New enzyme could aid anticancer drug development

Rice U. study provides complete roadmap to complete molecule assembly

2023-06-27

(Press-News.org) HOUSTON – (June 27, 2023) – Many of the drugs we use to treat cancer and infectious disease are ⎯ or derive from ⎯ natural products, but it’s difficult to know exactly how nature assembles them.

Retracing nature’s steps, Rice University chemical engineer Xue Gao and her team mapped out the full series of enzyme-powered reactions a marine fungus uses to produce 21R-citrinadin A, a complex molecule with anticancer properties.

In the process, Gao and her collaborators identified a new enzyme, CtdY, which is the only one of its kind known to break an amide bond, according to the study published in the Journal of the American Chemical Society.

“CtdY belongs to a large family of enzymes known as cytochrome P450s that perform a variety of different functions and are being studied for their potential use in industrial and pharmaceutical settings,” Gao said. “However, none of the P450s documented so far can break an amide bond.

“Amide bonds are found in all proteins ⎯ they’re the ones linking the amino acids together. It’s a fundamental, very stable type of bond.”

The enzyme’s ability to cleave amide bonds could make it a useful tool for creating new drugs.

“The fact that CtdY can do this is quite remarkable,” said Qiuyue Nie, a postdoctoral researcher in the Gao lab who is one of the lead authors of the study. “It holds significant promise for the pharmaceutical industry,” she said.

The enzyme is notable not only because it can break a highly-stable bond, but also because it does so for a very complex molecular structure.

“You want to maintain the rest of this structure and only want to break this single, hard-to-break bond ⎯ this is a very specific and difficult task,” Gao said.

Once CtdY breaks the amide bond ⎯ which has a circular 3D structure ⎯ a group of seven other enzymes intervene to complete the assembly of the 21R-citrinadin A molecule.

“Once it opens the ring, all the other enzymes are able to perform oxidation and install oxygen-hydrogen groups in a highly precise way,” Gao said. “It’s like CtdY brings the Christmas tree home, and then these other enzymes come together to decorate it.”

The Gao lab has been working for years to uncover all the steps involved in the production of the 21R-citrinadin A compound, which has been shown to be effective against leukemia in rats and human throat cancer cells, according to Shuai Liu, a Rice postdoctoral researcher who is the study’s lead co-author.

The newly identified enzyme is one of several discovered by the Gao lab that can perform singular catalytic functions such as controlling chirality and facilitating the Diels-Alder reaction.

“This really is a complete story,” Gao said. “We used gene knockout, heterologous expression, mutagenesis studies, enzymology and so on to solve nearly every single step in the biosynthesis of this compound. Over 20 enzymes assemble and coordinate to produce the molecule. I find it fascinating that enzymes work cooperatively in this way to produce this wonderfully complex molecule.”

Gao is Rice’s T.N. Law Assistant Professor of Chemical and Biomolecular Engineering and an assistant professor of bioengineering and chemistry.

The National Institutes of Health (R35GM138207) and the Robert A. Welch Foundation (C-1952) supported the research.

-30-

This release can be found online at news.rice.edu.

Follow Rice News and Media Relations via Twitter @RiceUNews.

Peer-reviewed paper:

Fungal P450 deconstructs the 2,5-diazabicyclo[2.2.2]octane ring en route to the complete biosynthesis of 21R-citrinadin A | Journal of the American Chemical Society | DOI: 10.1021/jacs.3c02109

https://doi.org/10.1021/jacs.3c02109

Authors: Shuai Liu, Qiuyue Nie, Zhiwen Liu, Siddhant Patil and Xue Gao

Image downloads:

https://news-network.rice.edu/news/files/2023/06/230608_Qiuyue-Nie-Shuai-Liu_Gustavo-05206.jpg
CAPTION: Qiuyue Nie (left) and Shuai Liu holding a petri dish with a culture of P. citrinum, the fungus that produces 21R-citrinadin A. (Photo by Gustavo Raskosky/Rice University)

https://news-network.rice.edu/news/files/2023/06/230608_Qiuyue-Nie-Shuai-Liu_Gustavo-05196.jpg
CAPTION: Qiuyue Nie (left) and Shuai Liu are lead co-authors on the study published in the Journal of the American Chemical Society. (Photo by Gustavo Raskosky/Rice University)

https://news-network.rice.edu/news/files/2023/06/230608_Qiuyue-Nie-Shuai-Liu_Gustavo-05214.jpg
CAPTION: Over twenty enzymes are involved in the production of the 21R-citrinadin A molecule. (Photo by Gustavo Raskosky/Rice University)

Related stories:

Rice scientists reengineer cancer drugs to be more versatile:
https://news.rice.edu/news/2023/rice-scientists-reengineer-cancer-drugs-be-more-versatile

New enzyme could mean better drugs:
https://news.rice.edu/news/2023/new-enzyme-could-mean-better-drugs

Rice University scientists get fungi to spill their secrets:
https://news.rice.edu/news/2023/rice-university-scientists-get-fungi-spill-their-secrets

Xue Sherry Gao wins CAREER Award:
https://news.rice.edu/news/2022/xue-sherry-gao-wins-career-award

Enzyme from fungi shows molecules which way to turn:
https://news.rice.edu/news/2021/enzyme-fungi-shows-molecules-which-way-turn

RNA-editing tool a fast, sensitive test for COVID-19:
https://news.rice.edu/news/2022/rna-editing-tool-fast-sensitive-test-covid-19

Engineers enlist fungi to advance against disease:
https://news.rice.edu/news/2020/engineers-enlist-fungi-advance-against-disease

Links:

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

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

Department of Chemistry: https://chemistry.rice.edu/

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

BioScience Research Collaborative: https://brc.rice.edu/

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 4,552 undergraduates and 3,998 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. 4 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.

If you do not wish to receive news releases from Rice University, reply to this email and write “unsubscribe” in the subject line. Office of News and Media Relations – MS 300, Rice University, 6100 Main St., Houston, TX 77005

END

[Attachments] See images for this press release:

New enzyme could aid anticancer drug development 2

New enzyme could aid anticancer drug development 3

ELSE PRESS RELEASES FROM THIS DATE:

Penn State researchers develop digital test to directly measure HIV viral load

2023-06-27

UNIVERSITY PARK, Pa. — A milliliter of blood contains about 15 individual drops. For a person with human immunodeficiency virus (HIV), each drop of blood could contain anywhere from fewer than 20 copies of the virus to more than 500,000 copies. Called the viral load, this is what is measured to allow clinicians to understand how patients are responding to anti-viral medications and monitor potential progression. The time-consuming viral load testing needs to be repeated several times as a patient undergoes treatment. Now, a Penn State research team has developed a time and cost-efficient digital assay that can directly measure the presence of HIV in ...

The more stakeholders are included in policy planning, the better those policies protect them

2023-06-27

Having a seat at the table, and voices heard, makes a world of difference when it comes to natural resources. It sounds intuitive, but experts didn’t have enough data to prove it until now. A team of researchers from across the country pored over 108 groundwater management plans in California to see how well they protect stakeholders like domestic well users, farmers and ecosystems. They found that the plans that incorporated stakeholder input offered greater protection from groundwater depletion. Unfortunately, only 9% of the sustainability plans integrated these users in a comprehensive manner. The findings have broad implications for resource management, both in California and ...

Penn State researchers use ultrasound to control orientation of small particles

2023-06-27

UNIVERSITY PARK, Pa. — Acoustic waves may be able to control how particles sort themselves. While researchers have been able to separate particles based on their shape — for example, bacteria from other cells — for years, the ability to control their movement has remained a largely unsolved problem, until now. Using ultrasound technology and a nozzle, Penn State researchers have separated, controlled and ejected different particles based on their shape and various properties. They ...

Fondant: Where baking and thermodynamics mix

2023-06-27

WASHINGTON, June 27, 2023 – With their unique appearance, texture, and mouthfeel, fondants have intrigued bakers and physicists for years. They present an appetizing enigma in the world of confectionery, an intriguing combination of sugar, water, and heat that, when manipulated correctly, yields a delectably creamy product. Researchers from the Max Planck Institute for Polymer Research and Technische Universität Berlin studied the kinetic and thermodynamic processes of sugar crystallization in the making of fondant. In Physics of Fluids, by AIP Publishing, they combined a controlled kneading machine with light microscopy ...

Prevalence of iron deficiency, iron-deficiency anemia in females ages 12-21

2023-06-27

About The Study: Among 12- to 21-year-old U.S. females between 2003 and 2020, iron deficiency affected almost 40% and iron deficiency anemia affected 6%, with variation by the ferritin or hemoglobin thresholds used. Menstruation was a risk factor for both, but more than one-quarter of premenarchal individuals had iron deficiency. Authors: Angela C. Weyand, M.D., of the University of Michigan Medical School in Ann Arbor, is the corresponding author. To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/ (doi:10.1001/jama.2023.8020) Editor’s Note: Please see the article for ...

Team proposes a new view on euchromatin in the cell

2023-06-27

In their paper the team discusses their novel view of euchromatin in the cell and shows how the revealed organization is relevant to genome functions. “Our ultimate goal is to reveal how genomic information is searched and read out in living cells,” said Kazuhiro Maeshima, a leading author and a professor with the National Institute of Genetics and SOKENDAI, Japan. Chromatin describes the combination of DNA and proteins in the cells of humans and other eukaryotes. According to typical textbook models, chromatin occurs in two forms— euchromatin, that is less condensed and can be transcribed, and heterochromatin, that is more condensed and usually not transcribed. ...

Monitoring British bats can help identify coronaviruses with pathogen potential

2023-06-27

Researchers who found novel coronaviruses in UK bats say genetic surveys of the viruses should be regularly conducted, even if none of those viruses can infect humans yet. Working with a network of bat conservationists, a research team led by Imperial College London and University College London researchers screened faecal samples from UK bats for coronaviruses. Their results, published today in Nature Communications, report circulation of four species of coronaviruses, including two novel ones, among the 16 UK bat species sampled. While some of these ...

Chemical imbalance in the forebrain discovered in people with obsessive-compulsive disorder

2023-06-27

Using a high-powered MRI scanner, scientists have discovered an imbalance between neurochemicals in parts of OCD patients’ brains key to decision-making and habit. Chemical imbalances were related to OCD symptom severity, as well as habitual tendencies in a decision-making task. A similar but less pronounced neurochemical imbalance was also detected in healthy individuals with milder compulsive tendencies. Neuroscientists argue that the findings are a “major piece of the puzzle” in understanding OCD, and could open up new ...

Researchers develop new base editing tools using AI-predicted protein structure clustering

2023-06-27

GAO Caixia's group from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences has pioneered the use of artificial intelligence (AI)-assisted methods to discover novel deaminase proteins with unique functions through structural prediction and classification. This approach has opened up a range of applications for the discovery and creation of desired plant genetic traits. The results were published in Cell. The discovery of new proteins and the exploitation of diverse engineered enzymes have contributed to the rapid advancement of biotechnology. Currently, efforts to mine novel proteins ...

New study sheds light on the evolution of animals

2023-06-27

Key points: Scientists have been mystified as to why animals are missing in much of the fossil record; Researchers have developed a new method to determine if animals really were absent during certain geological eras, or if they were present but too fragile to be preserved; The findings establish a new maximum point at which animals first evolved on Earth. A study led by the University of Oxford has brought us one step closer to solving a mystery that has puzzled naturalists since Charles Darwin: when did animals first appear in the history of Earth? The results have been published ...

New enzyme could aid anticancer drug development

ELSE PRESS RELEASES FROM THIS DATE:

LAST 30 PRESS RELEASES: