Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Water-powered reactions

29.06.2009
An international team, led by Shingo Nagano from the RIKEN SPring-8 Center in Harima and Hiroyasu Onaka from Toyama Prefectural University, has uncovered the vital role of water in the generation of the antitumor drug staurosporine (1).

The researchers mainly focus on the enzyme P450 StaP, which belongs to the cytochrome P450 enzyme family. These enzymes are involved in metabolic and biosynthetic reactions, including the activation and degradation of drugs in humans, and the synthesis of medically relevant natural products.

P450 StaP’s active site consists of a sulfur-bound iron atom enclosed in a large hydrocarbon ring called heme. It catalyzes the oxidation of a five-ring compound called chromopyrrolic acid (CPA) and facilitates the formation of an intramolecular carbon–carbon bond to generate a six-ring staurosporine precursor. This carbon–carbon bond formation is unusual for P450 enzymes, which typically insert an oxygen atom into bonds. The researchers demonstrated that water molecules mediate this carbon–carbon coupling.

Nagano and co-workers had previously revealed that strong interactions held CPA tightly in a binding pocket, modulating proton and electron transfer reactions between substrate and enzyme. However, they observed that those interactions kept the substrate away from the heme oxygen, impeding any direct contact, and thus proton transfer, between the two species.

In their latest work, they mutated the enzyme by replacing a residue positioned between the two water molecules with hydrocarbons, which significantly decreased its activity. They also substituted CPA with a chlorine-containing compound (CCA) and discovered that the chlorine atom prevented water molecules from approaching the heme. Further, they observed decreased activity in presence of CCA, highlighting the importance of water in the mechanism.

“CCA is very poor substrate but we had no idea why this happens,” says Nagano. Since his collaborator proposed that this water molecule was very likely to be a key player in this enzyme catalysis, they ran a detailed computational investigation. They found that two water molecules in the enzyme active site acted as a proton relay between CPA and the heme.

“Similar water-assisted proton transfer between heme and substrate is also found in horseradish peroxidase (HRP), another heme enzyme,” explains Nagano. “The natural substrate-bound HRP has a water molecule close to the substrate and heme as we have observed in CPA-bound P450 StaP.” The researchers’ ultimate goal is to transpose this carbon–carbon coupling to other P450 enzymes and generate new staurosporine-like therapeutic agents.

Reference

1. Wang, Y., Chen, H., Makino, M., Shiro, Y., Nagano, S., Asamizu, S., Onaka, H. & Shaik, S. Theoretical and experimental studies of the conversion of chromopyrrolic acid to an antitumor derivative by cytochrome P450 StaP: the catalytic role of water molecules. Journal of the American Chemical Society 131, 6748–6762 (2009).

The corresponding author for this highlight is based at the RIKEN Photon Science Research Division, Biometal Science Laboratory

Saeko Okada | Research asia research news
Further information:
http://www.rikenresearch.riken.jp/research/731/
http://www.researchsea.com

More articles from Life Sciences:

nachricht Why developing nerve cells can take a wrong turn
04.06.2020 | Universität zu Köln

nachricht Innocent and highly oxidizing
04.06.2020 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Small Protein, Big Impact

In meningococci, the RNA-binding protein ProQ plays a major role. Together with RNA molecules, it regulates processes that are important for pathogenic properties of the bacteria.

Meningococci are bacteria that can cause life-threatening meningitis and sepsis. These pathogens use a small protein with a large impact: The RNA-binding...

Im Focus: K-State study reveals asymmetry in spin directions of galaxies

Research also suggests the early universe could have been spinning

An analysis of more than 200,000 spiral galaxies has revealed unexpected links between spin directions of galaxies, and the structure formed by these links...

Im Focus: New measurement exacerbates old problem

Two prominent X-ray emission lines of highly charged iron have puzzled astrophysicists for decades: their measured and calculated brightness ratios always disagree. This hinders good determinations of plasma temperatures and densities. New, careful high-precision measurements, together with top-level calculations now exclude all hitherto proposed explanations for this discrepancy, and thus deepen the problem.

Hot astrophysical plasmas fill the intergalactic space, and brightly shine in stellar coronae, active galactic nuclei, and supernova remnants. They contain...

Im Focus: Biotechnology: Triggered by light, a novel way to switch on an enzyme

In living cells, enzymes drive biochemical metabolic processes enabling reactions to take place efficiently. It is this very ability which allows them to be used as catalysts in biotechnology, for example to create chemical products such as pharmaceutics. Researchers now identified an enzyme that, when illuminated with blue light, becomes catalytically active and initiates a reaction that was previously unknown in enzymatics. The study was published in "Nature Communications".

Enzymes: they are the central drivers for biochemical metabolic processes in every living cell, enabling reactions to take place efficiently. It is this very...

Im Focus: New double-contrast technique picks up small tumors on MRI

Early detection of tumors is extremely important in treating cancer. A new technique developed by researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from normal tissue. The work is published May 25 in the journal Nature Nanotechnology.

researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Dresden Nexus Conference 2020: Same Time, Virtual Format, Registration Opened

19.05.2020 | Event News

Aachen Machine Tool Colloquium AWK'21 will take place on June 10 and 11, 2021

07.04.2020 | Event News

International Coral Reef Symposium in Bremen Postponed by a Year

06.04.2020 | Event News

 
Latest News

Why developing nerve cells can take a wrong turn

04.06.2020 | Life Sciences

The broken mirror: Can parity violation in molecules finally be measured?

04.06.2020 | Physics and Astronomy

Innocent and highly oxidizing

04.06.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>