The Bulldogs missed out Saturday on a couple of transfers: Louisiana-Monroe's Michael Ertel to UAB and Santa Clara's Trey Wertz to Notre Dame.

Butler has been active in the transfer market this offseason, but had come up empty — until Friday.

Bolden averaged 8.5 points in 21 minutes a game for South Carolina, starting 15 of 30 games.

As Dallara's Stefano DePonti saw his parent company begin to manufacture parts for ventilators back in Italy, he knew the IndyCar shop needed to step in to help fight COVID-19.

Anderson, a 6-7 wing from South Bend, put his name in the transfer portal exactly a week ago.

Former Center Grove High School standout attended Stanford but will play for the Hoosiers in his remaining season.

Paul Corsaro is already busy at UIndy and a bunch of local players are on the move.

Carmel and IU grad Sage Steele will co-host and star athletes like Drew Brees and Venus Williams will announce winners during the online broadcast.

Former Center Grove High School standout attended Stanford but will play for the Hoosiers in his remaining season.

Cardaño-Hillary leaves George Mason as the school's all-time leading scorer and was named Atlantic 10 Player of the Year last season.

High school football and track standout for the Royals appeared in two games for Hoosiers

Nicole Cardaño-Hillary wanted to take her game to another level after setting records for three seasons at George Mason.

After a record-setting career at South Bend Riley, he rarely cracked the Hoosiers lineup in two seasons.

Anderson, a 6-7 wing from South Bend, put his name in the transfer portal exactly a week ago.

Former Center Grove High School standout attended Stanford but will play for the Hoosiers in his remaining season.

The owner of FoxGardin in Fortville transformed himself into Joe Exotic to help his workers.

Matt Haarms will join the Cougars as a graduate transfer with one season of eligibility remaining.

LaVall Jordan on transfers: 'We'd rather have nobody than the wrong guy.'

Butler Bulldogs is a finalist for some prominent college basketball transfers after missing out on a guard.

The Bulldogs missed out Saturday on a couple of transfers: Louisiana-Monroe's Michael Ertel to UAB and Santa Clara's Trey Wertz to Notre Dame.

Butler has been active in the transfer market this offseason, but had come up empty — until Friday.

Bolden averaged 8.5 points in 21 minutes a game for South Carolina, starting 15 of 30 games.

The owner of FoxGardin in Fortville transformed himself into Joe Exotic to help his workers.

Chelsea in talks over Chilwell, Blues and Manchester United interested in Chiesa, Red Devils ask about Salisu, plus more.

With uncertainty around the next transfer window, what shape are Premier League squads in? We take a look at the clubs in the bottom half.

Former Center Grove High School standout attended Stanford but will play for the Hoosiers in his remaining season.

Carmel and IU grad Sage Steele will co-host and star athletes like Drew Brees and Venus Williams will announce winners during the online broadcast.

• The storied investment bank is seeing leadership shakeups under CEO David Solomon and a slew of partner departures. 
• Goldman has been moving away from high-risk businesses like trading and is making pushes into more stable areas like consumer lending, wealth management, and transaction banking. 
• There have been big cultural changes, too. Solomon is looking to create a more transparent workplace, while new tech execs are taking cues from Silicon Valley heavy-hitters. 
• At Business Insider, we are closely tracking the latest developments at Goldman. You can read all of our Goldman coverage on BI Prime.

Storied Wall Street bank Goldman Sachs is going through some massive changes under CEO David Solomon.

It's taken big steps involving transparency and inclusion to change up its culture. It has seen a slew of partner departures — many in the securities division. And it's making big pushes into businesses like wealth management and transaction banking.  

The latest people moves

• Goldman Sachs just hired Kurt Hoffman, an expert in distressed situations and bankruptcy, to join a trading unit known for some of the bank's most lucrative deals
• Goldman Sachs' top tech exec explains how a fresh slew of senior hires are transforming the bank's approach to building products
• Read the full memo Goldman Sachs just sent naming 4 execs to lead its private-equity investments across the merchant-banking division

Culture and talent

• Read the full memo Goldman Sachs just sent to staff announcing its new head of regulatory affairs. The former White House counsel will be tasked with helping clean up the bank's 1MDB drama.
• Goldman Sachs just hired 2 senior recruiting execs focused on luring top talent from other firms —and it's a huge departure from the firm's traditional promote-from-within mentality
• Read the full memo David Solomon just sent to 38,000 Goldman Sachs employees explaining why he's moving his management team out of stuffy offices and into open seating
• Goldman Sachs CEO David Solomon and his management team are ditching their stuffy offices and moving to an open floor plan closer to the people so they can feel the buzz of New York headquarters
• Goldman Sachs just unveiled a new gender pronouns initiative as part of a broader inclusion push at the Wall Street firm
• Read the memo Goldman Sachs just sent to its employees unveiling a new pronouns initiative

Coronavirus response

• Inside a 38,000-person remote work rollout at Goldman Sachs: sleepless nights, assembly lines, and an Amazon-like hub on a Manhattan trading floor
• How a massive New York hospital secured 130,000 N95 masks from China with help from a senior partner at Goldman Sachs, private jets, and a call to Warren Buffett
• Goldman Sachs CEO David Solomon just sent a firm-wide voicemail about the coronavirus crisis. Here's what he told employees.
• Goldman Sachs and Bank of America just updated their WFH policies — again. Here's what they're telling employees about the latest steps aimed at combating the spread of coronavirus.
• Read the full memo Goldman Sachs top brass just sent detailing the firm's coronavirus contingency plans, including separating employees into 'blue' and 'white' teams to alternate working from the office and home

Consumer push, transaction banking, wealth management

• Goldman Sachs just announced its first partnership for transaction banking as it looks to build a new $1 billion business moving money around the world
• Goldman Sachs is sending much less mail to potential Marcus customers. A senior exec lays out the reason why.
• A Goldman Sachs exec explains why the bank isn't sweating concerns over the Apple Card's profitability
• A Wall Street firm crunched the numbers around how much Apple will make from its new credit card with Goldman Sachs
• Here's why Goldman Sachs just did its biggest deal in nearly 20 years as part of a pivot to less wealthy clients
• Goldman Sachs execs are opening up about their plans for Marcus, and they think it can do to banking what iTunes did to the music industry
• Goldman Sachs' partnership with Apple could move it a step closer to being 'a bank branch in your pocket'
• Human resources is the next battleground for Wall Street wealth advisers as Morgan Stanley and Goldman Sachs jockey over new turf
• Goldman Sachs has a novel method for predicting the next economic slump, and it's at the heart of its hot new business

Technology

• JPMorgan and Goldman Sachs are finally beginning to embrace fintech startups. Here's how they test the waters before committing to working with them.
• We talked to the execs behind Bloomberg's new data partnership with Goldman Sachs. Here's why they think it's a sign of Wall Street's future.
• Goldman Sachs is putting its own Marquee app on Amazon's cloud in a pitch to lure more fintech developers
• Goldman Sachs is embracing open-source code and its chief data officer says it's part of a "new world" of software
• Read the memo the new Goldman tech chief sent to the firm's 9,000-plus engineers where he urges them to ditch presentations in favor of Amazon's famous narratives
• A new Goldman Sachs tech exec hired from Amazon is taking a page from the Jeff Bezos playbook by urging engineers to ditch PowerPoint and write memos
• Goldman Sachs' new CTO shares his strategy for attracting outside developers to work more closely with the bank, giving a glimpse into the future of how Wall Street will work
• A Verizon executive is joining Goldman Sachs as chief technology officer as the Wall Street bank reshuffles its ranks
• Marty Chavez is retiring from Goldman Sachs. We chatted with him about the bank's tech transformation, why now is the right time for him to step down, and what he's planning next.
• Goldman Sachs tech guru Marty Chavez is retiring from the bank
• Goldman Sachs' CEO just warned that the bank's big tech bets might not pay off as quickly as people hope
• Goldman Sachs is scrapping a homegrown email app it once touted — and it's a sign the bank is moving away from building tech in house
• Goldman Sachs is exploring plans to create a Netflix for data, and it marks a new frontier for Wall Street
• Goldman Sachs' internal idea factory hatched a plan for the Google of Wall Street, and it's now looking for the next big thing to disrupt the bank
• Goldman Sachs' big bet on the future of Wall Street had a rocky start. Here's the inside story of the bank's struggle to grow its next business and an exclusive look at its plans

Trading

• Bank of America is shaking up its global markets division and poached a Goldman Sachs exec to fill a key new role
• Goldman Sachs' massive quant business now rivals AQR and Two Sigma. We talked to the bank's top quant about asset growth, finding data sources, and why critics of computerized trading are wrong.
• Goldman Sachs' CEO tells us the bank is winning over quant clients. That helped it outpace rivals like JPMorgan last quarter.
• Goldman Sachs is cutting about 5% of sales and trading staff after senior equities leaders delivered a tough town-hall talk
• Goldman Sachs is moving away from a tool championed by its former CFO as it pushes its traders to see clients where they once saw quick wins
• Goldman Sachs is shuffling its top stock trading executives as the business tries to claw back market share from Morgan Stanley and JPMorgan
• Goldman Sachs's bond trading unit is still trying to find its way — and it represents a key challenge for new CEO David Solomon

Alternatives

• Read the full memo Goldman Sachs just sent naming 4 execs to lead its private-equity investments across the merchant-banking division
• Goldman Sachs is making targeted hires for a 'storefront' for alternative investments that's modeled after firms like KKR and Blackstone
• Goldman Sachs' push into private equity is ruffling feathers at Blackstone — and it might be a sign of big client skirmishes to come
• Goldman Sachs execs are jockeying for control of the firm's lucrative private investing units after a plan to merge it — and the stakes couldn't be higher
• Meet the Goldman Sachs execs tasked with building the firms' new Blackstone-esque private-investing unit — and pumping up the bank's flagging stock price
• 'It's good to be Rich': Meet the Goldman Sachs banker who has built a private investing empire that goes head-to-head with Blackstone — and you've probably never heard of him
• Goldman Sachs is considering a shakeup of its alternative investing units as part of a plan to simplify the bank's strategy

Deals

• Goldman Sachs is assembling a team of senior bankers focused on middle-market private equity. Here are the key hires and the playbook they'll use to land new clients.
• Goldman Sachs unloaded some of its WeWork shares before its investment bankers pitched investors on what it once considered a $60 billion-plus IPO
• Goldman Sachs just revealed it sold part of its Uber stake to SoftBank and it helped boost a $4.5 billion business
• A senior Goldman Sachs fintech banker was about to join JPMorgan — but then got lured back —and it's another sign of the fierce battle for M&A talent
• Goldman just promoted a star tech banker close to Tesla and Microsoft to co-head one of its most profitable businesses, as incoming CEO Solomon makes his mark
• Goldman Sachs just announced a shakeup of its leadership — and it signals the rise of bankers over traders
• A tug-of-war between Goldman Sachs and JPMorgan over a top banker highlights Wall Street's $1 trillion battleground

Investor day 2020

• Inside Goldman Sachs' first investor day, where avocado toast and crab apples were served with tech talk, 3-year plans, and a surprising trading mea culpa
• Goldman Sachs just revealed a new wealth brand at its first-ever investor day. It shows how the bank is trying to reshape its strategy — and image.
• Goldman Sachs just unveiled hundreds of slides laying out the future of the company. Here are the 10 crucial slides that show how it plans to transform into a bank for everyone.
• Goldman Sachs is rethinking how it makes private-equity bets with its own money – and one analyst thinks that shift will be a big driver of its stock price

Careers 

• Goldman Sachs is now hiring high-school graduates for roles in Salt Lake City, one of the company's 'high value' locations
• Goldman Sachs has lost at least 54 partners since David Solomon became CEO. We're keeping a running list — and compiling details from insiders about how the exits are being celebrated.
• Read the full memo Goldman Sachs' top brass just sent to staff announcing 2 heads of the bank's private-investing arm are out as it's gearing up to raise billions
• 2 coheads of Goldman Sachs' private-investing business are retiring, in a blow to David Solomon's fundraising plans
• A Goldman Sachs partner who just resigned is leaving behind a job overseeing $2 billion for a London VC with a leading stake in neobank Revolut
• Read the memo announcing the departure of Adam Korn, the Goldman Sachs exec who was 'instrumental in building and championing' innovations like the bank's Marquee platform
• Another Goldman Sachs partner is out. HR chief Dane Holmes is the latest key player to leave the Wall Street bank in a matter of days.
• Goldman Sachs is offering buyouts to encourage partners to leave as CEO David Solomon works to shrink one of the most elite clubs on Wall Street
• Goldman Sachs is making renewable energy a big priority based on its hiring strategy. It's a sign that its ideas incubator is working.
• The David Solomon era at Goldman Sachs kicked off with 43 words Lloyd Blankfein would never say
• Goldman Sachs CEO David Solomon shares his best leadership advice
• Goldman Sachs is shaking up the way it stocks one of the most elite clubs on Wall Street — and it shows how banks are back to making money again
• Goldman Sachs' 1MDB problems are eating into employee morale, and insiders worry the firm will use its legal woes as an excuse to scrimp on bonuses
• Goldman Sachs is about to move dozens of jobs out of pricey New York to Utah as Wall Street turns to cheaper cities

Join the conversation about this story »

NOW WATCH: A cleaning expert reveals her 3-step method for cleaning your entire home quickly

While we have covered a number of tutorials on PayPal in the past, in this tutorial we will look at a relatively new platform that goes by the name of TransferWise. I will discuss what TransferWise is and how you can use it with your PayPal account. I will also cover why this platform is […]

The post PayPal to TransferWise – Cheap International Money Transfer appeared first on Tips and Tricks HQ.

The days of your family member sending you money in an envelope from overseas are decreasing due to the risk of this money getting lost in transit or removed from your letterbox before you’ve arrived home. While many merchants and everyday people are sending money to family and friends abroad using PayPal, TransferWise is, in […]

The post How to Send Money Overseas with TransferWise appeared first on Tips and Tricks HQ.

“Breathing would be delightful,” the director of products told me in our kickoff. His startup was growing fast. It had a bunch of new funding, the pressure was on to ship, and the team was underwater. I was there to help and take the pressure off so they could breathe. “Let’s begin to think strategically […]

The post Successful Scaling: How to Grow Without Tumbling Back Down appeared first on ReadWrite.

Local news publishers have struggled to monetize spike in consumer interest.

Please visit Search Engine Land for the full article.

velocityconf: Help your dev + ops teams be cross-functional and more successful. http://t.co/1mqGK3zh0U Free webcast 5/22 w/ @lnxchk

velocityconf: RT @suzaxtell: #WomeninTech You're invited to a women's meetup on Tues May 28 in SF w/ @courtneynash @mjawili, more http://t.co/MsMZ0IK8L2

velocityconf: Call for speakers and registration is open for @webperfdays in Silicon Valley http://t.co/cJKBmynkjI June 22, Google HQ (cc @sfwebperf)

If you’re an entrepreneur or marketer who hasn’t embraced webinars yet, you probably need to rethink your strategies. Over 60 percent of marketers say they use webinars as a key part of their content marketing strategy — and over 70 percent say it’s the best way to generate high-quality business leads.

Thankfully, one of the silver linings to our new quarantine, work from home lifestyles lately is the explosion of conferencing software and Americans’ newfound enthusiasm for video group meetups. 

Vidthere is one of the services that has considered the needs of large and small groups trying to maintain connections over distance, offering a suite of web-based communication tools that centralizes everything in one easy-to-use place.

Vidthere is a live video platform for everyone, featuring loads of internal communications features as well as options to sell and market directly to customers.

With webinars emerging as a key means to engage customers and sell products, Vidthere gives you all the tools to do that from any location. Vidthere offers the opportunity to deliver live video webinars that are easy for both presenters and users. 

Vidthere is entirely web-based, so users never need to download any software to join a Vidthere session. As for sessions, they combine no-lag high-quality performance with the ability to scale to the size of an audience with no video loss. Plus, every Vidthere meeting or webinar has a powerful chat feature so users can engage easily.

As for presenters, Vidthere events support up to 30 meeting participants and an unlimited number of webinar viewers, with options to support screen sharing, video in video presentation, and a whiteboard mode, a full basket of tools to help contour any presentation just the way you want it. Read the rest

Omer Golan, founder and CEO of Outernets, discusses how artificial intelligence can improve the digital out-of-home industry.

An "appalling prank" in Innisfil sent South Simcoe Police officers on a mission to identify the culprits involved.

The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

26 February 2020

Médecins Sans Frontières, the medical humanitarian organization, has been awarded the Chatham House Prize 2015 for its life-saving work in combating the outbreak of Ebola in West Africa.

The protein-tyrosine phosphatase SHP2 is an allosteric enzyme critical for cellular events downstream of growth factor receptors. Mutations in the SHP2 gene have been linked to many different types of human diseases, including developmental disorders, leukemia, and solid tumors. Unlike most SHP2-activating mutations, the T507K substitution in SHP2 is unique in that it exhibits oncogenic Ras-like transforming activity. However, the biochemical basis of how the SHP2/T507K variant elicits transformation remains unclear. By combining kinetic and biophysical methods, X-ray crystallography, and molecular modeling, as well as using cell biology approaches, here we uncovered that the T507K substitution alters both SHP2 substrate specificity and its allosteric regulatory mechanism. We found that although SHP2/T507K exists in the closed, autoinhibited conformation similar to the WT enzyme, the interactions between its N-SH2 and protein-tyrosine phosphatase domains are weakened such that SHP2/T507K possesses a higher affinity for the scaffolding protein Grb2-associated binding protein 1 (Gab1). We also discovered that the T507K substitution alters the structure of the SHP2 active site, resulting in a change in SHP2 substrate preference for Sprouty1, a known negative regulator of Ras signaling and a potential tumor suppressor. Our results suggest that SHP2/T507K's shift in substrate specificity coupled with its preferential association of SHP2/T507K with Gab1 enable the mutant SHP2 to more efficiently dephosphorylate Sprouty1 at pTyr-53. This dephosphorylation hyperactivates Ras signaling, which is likely responsible for SHP2/T507K's Ras-like transforming activity.

Heme-regulatory motifs (HRMs) are present in many proteins that are involved in diverse biological functions. The C-terminal tail region of human heme oxygenase-2 (HO2) contains two HRMs whose cysteine residues form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs occurs independently of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the HO2 core. Using hydrogen-deuterium exchange (HDX)-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle—when Fe3+-heme is bound to the HRMs and the core is in the apo state. These conformational changes were consistent with transfer of heme between binding sites. Indeed, we observed that HRM-bound Fe3+-heme is transferred to the apo-core either upon independent expression of the core and of a construct spanning the HRM-containing tail or after a single turnover of heme at the core. Moreover, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We therefore propose an Fe3+-heme transfer model in which HRM-bound heme is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.

Bacterial biofilms are cellular communities that produce an adherent matrix. Exopolysaccharides are key structural components of this matrix and are required for the assembly and architecture of biofilms produced by a wide variety of microorganisms. The human bacterial pathogens Escherichia coli and Salmonella enterica produce a biofilm matrix composed primarily of the exopolysaccharide phosphoethanolamine (pEtN) cellulose. Once thought to be composed of only underivatized cellulose, the pEtN modification present in these matrices has been implicated in the overall architecture and integrity of the biofilm. However, an understanding of the mechanism underlying pEtN derivatization of the cellulose exopolysaccharide remains elusive. The bacterial cellulose synthase subunit G (BcsG) is a predicted inner membrane–localized metalloenzyme that has been proposed to catalyze the transfer of the pEtN group from membrane phospholipids to cellulose. Here we present evidence that the C-terminal domain of BcsG from E. coli (EcBcsGΔN) functions as a phosphoethanolamine transferase in vitro with substrate preference for cellulosic materials. Structural characterization of EcBcsGΔN revealed that it belongs to the alkaline phosphatase superfamily, contains a Zn2+ ion at its active center, and is structurally similar to characterized enzymes that confer colistin resistance in Gram-negative bacteria. Informed by our structural studies, we present a functional complementation experiment in E. coli AR3110, indicating that the activity of the BcsG C-terminal domain is essential for integrity of the pellicular biofilm. Furthermore, our results established a similar but distinct active-site architecture and catalytic mechanism shared between BcsG and the colistin resistance enzymes.

3-Mercaptopyruvate sulfur transferase (MPST) catalyzes the desulfuration of 3-mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly-studied MPST1 variant and demonstrated that substitutions in its Ser–His–Asp triad, proposed to serve a general acid–base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney, and brain tissues, finding that it ranges from 0.4 μmol·kg−1 in brain to 1.4 μmol·kg−1 in kidney. We also show that N-acetylcysteine, a widely-used antioxidant, is a poor substrate for MPST and is unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ∼15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically-relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ∼3.5-fold as its concentration decreases from 10 to 1 μm, whereas the total MPST reaction rate increases ∼7-fold. The simulations also predicted that cysteine is a quantitatively-significant sulfane sulfur acceptor, revealing MPST's potential to generate low-molecular-weight persulfides. We conclude that the MPST1 and MPST2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPST-catalyzed reaction in a physiologically-relevant concentration range.

13 March 2014 , Volume 90, Number 2

Invitation Only Research Event