Biochemistry: Finding nitric oxide in an oxygen haystack
DOI: 10.1038/nchembio704
A glimpse of how molecular processes such as muscle relaxation and neuronal signaling are triggered by nitric oxide is published in the June issue of Nature Chemical Biology. Michael Marletta and colleagues show how nitric oxide acts as a signaling molecule in the presence of vast excesses of oxygen - until now scientists had puzzled as to how this occurs.
Although the nitric oxide-sensing enzyme, soluble guanylate cyclase (sGC), is well characterized, the basis for selective binding of nitric oxide was not known. However, by changing a single amino acid in the active site of the enzyme from isoleucine to tyrosine, the authors converted sGC from an enzyme that excludes oxygen to one that binds oxygen. Conversely, a related bacterial enzyme with a tyrosine in the active site normally binds oxygen, but the oxygen affinity can be dramatically reduced by removal of the tyrosine. These results suggest that the active site of sGC is designed to prevent oxygen binding by maintaining a hydrophobic pocket with no hydrogen-bond donor to stabilize bound oxygen.
The authors hypothesize that this simple mechanism for controlling oxygen binding has allowed members of this enzyme family to evolve as both oxygen and nitric oxide sensors.
Author contact:
Michael A. Marletta (University of California, Berkeley, CA, USA)
Tel: +1 510) 643-9325, [email protected]
Additional contact for comment on paper:
Thomas G. Spiro (Princeton University, NJ, USA)
Tel: +1 609 258 3907; E-mail: [email protected]
Drug discovery: Keeping iron away from bacteria
DOI: 10.1038/nchembio706
During bacterial infection, there is a tug of war between the host and the bacteria to control access to the iron the bacteria need to grow. Although the host has mechanisms for sequestering iron involving tight iron-binding proteins, bacteria fight back with molecules called siderophores that can rip the iron right out of these proteins.
In the June issue of Nature Chemical Biology, Luis Quadri, Derek Tan and colleagues identify a new antibiotic lead that blocks the formation of bacterial siderophores. By inhibiting the enzyme involved in the final step of making siderophores, the authors were able to prevent Mycobacterium tuberculosis and Yersinia pestis - Bubonic Plague- from producing these iron-scavenging molecules. They found that this inhibitor was able to prevent the growth of both bacteria in conditions with restricted iron levels.
This first inhibitor of siderophore biosynthesis is a promising lead in the fight against the continued threat of tuberculosis and plague.
Author contact:
Luis Quadri (Weill Medical College of Cornell University, New York, NY USA)
Tel: +1 212 746 4497; E-mail: [email protected]
Derek Tan (Memorial Sloan-Kettering Cancer Center, New York, NY, USA)
Tel: +1 212 639 7321; E-mail: [email protected]
Additional contact for comment on paper:
Chaitan Khosla (Stanford University, CA, USA)
Tel: +1 650 723 6538; E-mail: [email protected]
Microbiology: Structure of the quorum-sensing pheromone ComX revealed
DOI: 10.1038/nchembio709
The post-translationally modified peptide pheromone ComX contains an unusual three-ring structure formed by the cyclization and prenylation of a tryptophan, according to a study published in the June issue of Nature Chemical Biology. ComX is a signal used by Bacillus subtilis to indicate cell crowding, a process known as quorum sensing. However the precise chemical structure of this important signaling molecule in Bacillus physiology was unknown.
Bacilli are an extremely diverse group of bacteria that include several species that synthesise important antibiotics. Bacillus spores are also used to test heat sterilization techniques and chemical disinfectants, due to their ability to tolerate both heat and disinfectants.
Youji Sakagami, David Dubnau and colleagues used the spectroscopic method nuclear magnetic resonance, or NMR, to determine the structure of the naturally occurring pheromone. The NMR spectra suggested the formation of an unusual tricyclic ring structure. Total chemical synthesis of the pheromone confirmed that the proposed structure had full biological activity.
Elucidation of the ComX structure is likely to open up new avenues in the molecular understanding of Bacillus quorum sensing, as well as to stimulate research into the chemical mechanism for forming this unusual peptide modification.
Author contact:
Youji Sakagami (Nagoya University, Aichi, Japan)
Tel: +81 52 789 4116; E-mail: [email protected]
David Dubnau (Public Health Research Institute, Newark, NJ, USA)
Tel: +1 973 854 3400; E-mail: [email protected]
Additional contact for comment on paper:
Richard Gibbs (Purdue University, West Lafayette, IN, USA)
Tel: +1 765 494 1456; E-mail: [email protected]
Other papers from Nature Chemical Biology to be published online at the same time and with the same embargo:
Chemistry in Living Systems
DOI: 10.1038/nchembio710
Molecular basis of inverse agonism in a G protein-coupled receptor
DOI: 10.1038/nchembio705
Activity-based probes that target diverse cysteine protease families
DOI: 10.1038/nchembio707
Small-molecule ligand induces nucleotide flipping in (CAG)n trinucleotide repeats
DOI: 10.1038/nchembio708
