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New enzyme could mean better drugs

NEWS RELEASE  Credit: Photo by Jeff Fitlow/Rice University NEWS RELEASE  Jeff Falk 713-348-6775 jfalk@rice.edu Silvia Cernea Clark 713-348-6728 silviacc@rice.edu…

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NEWS RELEASE 

Credit: Photo by Jeff Fitlow/Rice University

NEWS RELEASE 

Jeff Falk
713-348-6775
jfalk@rice.edu

Silvia Cernea Clark
713-348-6728
silviacc@rice.edu

HOUSTON – (Jan. 23, 2023) – Just as a choreographer’s notation tells a dancer to strike a particular pose, an enzyme newly discovered by Rice University scientists is able to tell specific molecules precisely how to arrange themselves, down to the angle of single hydrogen bonds. 

Biomolecular engineers at Rice identified a new Diels-Alderase (DAase), an enzyme that catalyzes the Diels-Alder reaction, a widely used method of synthesizing important materials and pharmaceuticals, from raw materials for plastics and fuels to synthetic steroids.

The enzyme, known as CtdP, was previously thought to be a different type of protein — a “regulator” controlling for gene expression. Regulators typically do not serve a catalytic function, meaning they cannot “transform compound A into compound B,” said study co-author Xue Sherry Gao.

The precision of CtdP’s catalytic activity is notable. Gao’s team was able to pinpoint a minute difference in a molecule’s spatial structure — or stereochemistry — as directly caused by the newly identified enzyme. “Only when our DAase is added do you get that very specific stereochemistry,” Gao said. “This is very important, because a subtle change in the stereochemistry of a small molecule can spell the difference between a drug and a poison.”

The study is published in Nature Chemistry.

First described by Kurt Alder and Otto Diels in 1928, the Diels-Alder reaction generated a wide range of industrial and pharmaceutical applications, earning the two German chemists the Nobel Prize in chemistry in 1950.

Gao explained that the Diels-Alder reaction is “very useful … because it can facilitate the formation of a wide range of cyclic ring structures” — characteristic features of many natural compounds that are medically useful. These bioactive natural products are found in microbes, plants and other organisms and can be used as drugs or as molecular blueprints for designing them.

Most Diels-Alder reactions, however, can be difficult to control with the precision required to achieve the desired 3D molecular structure. This is where the Gao lab’s CtdP discovery comes into play.

Knowing that a molecule’s stereochemistry can spell the difference between its behavior as a life-saving drug or as a lethal poison, Gao was curious how a fungal organism synthesized the 21R-citrinadin A molecule in only one of four possible configurations, or “stereochemical products.”

“Our question is, how does the living organism control the stereochemistry of this compound so precisely while achieving the same result through organic synthesis is so challenging?” she said.

CtdP turned out to be one of the answers. “Our enzyme ensures that the chemical reaction takes place with the desired stereochemical control,” she said.

Enzymes expedite or render a chemical reaction more efficient, but they typically do not determine whether a reaction will occur or not. What sets CtdP apart from other DAases is that it uses a unique mechanism to prime the substrate substance while simultaneously converting nicotinamide adenine dinucleotide phosphate, or NADP+, into its reduced form, or NADPH, which makes the Diels-Alder reaction possible in the first place, Gao said. “In sum, our study reveals a new class of DAases,” she said.

“Very few DAases work like our enzyme and very strictly synthesize a chemical reaction that is impossible without it,” she said. “We hope that our discovery will help develop biocatalysts that enable the production of useful pharmaceuticals in the near future.”

Gao and collaborators used computational analysis, in vivo and in vitro testing and X-ray crystallography to determine the molecular structure and mechanisms underlying CtdP’s catalytic activity.

Gao, the T.N. Law Assistant Professor of Chemical and Biomolecular Engineering and an assistant professor of bioengineering and chemistry, is a 2022 recipient of a prestigious CAREER Award from the National Science Foundation.

The National Institutes of Health (GM138207, GM11810, AI41481, GM122218, GM132046, GM116961), the Robert A. Welch Foundation (C-1952) and the University of Michigan supported the research. Computational resources were supported by the National Science Foundation via the UCLA Institute for Digital Research and Education, the San Diego Supercomputing Center through XSEDE (1548562) and D.E. Shaw Research.

-30-

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

Follow Rice News and Media Relations via Twitter @RiceUNews.

Peer-reviewed paper:

“An NmrA-like enzyme-catalyzed redox-mediated Diels-Alder cycloaddition with anti-selectivity” | Nature Chemistry | DOI: 10.1038/s41557-022-01117-6

https://www.nature.com/articles/s41557-022-01117-6

Authors: Zhiwen Liu, Sebastian Rivera, Sean Newmister, Jacob Sanders, Qiuyue Nie, Shuai Liu, Fanglong Zhao, Joseph Ferrara, Hao-Wei Shih, Siddhant Patil, Weijun Xu, Mitchell Miller, George Phillips, Jr., K. N. Houk, David Sherman and Xue Gao

Image downloads:

https://news-network.rice.edu/news/files/2023/01/230118_CtdP_LG.jpg
CAPTION: A new Diels-Alderase, CtdP, uses a unique mechanism to prime the substrate substance while converting nicotinamide adenine dinucleotide phosphate, or NADP+, into its reduced form, or NADPH, enabling the Diels-Alder reaction, a widely used method of synthesizing important materials and pharmaceuticals.
(Image courtesy of Gao lab/Rice University)

https://news-network.rice.edu/news/files/2023/01/CtdP_researchers_LG.jpg
CAPTION: Researchers in the lab of Rice’s Xue Sherry Gao discovered a new class of Diels-Alderases.
(Photo by Jeff Fitlow/Rice University)

https://news-network.rice.edu/news/files/2023/01/Siddhanth_Patil_2_LG.jpg
CAPTION: Siddhant Patil, a Rice undergraduate biosciences student and a member of the Gao lab, is a co-author on the study. (Photo by Jeff Fitlow/Rice University)

https://news-network.rice.edu/news/files/2023/01/Qiuyue_Nie_GaoLab_LG.jpg
CAPTION: Qiuyue Nie, a Rice postdoctoral research associate in chemical and biomolecular engineering and a member of the Gao lab, is a co-author on the study. (Photo by Jeff Fitlow/Rice University)

https://news-network.rice.edu/news/files/2023/01/CtdP_Bart_LG.jpg
CAPTION: A scientist works in the lab of Rice’s Xue Sherry Gao. (Photo by Jeff Fitlow/Rice University)

Related stories:

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 4,240 undergraduates and 3,972 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.


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Government

Federal Food Stamps Program Hits Record Costs In 2022

Federal Food Stamps Program Hits Record Costs In 2022

In early January, The Wall Street Journal Editorial Board warned that one peril of a…

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Federal Food Stamps Program Hits Record Costs In 2022

In early January, The Wall Street Journal Editorial Board warned that one peril of a large administrative state is the mischief agencies can get up to when no one is watching.

Specifically, they highlight the overreach of the Agriculture Department, which expanded food-stamp benefits by evading the process for determining benefits and end-running Congressional review.

Exhibit A in the over-reach is the fact that the cost of the federal food stamps program known as the Supplemental Nutrition Assistance Program (SNAP) increased to a record $119.5 billion in 2022, according to data released by the U.S. Department of Agriculture...

Food Stamp costs have literally exploded from $60.3 billion in 2019, the last year before the pandemic, to the record-setting $119.5 billion in 2022.

In 2019, the average monthly per person benefit was $129.83 in 2019, according to the U.S. Department of Agriculture. That increased by 78 percent to $230.88 in 2022.

Even more intriguing is the fact that the number of participants had increased from 35.7 million in 2019 to 41.2 million in 2022...

All of which is a little odd - the number of people on food stamps remains at record highs while the post-COVID-lockdown employment picture has improved dramatically...

Source: Bloomberg

If any of this surprises you, it really shouldn't given that 'you, the people' voted for the welfare state. However, as WSJ chided: "abuse of process doesn’t get much clearer than that."

In its first review of USDA, the GAO skewered Agriculture’s process for having violated the Congressional Review Act, noting that the “2021 [Thrifty Food Plan] meets the definition of a rule under the [Congressional Review Act] and no CRA exception applies. Therefore, the 2021 TFP is subject to the requirement that it be submitted to Congress.” GAO’s second report says “officials made this update without key project management and quality assurance practices in place.”

Abuse of process doesn’t get much clearer than that. The GAO review won’t unwind the increase, which requires action by the USDA. But the GAO report should resonate with taxpayers who don’t like to see the politicization of a process meant to provide nutrition to those in need, not act as a vehicle for partisan agency staffers to impose their agenda without Congressional approval.

All of this undermines transparency and accountability for a program that provided food stamps to some 41 million people in 2021. The Biden Administration is using the cover of the pandemic to expand the entitlement state beyond what Congress authorized.

The question now is, will House Republicans draw attention to this lawlessness and use their power of the purse to stop it to the extent possible with a Democratic Senate.

And don't forget, the US economy is "strong as hell."

Tyler Durden Sat, 01/28/2023 - 09:55

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Spread & Containment

A Royal Caribbean Cruise Line Adult Favorite Has Not Come Back

The cruise line has almost fully returned to normal after the covid pandemic, but one very popular activity hasn’t been brought back.

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The cruise line has almost fully returned to normal after the covid pandemic, but one very popular activity hasn't been brought back.

In the early days of Royal Caribbean Group's (RCL) - Get Free Report return from its 15-month covid pandemic shutdown, cruising looked a lot different. Ships sailed with limited capacities, masks were required in most indoor areas, and social distancing was a thing.

Keeping people six feet apart made certain aspects of taking a cruise impossible. Some were made easier by the lower passenger counts. For example, all Royal Caribbean Windjammer buffets required reservations to keep the crowds down, but in practice that system was generally not needed because capacities were never reached.

Dance parties and nightclub-style events had to be held on the pool decks or in larger spaces, and shows in the big theaters left open seats between parties traveling together. In most cases, accommodations were made and events more or less happened in a sort of normal fashion.

A few very popular events were not possible, however, in an environment where keeping six feet between passengers was a goal. Two of those events -- the first night balloon drop and the adult "Crazy Quest" game show -- simply did not work with social-distancing requirements.

One of those popular events has now made its comeback while the second appears to still be missing (aside from a few one-off appearances).

TheStreet

The Quest Is Still Mostly Missing

In late November, Royal Caribbean's adult scavenger hunt, "The Quest," (sometimes known as "Crazy Quest") began appearing on select sailings. And at the time it appeared like it was coming back across the fleet: A number of people posted about the return of the interactive adult game show in an unofficial Royal Caribbean Facebook group.

It first appeared during a Wonder of the Seas transatlantic sailing.

Since, then its appearances continue to be spotty and it has not returned on a fleetwide basis. This might not be due to any covid-related issues directly, but covid may play a role.

On some ships, Studio B, which hosts "The Quest," has been used for show rehearsals. That has been more of an issue with the trouble Royal Caribbean has had in getting new crew members onboard. And while that staffing issue has been improving, some shows may not have had full complements of performers, so using the space for rehearsal has been a continuing need.

In addition, while covid rules have gone away, covid has not, and ill cast members may force the need for more rehearsals.

Royal Caribbean has not publicly commented on when (or whether) "The Quest" will make a full comeback

Royal Caribbean Balloon Drops Are Back   

Before the pandemic, Royal Caribbean kicked off many of its cruises with a balloon drop on the Royal Promenade. That went away because it forced people to cluster as music was performed and, at midnight, balloons fell from the ceiling.

Now, the cruise line has brought back the balloon drop, albeit with a twist. The drop itself is appearing on activity schedules for upcoming Royal Caribbean cruises. Immediately after it, however, the cruise line has added something new: "The Big Recycle Balloon Pickup."

Most of the dropped balloons get popped during the drop. Previously, crewmembers picked up the used balloons. Now, the cruise line has made it a "fun" passenger activity.

"Get environmentally friendly as you help us gather our 100% biodegradable balloons in recycle baskets," the cruise line shared in its app. 

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Spread & Containment

What’s Still Missing on Royal Caribbean Cruises Post Covid

The cruise line has almost fully returned to normal after the covid pandemic, but one very popular activity hasn’t been brought back.

Published

on

The cruise line has almost fully returned to normal after the covid pandemic, but one very popular activity hasn't been brought back.

In the early days of Royal Caribbean Group's (RCL) - Get Free Report return from its 15-month covid pandemic shutdown, cruising looked a lot different. Ships sailed with limited capacities, masks were required in most indoor areas, and social distancing was a thing.

Keeping people six feet apart made certain aspects of taking a cruise impossible. Some were made easier by the lower passenger counts. For example, all Royal Caribbean Windjammer buffets required reservations to keep the crowds down, but in practice that system was generally not needed because capacities were never reached.

Dance parties and nightclub-style events had to be held on the pool decks or in larger spaces, and shows in the big theaters left open seats between parties traveling together. In most cases, accommodations were made and events more or less happened in a sort of normal fashion.

A few very popular events were not possible, however, in an environment where keeping six feet between passengers was a goal. Two of those events -- the first night balloon drop and the adult "Crazy Quest" game show -- simply did not work with social-distancing requirements.

One of those popular events has now made its comeback while the second appears to still be missing (aside from a few one-off appearances).

TheStreet

The Quest Is Still Mostly Missing

In late November, Royal Caribbean's adult scavenger hunt, "The Quest," (sometimes known as "Crazy Quest") began appearing on select sailings. And at the time it appeared like it was coming back across the fleet: A number of people posted about the return of the interactive adult game show in an unofficial Royal Caribbean Facebook group.

It first appeared during a Wonder of the Seas transatlantic sailing.

Since, then its appearances continue to be spotty and it has not returned on a fleetwide basis. This might not be due to any covid-related issues directly, but covid may play a role.

On some ships, Studio B, which hosts "The Quest," has been used for show rehearsals. That has been more of an issue with the trouble Royal Caribbean has had in getting new crew members onboard. And while that staffing issue has been improving, some shows may not have had full complements of performers, so using the space for rehearsal has been a continuing need.

In addition, while covid rules have gone away, covid has not, and ill cast members may force the need for more rehearsals.

Royal Caribbean has not publicly commented on when (or whether) "The Quest" will make a full comeback

Royal Caribbean Balloon Drops Are Back   

Before the pandemic, Royal Caribbean kicked off many of its cruises with a balloon drop on the Royal Promenade. That went away because it forced people to cluster as music was performed and, at midnight, balloons fell from the ceiling.

Now, the cruise line has brought back the balloon drop, albeit with a twist. The drop itself is appearing on activity schedules for upcoming Royal Caribbean cruises. Immediately after it, however, the cruise line has added something new: "The Big Recycle Balloon Pickup."

Most of the dropped balloons get popped during the drop. Previously, crewmembers picked up the used balloons. Now, the cruise line has made it a "fun" passenger activity.

"Get environmentally friendly as you help us gather our 100% biodegradable balloons in recycle baskets," the cruise line shared in its app. 

Read More

Continue Reading

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