Featured Research

from universities, journals, and other organizations

IspH -- a protein free to choose its partners

Date:
October 9, 2012
Source:
Technische Universitaet Muenchen
Summary:
The iron-sulfur protein IspH plays a central role in the terpene metabolism of several pathogens. The mechanism of the reaction provides an approach for developing new antibiotics, particularly against malaria and tuberculosis. While researching this enzyme, biochemists discovered a previously unknown reaction: IspH accepts two completely different classes of molecules as partners. This surprising insight opens up new perspectives in combating infectious diseases.

Cross-section of a surface model of IspH, showing the reaction center and the bound ligand.
Credit: TUM

The iron-sulfur protein IspH plays a central role in the terpene metabolism of several pathogens. The mechanism of the reaction provides an approach for developing new antibiotics, particularly against malaria and tuberculosis. While researching this enzyme, biochemists at the Technische Universitδt Mόnchen (TUM) discovered a previously unknown reaction: IspH accepts two completely different classes of molecules as partners. This surprising insight, published in Nature Communications, opens up new perspectives in combating infectious diseases.

Terpenes constitute one of the largest and most versatile classes of natural compounds -- familiar examples are cholesterol and estrogen. In all organisms the biosynthesis of terpenes starts from the two building blocks isopentenyl-diphosphate (IPP) and dimethylallyl diphosphate (DMAPP); however, mammals and bacteria use different biosynthetic pathways to do this. In bacteria and pathogenic microorganisms the enzyme IspH catalyzes the last step in the production of IPP and DMAPP. Thus for several years scientists have recognized the potential of IspH as a point of attack in developing drugs against malaria and tuberculosis.

Now Prof. Michael Groll and Dr. Ingrid Span at the TUM Chair of Biochemistry have made a significant breakthrough in this area. They have been working with Prof. Eric Oldfield and his group at the University of Illinois to characterize certain acetylene compounds that inhibit the IspH enzyme. With the aid of X-ray crystallography, they discovered that the enzyme not only binds several of these molecules to its active site but also modifies them: Through the additionof water to the acetylene groups (hydrocarbons with triple bonds), the compounds are converted to aldehydes or ketones. "In general enzymes react with only one specific substrate," explains Ingrid Span. "So we were surprised to find that IspH, in contrast, accepts two completely different classes of molecules."

IspH owes its flexibility to the structure and location of its active site. The enzyme is composed of three structural units that harbor a cubic iron-sulfur cluster at their center. This unusual structure enables the enzyme to accomplish a challenging reaction: converting an allyl alcohol to a mixture of the two isoprene components. While iron-sulfur proteins normally act as electron transmitters (deoxidation and oxidation respectively), the IspH enzyme binds the substrate directly to the iron-sulfur cluster.

Basis for industrial applications

Apart from acetylene hydratase and nitrogenase, IspH is just the third enzyme known to convert acetylene compounds. In addition, until now there were no known iron-containing catalysts that could carry out this reaction. Thus the newly discovered property of IspH could enable the development of new active pharmaceutical ingredients, particularly for the battle against malaria and tuberculosis.

This work was carried out in the bioinorganic department of the Chair of Biochemistry. Bioinorganic chemistry is concerned with elucidating the function of classical "inorganic" elements, especially metals, in biological processes and in nature. Here, metalloproteins (proteins with one or more metal ions or clusters) play a particularly important role as they combine the advantages of proteins (acid/alkaline catalysis, proximity of reaction partners, enclosed reaction space) with the versatile catalytic properties of metals. "The aim of our research is to understand enzymatic reactions and to produce new catalysts, to establish the foundation for applications in the chemical and pharmaceutical industries," explains Michael Groll.

The work was funded by grants from the German Research Foundation (DFG -- GR1861/5-1), the NIH Funds GM65307 and AI074233, the Hans-Fischer Society, and the American Heart Association Predoctoral Fellowship 10PRE4430022, as well as the Excellence Cluster "Center for Integrated Protein Science Munich" (CIPSM). The measurements were carried out using the PXI and PXIII beamlines at the Paul Scherrer Institute (Villigen, Switzerland).


Story Source:

The above story is based on materials provided by Technische Universitaet Muenchen. Note: Materials may be edited for content and length.


Journal Reference:

  1. Ingrid Span, Ke Wang, Weixue Wang, Yonghui Zhang, Adelbert Bacher, Wolfgang Eisenreich, Kai Li, Charles Schulz, Eric Oldfield, Michael Groll. Discovery of acetylene hydratase activity of the iron–sulphur protein IspH. Nature Communications, 2012; 3: 1042 DOI: 10.1038/ncomms2052

Cite This Page:

Technische Universitaet Muenchen. "IspH -- a protein free to choose its partners." ScienceDaily. ScienceDaily, 9 October 2012. <www.sciencedaily.com/releases/2012/10/121009121613.htm>.
Technische Universitaet Muenchen. (2012, October 9). IspH -- a protein free to choose its partners. ScienceDaily. Retrieved October 22, 2014 from www.sciencedaily.com/releases/2012/10/121009121613.htm
Technische Universitaet Muenchen. "IspH -- a protein free to choose its partners." ScienceDaily. www.sciencedaily.com/releases/2012/10/121009121613.htm (accessed October 22, 2014).

Share This



More Plants & Animals News

Wednesday, October 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Working Mother DIY: Pumpkin Pom-Pom

Working Mother DIY: Pumpkin Pom-Pom

Working Mother (Oct. 22, 2014) — How to make a pumpkin pom-pom. Video provided by Working Mother
Powered by NewsLook.com
San Diego Zoo's White Rhinos Provide Hope for the Critically Endangered Species

San Diego Zoo's White Rhinos Provide Hope for the Critically Endangered Species

Reuters - Light News Video Online (Oct. 22, 2014) — The pair of rare white northern rhinos bring hope for their species as only six remain in the world. Elly Park reports. Video provided by Reuters
Powered by NewsLook.com
Raw: Bear Cub Strolls Through Oregon Drug Store

Raw: Bear Cub Strolls Through Oregon Drug Store

AP (Oct. 22, 2014) — Shoppers at an Oregon drug store were surprised by a bear cub scurrying down the aisles this past weekend. (Oct. 22) Video provided by AP
Powered by NewsLook.com
Family Pleads for Pet Pig to Stay at Home

Family Pleads for Pet Pig to Stay at Home

AP (Oct. 22, 2014) — The Johnson family lost their battle with the Chesterfield County, Virginia Planning Commission to allow Tucker, their pet pig, to stay in their home, but refuse to let the board keep Tucker away. (Oct. 22) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Plants & Animals

Earth & Climate

Fossils & Ruins

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins