The EDGE: Nature Chemical Biology Contents: April 2012 Volume 8 Number 4, pp 320

TABLE OF CONTENTS

April 2012 Volume 8, Issue 4

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Research Highlights

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News and Views

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Biosynthesis: An HR-PKS stereo surprise pp322 - 323 Ikuro Abe doi:10.1038/nchembio.924 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. Full Text \| PDF See also: Brief Communication by Zhou et al.



Ubiquitin ligases: Taming the APC pp323 - 324 Ian T Foe and David P Toczyski doi:10.1038/nchembio.923 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. Full Text \| PDF See also: Article by Zeng & King



Neurodegeneration: Recall sugars, forget Alzheimer's pp325 - 326 Tony Lefebvre doi:10.1038/nchembio.920 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. Full Text \| PDF See also: Article by Yuzwa et al.



Infectious diseases: Transporter targeted in tuberculosis pp326 - 327 Stewart T Cole doi:10.1038/nchembio.918 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. Full Text \| PDF See also: Article by Grzegorzewicz et al.

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Brief Communications

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Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA pp328 - 330
Liang Zhang, Xingyu Lu, Junyan Lu, Haihua Liang, Qing Dai, Guo-Liang Xu, Cheng Luo, Hualiang Jiang and Chuan He
doi:10.1038/nchembio.914

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.
Abstract | Full Text | PDF

A fungal ketoreductase domain that displays substrate-dependent stereospecificity pp331 - 333
Hui Zhou, Zhizeng Gao, Kangjian Qiao, Jingjing Wang, John C Vederas and Yi Tang
doi:10.1038/nchembio.912

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.
First paragraph | Full Text | PDF | Chemical compounds
See also: News and Views by Abe

Articles

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Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane pp334 - 341
Anna E Grzegorzewicz, Ha Pham, Vijay A K B Gundi, Michael S Scherman, Elton J North, Tamara Hess, Victoria Jones, Veronica Gruppo, Sarah E M Born, Jana Korduláková, Sivagami Sundaram Chavadi, Christophe Morisseau, Anne J Lenaerts, Richard E Lee, Michael R McNeil and Mary Jackson
doi:10.1038/nchembio.794

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.
Abstract | Full Text | PDF | Chemical compounds
See also: News and Views by Cole

Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein pp342 - 349
Lei Zhang, Feng Yan, Shengli Zhang, Dongsheng Lei, M Arthur Charles, Giorgio Cavigiolio, Michael Oda, Ronald M Krauss, Karl H Weisgraber, Kerry-Anne Rye, Henry J Pownall, Xiayang Qiu and Gang Ren
doi:10.1038/nchembio.796

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.
Abstract | Full Text | PDF

The radical SAM enzyme AlbA catalyzes thioether bond formation in subtilosin A pp350 - 357
Leif Flühe, Thomas A Knappe, Michael J Gattner, Antje Schäfer, Olaf Burghaus, Uwe Linne and Mohamed A Marahiel
doi:10.1038/nchembio.798

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.
Abstract | Full Text | PDF

A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion pp358 - 365
Felix Kopp, Christopher F Stratton, Lakshmi B Akella and Derek S Tan
doi:10.1038/nchembio.911

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.
Abstract | Full Text | PDF | Chemical compounds

Highly specific, bisubstrate-competitive Src inhibitors from DNA-templated macrocycles pp366 - 374
George Georghiou, Ralph E Kleiner, Michael Pulkoski-Gross, David R Liu and Markus A Seeliger
doi:10.1038/nchembio.792

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.
Abstract | Full Text | PDF | Chemical compounds

Regulation of nuclear PKA revealed by spatiotemporal manipulation of cyclic AMP pp375 - 382
Vedangi Sample, Lisa M DiPilato, Jason H Yang, Qiang Ni, Jeffrey J Saucerman and Jin Zhang
doi:10.1038/nchembio.799

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.
Abstract | Full Text | PDF

An APC/C inhibitor stabilizes cyclin B1 by prematurely terminating ubiquitination pp383 - 392
Xing Zeng and Randall W King
doi:10.1038/nchembio.801

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.
Abstract | Full Text | PDF
See also: News and Views by Foe & Toczyski

Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation pp393 - 399
Scott A Yuzwa, Xiaoyang Shan, Matthew S Macauley, Thomas Clark, Yuliya Skorobogatko, Keith Vosseller and David J Vocadlo
doi:10.1038/nchembio.797

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.
Abstract | Full Text | PDF
See also: News and Views by Lefebvre

Peptides induce persistent signaling from endosomes by a nutrient transceptor pp400 - 408
Marta Rubio-Texeira, Griet Van Zeebroeck and Johan M Thevelein
doi:10.1038/nchembio.910

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.
Abstract | Full Text | PDF

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