PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Enzyme from fungi shows molecules which way to turn

Xue Sherry Gao and team isolate natural catalysts for better drug synthesis

Enzyme from fungi shows molecules which way to turn
2021-07-06
(Press-News.org) HOUSTON - (July 6, 2021) - A small fungal enzyme could play a significant role in simplifying the development and manufacture of drugs, according to Rice University scientists.

The Rice lab of chemical and biomolecular engineer Xue Sherry Gao and collaborators isolated a biocatalyst known as CtdE after identifying it as the natural mechanism that controls the chirality -- the left- or right-handedness -- of compounds produced by the native fungal host.

The open-access study appears in Nature Communications.

Two chiral things are, like hands, alike in structure but cannot perfectly overlap. Because the property is important in designing drugs that bind correctly to their targets, the ability to achieve 100% correct chirality is highly desired, Gao said.

"It's important because if a pharmaceutical drug has the wrong stereochemistry (chirality in three dimensions), it could become a poison to humans, even if the planar chemical structure is the same," she said.

Like "left" or "right" orientation in chiral objects, what's known as a 3S or 3R orientation is determined by a molecule's stereocenter, a one-atom connection between parts of a molecule, Gao said.

But while nature handles the process with ease, selectively synthesizing stereocenters has been a challenge for chemists. The entire mechanism behind nature's ability to control whether a molecule has a 3S or 3R orientation has been hidden from view until now. Understanding how it works in fungi and analyzing its structure could give scientists, particularly those who design drugs, a new chemical synthesis tool.

The focus of the study, a bioactive natural product known as 21R-citrinadin A, discovered in 2004 in a marine-derived fungal strain of Penicillium citrinum, is toxic to leukemia in mice and human lung cancer cells.

"21R-citrinadin A is a very complicated molecule, with eight stereocenters," Gao said. "In a way, the paper emphasizes how nature uses enzymes to synthesize a complex molecule with such a precision. Eight different stereocenters are a lot to control."

She said the molecule incorporates a "very intriguing" 3S spirooxindole ring. "Nature produces several other chemicals with a similar spirooxindole pharmacophore," Gao said. "However, we became very curious that some of them contain a 3R spirooxindole ring, the opposite of 3S in citrinadins.

"All the genes responsible for expressing this small molecule are clustered together in these fungi, so first we found the gene cluster and looked at each gene individually to see which one could be the most important to catalyze the specific chemical transformations," she said.

"Once we find it, we can take that gene outside of the fungus, put it back into a user-friendly host, E. coli, and then use protein purification technology to isolate and test its function in a test tube," Gao said. "By doing everything outside of the fungus, we can be sure there's only one enzyme that performs this one function."

The modified E. coli express CtdE protein in bulk. When subsequently used in chemical transformations, CtdE catalyzed the desired 3S stereoselectivity across the board. "A spirooxindole is hard to synthesize already," she said. "Our goal was to understand the mechanism of how the enzyme controls this specific 3S stereochemistry."

Bioinformatic analysis, X-ray crystallography and experiments confirmed that CtdE is solely responsible for catalyzing 3S stereoselectivity, Gao said. (Another enzyme, PhqK, was already known to catalyze 3R orientation.) "Having a set of two enzymes that give precise control over stereochemistry will eventually improve the synthesis in pharmaceutical production," she said.

Gao noted that because CtdE works at room temperature, it will help keep chemistry "green" as well. "Hopefully, these biocatalysts will catalyze chemical reactions in a more environmentally friendly way," she said.

Postdoctoral researchers Zhiwen Liu and Fanglong Zhao of Rice and graduate student Boyang Zhao of Baylor College of Medicine are co-lead authors of the paper.

INFORMATION:

Co-authors are staff researcher Jie Yang, alumnus graduate student Biki Bapi Kundu, Yang Gao, an assistant professor of biosciences, and George Phillips, the Ralph and Dorothy Looney Professor of BioSciences, of Rice; Liya Hu, an assistant professor of biochemistry, and B.V. Venkataram Prasad, the Verna and Marrs McLean Department of Biochemistry and Molecular Biology, at Baylor; Joseph Ferrara of Rigaku Americas Corp., The Woodlands, Texas; research scientist Banumathi Sankaran of Lawrence Berkeley National Laboratory; and co-principal investigator Tong Zhu, an associate professor at East China Normal University, Shanghai.

The National Institutes of Health, the Robert A. Welch Foundation, the Innovation Program of the Shanghai Municipals Education Commission and the National Natural Science Foundation of China supported the research.

Read the abstract at https://doi.org/10.1038/s41467-021-24421-0.

This news release can be found online at https://news-network.rice.edu/news/2021/07/06/enzyme-from-fungi-shows-molecules-which-way-to-turn/

Follow Rice News and Media Relations via Twitter @RiceUNews.

Related materials:

Engineers enlist fungi to advance against disease: http://news.rice.edu/2020/08/10/engineers-enlist-fungi-to-advance-against-disease-2/

'Bystander' Cs meet their match in gene-editing technique: http://news.rice.edu/2020/07/15/bystander-cs-meet-their-match-in-gene-editing-technique-2/

The Gao Laboratory: https://gaolab.rice.edu

Department of Chemical and Biomolecular Engineering: https://chbe.rice.edu/

George R. Brown School of Engineering: https://engineering.rice.edu

Images for download:

https://news-network.rice.edu/news/files/2021/07/0712_CTDE-1-web.jpg

Rice University chemical and biomolecular engineers led the discovery of a new biocatalyst, CtdE, used in this illustration to construct an alkaloid with a critical 3S-spirooxindole framework, as seen in blue in the bottom molecule. Their study also provides deeper insight into the mechanism of stereoselective catalysis. FAD (flavin adenine dinucleotide) and NADH (nicotinamide adenine dinucleotide) are cofactors used in the reaction. (Credit: Illustration by Zhiwen Liu/Rice University)

https://news-network.rice.edu/news/files/2021/07/0712_CTDE-3-web.jpg

CAPTION: Xue Sherry Gao.

https://news-network.rice.edu/news/files/2021/07/0712_CTDE-2-web.jpg

Rice postdoctoral researchers Fanglong Zhao, left, and Zhiwen Liu work with a marine fungus, Penicillium citrinum, from which they isolated an enzyme that could simplify the development and manufacture of drugs. (Credit: Jeff Fitlow/Rice University)

https://news-network.rice.edu/news/files/2021/07/0712_CTDE-4-web.jpg

Rice University postdoctoral researcher Zhiwen Liu shows a marine fungus, Penicillium citrinum, the source of a catalytic enzyme that could simplify the development and manufacture of drugs. (Credit: Jeff Fitlow/Rice University)

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation's top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,978 undergraduates and 3,192 graduate students, Rice's undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 1 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger's Personal Finance.


[Attachments] See images for this press release:
Enzyme from fungi shows molecules which way to turn

ELSE PRESS RELEASES FROM THIS DATE:

Why men take more risks than women

2021-07-06
Researchers from HSE University and Max Planck Institute for Human Cognitive and Brain Sciences have discovered how the theta rhythm of the brain and the gender differences in attitudes to risk are linked. In an article published in the journal Frontiers in Neuroscience, the researchers addressed which processes can be explained by knowing this connection. https://www.frontiersin.org/articles/10.3389/fnins.2021.608699/full By transmitting signals, the brain's neurons generate electromagnetic fields. The multiplicity of neurons makes these fields strong enough to be recorded on the surface of the head using magneto- and electroencephalography techniques. ...

Predicting the future of cod

Predicting the future of cod
2021-07-06
The future of cod stocks in the North Sea and the Barents Sea may be much easier to predict than before. This is the result of an international research project led by the Helmholtz-Zentrum Hereon and its Institute of Coastal Systems - Analysis and Modeling. For the first time, the team has succeeded in predicting the development of stocks for ten years in advance, taking into account both changes due to climate and fishing. Traditionally, fisheries experts provide catch recommendations for about a year in advance, on the basis of which fishing quotas are negotiated and set internationally. This involves first estimating the size of current cod stocks and then calculating how much cod can be caught in the coming year without endangering the stocks ...

Acid sensor discovered in plants

Acid sensor discovered in plants
2021-07-06
Climate change is causing increased flooding and prolonged waterlogging in northern Europe, but also in many other parts of the world. This can damage meadow grasses, field crops or other plants - their leaves die, the roots rot. The damage is caused by a lack of oxygen and the accumulation of acids. How do plants perceive this over-acidification, how do they react to it? This is what researchers from Würzburg, Jena (Germany) and Talca (Chile) describe in the journal Current Biology. Biophysicists Dr. Tobias Maierhofer and Professor Rainer Hedrich from the Chair of Molecular Plant Physiology and Biophysics at Julius-Maximilians-Universität ...

Ultrathin semiconductors electrically connected to superconductors for the first time

2021-07-06
For the first time, University of Basel researchers have equipped an ultrathin semiconductor with superconducting contacts. These extremely thin materials with novel electronic and optical properties could pave the way for previously unimagined applications. Combined with superconductors, they are expected to give rise to new quantum phenomena and find use in quantum technology. Whether in smartphones, televisions or building technology, semiconductors play a central role in electronics and therefore in our everyday lives. In contrast to metals, it is possible to adjust their electrical conductivity by applying a voltage and hence to switch the current flow on and off. With a view to future applications in electronics and quantum technology, researchers are focusing on the development ...

NYU Abu Dhabi researchers unlock secrets behind liver regrowth and regenerative medicine

NYU Abu Dhabi researchers unlock secrets behind liver regrowth and regenerative medicine
2021-07-06
Abu Dhabi, UAE, July 5, 2021: NYU Abu Dhabi (NYUAD) researchers uncovered a code that sets the genome of the liver to account for the remarkable ability for this organ to regenerate. This finding offers new insight into how the specific genes that promote regeneration can be activated when part of the liver is removed. These findings have the potential to inform the development of a new form of regenerative medicine that could help non-regenerative organs regrow in mice and humans. While other animals can regenerate most organs, humans, mice, and other mammals can only regenerate their liver in response to an injury or when a piece is removed. NYUAD researchers ...

Work like a dream: new anticholinergic drug keeps PTSD flashbacks and nightmares away

2021-07-06
Post-traumatic stress disorder (PTSD) rings a bell for many, due to its rampant references in pop culture, and more, importantly, its prevalence in today's society. It is only probable that this disorder, which develops after shocking or dangerous events, would unfortunately affect the lives of many people. Medical researchers have been hard at work trying to come up with solutions to combat this condition and its manifestations effectively. Unfortunately, the neurological mechanisms of PTSD aren't clear, and without knowing this exactly, trying to find a cure is a shot in the dark. Fortunately, a group ...

From eyebrow beans to 'lost' rice: community seedbanks are protecting China's crops

From eyebrow beans to lost rice: community seedbanks are protecting Chinas crops
2021-07-06
"Plant a hundred kinds of crops" Wangjinzhuang village is nestled amongst the steep slopes of the South Taihang Mountains in Hebei Province, China. To prosper in the northern climate, the villagers have developed a tried-and-true strategy: "using the land to plant a hundred kinds of crops and not rely on the sky". Their fields contain red millet, white sorghum, purple and green eyebrow beans, and yellow radishes. Having survived for over a thousand years, this agrobiodiversity is a vibrant cornerstone of the village's agricultural heritage that is too precious to lose. In an effort to combat dwindling crop diversity across China (the Ministry of Agriculture found that of 11,590 grain crop varieties planted ...

Do heart medications affect COVID-19 outcomes?

2021-07-06
Cardiovascular drugs do not affect COVID-19 outcomes--such as disease severity, hospitalizations, or deaths--according to an analysis of all relevant studies published as of November 2020. The findings are published in the END ...

About half of people living with HIV have coronary artery plaque despite low cardiac risk

2021-07-06
BOSTON - Significant amounts of atherosclerotic plaque have been found in the coronary arteries of people with HIV, even in those considered by traditional measures to be at low-to-moderate risk of future heart disease, according to a study published in JAMA Network Open. This finding emerged from the global REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) study, in which Massachusetts General Hospital (MGH) is playing a key coordinating role. Researchers found that the higher-than-expected levels of plaque could not be attributed simply to traditional cardiovascular disease risk factors like smoking, hypertension, and lipids in the blood, but were independently related to increased arterial inflammation ...

What to do with food waste? Well, that depends

2021-07-06
The expected decline in the number of landfills across the United States coupled with bans on disposing large amounts of organic waste in landfills that have been enacted in multiple states has prompted researchers at the U.S. Department of Energy's (DOE's) National Renewable Energy Laboratory (NREL) to examine other ways to grapple with the issue of food waste disposal. The researchers determined no single solution exists in the United States for dealing with food waste disposal. NREL researchers Alex Badgett a­­nd Anelia Milbrandt came to that conclusion after examining the economics involved in five different ways to ...

LAST 30 PRESS RELEASES:

Reality check: making indoor smartphone-based augmented reality work

Overthinking what you said? It’s your ‘lizard brain’ talking to newer, advanced parts of your brain

Black men — including transit workers — are targets for aggression on public transportation, study shows

Troubling spike in severe pregnancy-related complications for all ages in Illinois

Alcohol use identified by UTHealth Houston researchers as most common predictor of escalated cannabis vaping among youths in Texas

Need a landing pad for helicopter parenting? Frame tasks as learning

New MUSC Hollings Cancer Center research shows how Golgi stress affects T-cells' tumor-fighting ability

#16to365: New resources for year-round activism to end gender-based violence and strengthen bodily autonomy for all

Earliest fish-trapping facility in Central America discovered in Maya lowlands

São Paulo to host School on Disordered Systems

New insights into sleep uncover key mechanisms related to cognitive function

USC announces strategic collaboration with Autobahn Labs to accelerate drug discovery

Detroit health professionals urge the community to act and address the dangers of antimicrobial resistance

3D-printing advance mitigates three defects simultaneously for failure-free metal parts 

Ancient hot water on Mars points to habitable past: Curtin study

In Patagonia, more snow could protect glaciers from melt — but only if we curb greenhouse gas emissions soon

Simplicity is key to understanding and achieving goals

Caste differentiation in ants

Nutrition that aligns with guidelines during pregnancy may be associated with better infant growth outcomes, NIH study finds

New technology points to unexpected uses for snoRNA

Racial and ethnic variation in survival in early-onset colorectal cancer

Disparities by race and urbanicity in online health care facility reviews

Exploring factors affecting workers' acquisition of exercise habits using machine learning approaches

Nano-patterned copper oxide sensor for ultra-low hydrogen detection

Maintaining bridge safer; Digital sensing-based monitoring system

A novel approach for the composition design of high-entropy fluorite oxides with low thermal conductivity

A groundbreaking new approach to treating chronic abdominal pain

ECOG-ACRIN appoints seven researchers to scientific committee leadership positions

New model of neuronal circuit provides insight on eye movement

Cooking up a breakthrough: Penn engineers refine lipid nanoparticles for better mRNA therapies

[Press-News.org] Enzyme from fungi shows molecules which way to turn
Xue Sherry Gao and team isolate natural catalysts for better drug synthesis