Featured Research

from universities, journals, and other organizations

Chemists document workings of key staph enzyme -- and how to block it

Date:
January 26, 2011
Source:
University of Illinois at Urbana-Champaign
Summary:
Researchers have determined the structure and mechanism of dehydrosqualene synthase (CrtM), an enzyme that performs the crucial first step in the formation of cholesterol and a key virulence factor in staph bacteria. The researchers already knew what CrtM looked like and its end product, but they didn't know how the enzyme did its job. Uncovering the mechanism of action will enable scientists to design better inhibitors, and even tailor them to other targets.

Chemists led by Illinois professor Eric Oldfield, center, determined the structure of a key enzyme that could lead to more efficient drugs to treat staph infections, parasites and high cholesterol. The research team, from left, research scientist Yonghui Zhang, graduate student Fu-Yang Lin, research scientist Rong Cao and postdoctoral associate Ke Wang.
Credit: L. Brian Stauffer

Researchers have determined the structure and mechanism of an enzyme that performs the crucial first step in the formation of cholesterol and a key virulence factor in staph bacteria.

Chemists at the University of Illinois and collaborators in Taiwan studied a type of enzyme found in humans, plants, fungi, parasites, and many bacteria that begins the synthesis of triterpenes -- one of the most abundant and most ancient classes of molecules. Triterpenes are precursors to steroids such as cholesterol.

"These enzymes are important drug targets," said chemistry professor Eric Oldfield, who co-led the study. "Blocking their activity can lead to new cholesterol-lowering drugs, antibiotics that cure staph infections, and drugs that target the parasites that cause tropical maladies such as Chagas disease -- a leading cause of sudden death in Latin America."

For the study, the team picked a representative enzyme, dehydrosqualene synthase (CrtM), from the Staphylococcus aureus bacterium. Staph is one of the most common, yet notoriously hard to kill, bacterial infections. A key reason for staph's resilience is a golden-colored coating called staphyloxanthin that protects it from the body's immune system. CrtM catalyzes the first reaction in making staphyloxanthin, so inhibiting it would strip the bacteria of their protective coats and leave them vulnerable to attack by white blood cells.

The researchers already knew what CrtM looked like and its end product, but they didn't know how the enzyme did its job. Uncovering the mechanism of action would enable scientists to design better inhibitors, and even tailor them to other targets.

The team crystallized the enzyme and soaked it with intermediates and inhibitors. They then studied the complex structures by X-ray crystallography using the synchrotron at the Advanced Photon Source at Argonne National Laboratory.

They found that CrtM performs a two-step reaction, individually removing two diphosphate groups from the substrate. The substrate switches between two active sites within the enzyme as the reaction progresses. The most effective inhibitors bind to both sites, blocking the enzyme from any action.

"The leads that people have been developing for treating these diseases really haven't had any structural basis," said Oldfield, also a professor of biophysics. "But now that we can see how the protein works, we're in a much better position to design molecules that will be much more effective against staph infections and parasitic diseases, and potentially, in cholesterol-lowering."

The researchers' inhibitor technologies have been licensed to AuricX Pharmaceuticals, which recently received a grant from the Texas Emerging Technology Fund for preclinical testing in staph infections.

The team published its work in the Proceedings of the National Academy of Sciences. The work was sponsored by the National Institutes of Health and the National Science Council. Co-authors were U. of I. graduate students Fu-Yang Lin and Yi-Liang Liu, research scientists Rong Cao and Yonghui Zhang, and postdoctoral associate Ke Wang. Taiwan collaborators included Chia-I Liu, Wen-Yih Jeng, Tzu-Ping Ko and Andrew H. Wang.


Story Source:

The above story is based on materials provided by University of Illinois at Urbana-Champaign. Note: Materials may be edited for content and length.


Journal Reference:

  1. F.-Y. Lin, C.-I. Liu, Y.-L. Liu, Y. Zhang, K. Wang, W.-Y. Jeng, T.-P. Ko, R. Cao, A. H.- J. Wang, E. Oldfield. Mechanism of action and inhibition of dehydrosqualene synthase. Proceedings of the National Academy of Sciences, 2010; 107 (50): 21337 DOI: 10.1073/pnas.1010907107

Cite This Page:

University of Illinois at Urbana-Champaign. "Chemists document workings of key staph enzyme -- and how to block it." ScienceDaily. ScienceDaily, 26 January 2011. <www.sciencedaily.com/releases/2011/01/110118143230.htm>.
University of Illinois at Urbana-Champaign. (2011, January 26). Chemists document workings of key staph enzyme -- and how to block it. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2011/01/110118143230.htm
University of Illinois at Urbana-Champaign. "Chemists document workings of key staph enzyme -- and how to block it." ScienceDaily. www.sciencedaily.com/releases/2011/01/110118143230.htm (accessed October 23, 2014).

Share This



More Health & Medicine News

Thursday, October 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola Fears Keep Guinea Hospitals Empty

Ebola Fears Keep Guinea Hospitals Empty

AP (Oct. 23, 2014) Fears of Ebola are keeping doctors and patients alike away from hospitals in the West African nation of Guinea. (Oct. 23) Video provided by AP
Powered by NewsLook.com
Orthodontist Mom Jennifer Salzer on the Best Time for Braces

Orthodontist Mom Jennifer Salzer on the Best Time for Braces

Working Mother (Oct. 22, 2014) Is your child ready? Video provided by Working Mother
Powered by NewsLook.com
U.S. Issues Ebola Travel Restrictions, Are Visa Bans Next?

U.S. Issues Ebola Travel Restrictions, Are Visa Bans Next?

Newsy (Oct. 22, 2014) Now that the U.S. is restricting travel from West Africa, some are dropping questions about a travel ban and instead asking about visa bans. Video provided by Newsy
Powered by NewsLook.com
More People Diagnosed With TB In 2013, But There's Good News

More People Diagnosed With TB In 2013, But There's Good News

Newsy (Oct. 22, 2014) The World Health Organizations says TB numbers rose in 2013, but it's partly due to better detection and more survivors. Video provided by Newsy
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


Health & Medicine

Mind & Brain

Living & Well

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