombinant Type 1 rat Ins(1,4,5)P(3)R which reveals etheno adenophostin as a high affinity fluorescent probe of the Ins(1,4,5)P(3)R. 8-Bromo adenophostin was only slightly less potent. The biological results support our current hypothesis regarding the binding mode of adenophostin A at the Ins(1,4,5)P(3)R, i. e. that a cation-pi interaction between the base moiety and Arg 504 of the receptor in combination with H-bonding may be responsible for the high potency of adenophostin A relative to Ins(1,4,5)P(3).