Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

How an important enzyme used in drug production recognizes its substrate

05.08.2015

Increased use of enzymes producing chiral amines

A research group at the University of Tokyo has demonstrated the mechanism by which an enzyme used in industrial production of an important drug for type-2 diabetes recognizes its target. This finding will further design of novel biocatalysts for industrial production of chiral amine compounds, crucial building blocks in the synthesis of some pharmaceutical drugs.


Comparison of loop conformation of Ab-R-ATA and artificially produced ATA-117-Rd11* © 2015 Masaru Tanokura.

Pure chiral amines are crucial building blocks in the synthesis of some pharmaceutical drugs, agrochemicals and other chemical compounds. Amine transaminases (ATAs) are the focus of increasing attention as useful tools for efficient chiral-amine production. In particular, R-stereospecific ATA (R-ATA), a type of ATA that produces only R-chiral amines, has great commercial value.

In 2010 two US pharmaceutical companies created a variant of an R-ATA allowing industrial-scale synthesis of sitagliptin, a medicine for type-2 diabetes. The improved enzyme gave a 53% increase in daily production volume and a 19% reduction in total cost, as compared to the chemical approach conventionally used to synthesize sitagliptin.

However, how the industrially-important enzyme R-ATA recognized its substrate and other details remained unclear.

The research group of Professor Masaru Tanokura at the Graduate School of Agricultural and Life Sciences of the University of Tokyo, in collaboration with Biotechnology and Development Laboratories of Kaneka Corporation, determined the crystal structures of R-ATA from a bacteria that lives in soil and other materials, Arthrobacter sp. KNK168 (Ab-R-RTA), and demonstrated the mechanism of the substrate recognition and substrate specificity of R-ATAs.

One unique characteristic of ATAs is that they recognize two different substrates in the same active site, and it was found that the active-site residue arginine (Arg138) functions on both substrates. Moreover, the structures of an artificial R-ATA and the G136F mutant of Ab-R-ATA (created by substituting the 136th base glycine for phenylalanine) revealed that a loop near the catalytic site was the target site that allowed the change in substrate specificity.

“These findings should lead to the rational design of R-ATAs based on this structural information to develop novel biocatalysts useful for the production of a diverse range of chiral amine compounds. This would accelerate the industrial uses of chiral-amine synthesis using R-ATAs,” says Professor Tanokura.

*Superimposed dimeric structures of Ab-R-ATA and ATA-117-Rd11. One protomer of the dimer is shown in surface representation (right) and the other is drawn as a ribbon diagram (left). The loops near the active sites of Ab-R-ATA and ATA-117-Rd11 are highlighted in orange and green, respectively, clearly showing the difference in structure.


Associated links
UTokyo Research article

Euan McKay | ResearchSea

More articles from Life Sciences:

nachricht BigH1 -- The key histone for male fertility
14.12.2017 | Institute for Research in Biomedicine (IRB Barcelona)

nachricht Guardians of the Gate
14.12.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Plasmonic biosensors enable development of new easy-to-use health tests

14.12.2017 | Health and Medicine

New type of smart windows use liquid to switch from clear to reflective

14.12.2017 | Physics and Astronomy

BigH1 -- The key histone for male fertility

14.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>