Volume 8 Issue 4, April 2012

Selective reduction of keto groups contributes to the structural diversity of polyketide natural products. New research on fungal polyketide synthases reveals unusual biosynthetic programming in which a single ketoreductase domain shows different stereochemical preferences on the basis of substrate-chain length.

The activity of the anaphase-promoting complex is regulated by the autoubiquitination of Cdc20. How this autoubiquitination is regulated remains an open question. The pharmacological inhibitor TAME now provides insight into this regulation.

Owing to population aging, the number of individuals suffering from Alzheimer's disease is rapidly increasing; consequently, finding an effective treatment is becoming an increasingly important goal. The use of O-GlcNAcase inhibitors is emerging as a promising track to prevent and slow disease progression.

The cell wall of tubercle bacilli is targeted by many drugs. A new adamantyl urea compound unveils MmpL3, a member of the resistance, nodulation and division protein family, as the long-sought trehalose monomycolate transporter, essential for translocation of mycolic acids into the cell envelope.

X-ray crystallographic analysis of thymine DNA glycosylase (TDG) in complex with DNA containing 5-carboxylcytosine (5caC) analogs reveals that 5caC is a preferred substrate of TDG, providing support for a 5-methylcytosine demethylation pathway involving 5-methylcytosine oxidation and removal by base-excision repair glycosylases.

The iterative, highly-reducing polyketide synthases use a single copy of each domain to transform multiple substrates, defying conventional rules regarding enzyme function. Synthetic tool compounds and hybrid constructs now provide insights into the specificity of the ketoreductase in dehydrozearalenol biosynthesis.

An adamantyl urea derivative identified as a potent bactericidal compound against Mycobacterium species and multidrug-resistant M. tuberculosis targets a late step in biogenesis of very-long-chain cell wall–bound mycolic acids—by inhibiting the transport of the fatty acids across the bacterial plasma membrane.

Optimized negative-staining and cryo–positive staining EM reveals that human cholesteryl ester transfer protein penetrates into HDL and LDL from each distal end and potentially forms a continuous tunnel by connecting its internal series of isolated hydrophobic cavities together for cholesteryl ester transfer.

The unusual crosslinks between cysteine residues and the peptide backbone in the antibiotic peptide subtilosin A are formed by a new member of the radical SAM enzyme superfamily that contains two functionally linked [4Fe-4S] clusters.

Macrocycles are well represented in natural product structures but have been challenging to access for inclusion in synthetic libraries. A new method uses ring expansion to convert fused small rings into macrolactones and macrolactams that occupy natural product–like chemical space.

DNA-templated macrocycles bind the ATP binding pocket of Src kinase, locking it into an inactive conformation. These small-molecule inhibitors compete with both ATP and substrate for binding and inhibit the T338I gatekeeper mutant version of Src.

Studying specific cellular responses elicited by compartmented cAMP signals in real time has been difficult. A new method called SMICUS overcomes this challenge and reveals a resident pool of nuclear PKA that can convert cAMP signals to rapid responses.

TAME, an inhibitor of the ubiquitin ligase APC, promotes autoubiquitination and dissociation of Cdc20, an APC activator. In the presence of APC substrate, TAME decreases the catalytic activity of APC-Cdc20 complex and decouples substrate ubiquitination from proteasomal degradation.

A compound that inhibits hydrolysis of O-GlcNAc groups decreases the neurodegenerative capacity of tau, a protein that forms neurofibrillary tangles in Alzheimer's disease.

Dipeptides transported by the yeast amino acid transceptor Gap1 act as persistent agonists by accumulating with the transceptor within endosomes and triggering rapid cytosolic acidification via Gap1's H⁺ cotransport function.