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Structure reveals genetic disorder clues

U. MICHIGAN (US) — Researchers have solved the structure of a protein that is integral to processes responsible for maintaining a healthy heart and nervous system.

The protein structure in question is cystathionine beta-synthase, known as CBS. CBS uses vitamin B6to make hydrogen sulfide (H2S), a gaseous signaling molecule that helps maintain a healthy heart and nervous system.
H2Salso induces a state of suspended animation or hibernation in animals by decreasing body temperature and lowering metabolic rate.

“The structure of full-length CBS, which has eluded the science community for more than a decade, provides a wealth of new information about gas generation by CBS, which is especially important in the brain,” says Ruma Banerjee, professor of biological chemistry at the University of Michigan.

“It also provides a framework for understanding homocystinuria-causing mutations.”

Details of the research are published in the Proceedings of the National Academy of Sciences.

Mutations in the gene for CBS cause homocystinuria,an inherited disorder that affects the central nervous system, ocular, skeletal, and cardiovascular systems.

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Revealing the structure of a protein related to the health of the heart and nervous system may lead to smarter drug design and a better understanding of a genetic disorder of the cardiovascular system. (Credit: Janet Smith, U. Michigan)

The structure of the full-length CBS, seen here for the first time, provides a molecular explanation for homocystinuria due to CBS defects.

The activity of CBS is increased by SAMe (S-adenosylmethionine), a dietary supplement that is used for its anti-depressant and anti-inflammatory activities. SAMe also increases production of H2S by binding to CBS.

“Molecular insights into the architecture of the CBS domain to which SAMe binds open doors to rational drug design for fine-tuning H2S production for pharmaceutical purposes,” says Markos Koutmos, a research investigator working with Janet Smith, a research professor at the Life Sciences Group at the University of Michigan.

“We captured the CBS enzyme at two points in its complex chemical reaction by trapping two highly reactive chemical intermediates in the active site of the enzyme,” says Omer Kabila postdoctoral fellow in Banerjee’s lab.

The structures of these trapped species reveal details of how vitamin B6 helps CBS perform the complex chemical reactions leading to H2S production.

“The important chemical details we see in CBS can be applied to understanding the other human enzymes that depend on vitamin B6, of which there are more than 50,” Smith says.

This work was supported by grants from the National Institutes of Health.

More news from University of Michigan: http://ns.umich.edu/

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