PRESS RELEASES
Please quote Nature Chemical Biology as the source of these items.
The June 2005 issue of Nature Chemical Biology is available online.
June 2005
Biochemistry: RNA enzymes use acid
pp 45 - 52A new way of understanding how RNA molecules may catalyze reactions central to retrovirus replication is presented in a paper published online in the new journal Nature Chemical Biology this week. The paper, by Joseph Piccirilli and colleagues, shows how a RNA molecule from the hepatitis delta virus (HDV) uses an acidic group to accelerate a chemical reaction central to its life cycle. The active HDV molecule, or ribozyme, is a catalytic RNA molecule that cuts long RNAs into smaller chunks and is essential for the life cycle of the virus. The three-dimensional structure of the HDV ribozyme previously showed that a cytosine residue was positioned near the chemical reaction site. However, the role of the cytosine has remained mysterious for several years.
Piccirilli shows that catalytic RNAs, like protein enzymes, may use acidic groups to accelerate chemical reactions. By subtly changing the structure of the HDV ribozyme and measuring how each change affected its ability to chop up RNA, the team showed that the central cytosine base acts as a 'general acid' and donates a proton at a key step in the reaction.
This study suggests that RNA bases in ribozyme active sites may be more versatile than was previously thought.
Biochemistry: Finding nitric oxide in an oxygen haystack
pp 53 - 59A 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.
Drug Discovery: Keeping iron away from bacteria
pp 29 - 32During 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.
Microbiology: Structure of the quorum-sensing pheromone ComX revealed
pp 23 -24The 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.
General acid catalysis by the hepatitis delta virus ribozyme
pp 45 - 52Subha R Das and Joseph A Piccirilli
Published online: 03 May 2005 | doi 10.1038/nchembio703
A molecular basis for NO selectivity in soluble guanylate cyclase
pp 53 - 59Elizabeth M Boon, Shirley H Huang and Michael A Marletta
Published online: 24 May 2005 | doi 10.1038/nchembio704
Small-molecule inhibition of siderophore biosynthesis in Mycobacterium tuberculosis and Yersinia pestis
pp 29 - 32Julian A Ferreras, Jae-Sang Ryu, Federico Di Lello, Derek S Tan and Luis E N Quadri
Published online: 24 May 2005 | doi 10.1038/nchembio706
Structure of the Bacillus subtilis quorum-sensing peptide pheromone ComX
pp 23 - 24Masahiro Okada, Isao Sato, Soo Jeong Cho, Hidehisa Iwata, Toshihiko Nishio, David Dubnau and Youji Sakagami
Published online: 24 May 2005 | doi 10.1038/nchembio709
