Protein function from first principles

Scientists have identified the function of a previously uncharacterized enzyme using a novel approach, according to a paper to be published in the August issue of Nature Chemical Biology.

As an increasing number of genomes are sequenced, scientists gain information on what proteins might exist but are still limited in understanding what these proteins do, or where and when they perform their unknown functions. Previous attempts to uncover the roles of new proteins have been based on their similarity to other known proteins, but this approach can fail for a variety of reasons.

John Gerlt and colleagues now apply computational docking of potential enzyme substrates into a structural model to assign the function of BC0371, a protein that had previously been misassigned based on its close relationship with another protein. The authors found that allowing the amino acid side chains in the protein to vary their position during the experiments resulted in improved docking and pointed towards a specific group of compounds as likely substrates. Experimental confirmation of these preferences allowed the team to reassign the protein with its proper function. Application of these ideas should lead to similar advances for other proteins, particularly those in protein superfamilies.

Hsp90 inhibitors allow small cell lung cancer to die

Scientists describe the role played by a protective protein called Hsp90 in maintaining the malignant state of small cell lung cancer cells, in a report in the August issue of Nature Chemical Biology.

Hsp90 is a chaperone protein that helps cellular proteins fold and mature. This protective function can also stabilise oncogenic proteins in cancer cells, exacerbating their cancer-causing potential. Gabriela Chiosis and colleagues show that Hsp90 plays a particularly important role in small cell lung cancer (SCLC) cells by inhibiting apoptosis, the programmed destruction of cells. The results in SCLC cell lines help explain why SCLC tumours are so malignant, resulting in relapses even after responding well to chemotherapy.

Various selective compounds identified by the authors are potential candidates for treating SCLC patients in the future, since they allow SCLC to overcome their apoptosis defects. Further studies should help to explore this possibility.

Carbon and phosphorus meet up

Scientists have identified the enzymes that create the compound phosphinothricin, which is biologically unusual because it contains a carbon-phosphorus bond, according to a paper online this week in Nature Chemical Biology.

Natural products are typically constructed from biologically abundant building blocks, such as amino acids and functionalized acetyl groups. The extensive variation in their structure then arises from the action of various enzymes that remodel the compounds.

William Metcalf and colleagues now characterize the gene cluster responsible for making phosphinothricin. Some of the enzymes needed to make this compound were known, but the full biosynthetic pathway was not understood. The authors created a mutant Escherichia coli that contained the gene cluster, and then tested the bacteria using chemical, biochemical and genetic experiments to determine the role of each enzyme in the biosynthetic pathway. Their results allowed them to redefine this pathway, including the identification of two new chemical intermediates. As phosphinothricin is the prototypical phosphinic acid-containing natural product, these studies open the door to increased understanding of these interesting enzymatic transformations.

Prediction and assignment of function for a divergent N-succinyl amino acid racemase

Ling Song, Chakrapani Kalyanaraman, Alexander A Fedorov, Elena V Fedorov, Margaret E Glasner, Shoshana Brown, Heidi J Imker, Patricia C Babbitt, Steven C Almo, Matthew P Jacobson and John A Gerlt

Published online: 1 July 2007 | doi 10.1038/nchembio.2007.11

Abstract | Full text | PDF | Supplementary information

Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer

Anna Rodina, Maria Vilenchik, Kamalika Moulick, Julia Aguirre, Joungnam Kim, Anne Chiang, Julie Litz, Cristina C Clement, Yanlong Kang, Yuhong She, Nian Wu, Sara Felts, Peter Wipf, Joan Massague, Xuejun Jiang, Jeffrey L Brodsky, Geoffrey W Krystal and Gabriela Chiosis

Published online: 1 July 2007 | doi 10.1038/nchembio.2007.10

Abstract | Full text | PDF | Supplementary information

Unusual transformations in the biosynthesis of the antibiotic phosphinothricin tripeptide

Joshua A V Blodgett, Paul M Thomas, Gongyong Li, Juan E Velasquez, Wilfred A van der Donk, Neil L Kelleher and William W Metcalf

Published online: 15 July 2007 | doi 10.1038/nchembio.2007.9

Abstract | Full text | PDF | Supplementary information