Monthly Archives: February 2009

What’s the hurry?

General John B. McClennan had a bad case of  “the slows.”  So said  Abraham Lincoln  early in the Civil War when “Prince John”  wasn’t moving fast enough for his commander-in-chief.

But when it really comes to the slows,  some biological reactions  would be hard to beat, especially those that occur in the absence of the catalyzing power of enzymes.

How slowly would these transformations occur —  days, weeks, months? And why even pose the question?

One UNC scientist who studies such issues is Richard Wolfenden, Ph.D., Alumni Distinguished Professor of biochemistry and biophysics and a member of the National Academy of Sciences. 

According to a study he reported four years ago, a biological reaction considered essential in creating the building blocks of DNA and RNA would take 78 million years without a particular enzyme. 

But another transformation in the absence of an enzyme Wolfenden recently described in PNAS is almost 30 times slower than that, roughly 2.3 billion years, or almost half the age of planet Earth.  Now ain’t that  “the slows.”

This reaction is essential for the biosynthesis of hemoglobin and chlorophyll.  But when catalyzed by the enzyme uroporphyrinogen decarboxylase, the rate of cholorophyll and hemoglobin production in cells is increased by a staggering factor — equivalent to the difference between the diameter of a bacterial cell and the distance from Earth to the sun.

“Enzymes allow organisms to channel the flow of matter to their own advantage, allowing some reactions to proceed rapidly compared with others that offer no selective advantage,” says Wolfenden.  He points out that after a substance is bound at an enzyme’s active site, it’s half-life,  the time it takes for half the substance to be consumed, is usually a small fraction of one second.

According to the researcher, rapid turnover is necessary if any enzyme is to produce a significant rate of reaction given their limited concentration witin cells.  “Not surprisingly , many enzymes have evolved to work nearly as efficiently  as is physcially possible, with second order rate constants that approach their rates of encounter with the substrate in solution.” 

Particularly remarkable are those cases in which enymes act alone as simple protein catalysts.

So why bother with wanting to know the rate of slowness of reactions in the absence of enzymes? For one, the information would allow biologists to appreciate what natural selection has accomplished in the evolution of enzymes as proficient catalysts, Wolfenden explains.

And such information has also found direct application in the development of  ‘transition state analogue inhibitors,’ leading to the design of drugs such as the ACE inhibitors that are now used to control high blood pressure and the protease inhibitors that are used to treat HIV infection.

But if that’s not enough, there’s always this:  Without enzymes as catalysts, there would be no life at all, neither microbial nor human.   

Les Lang

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Clocking Cancer

You might say that Dr. Aziz Sancar is trying to clock cancer. 

In a nifty double play involving a pair of recent publications in the Proceedings of the National Academy of Sciences (PNAS), the Sarah Graham Kenan professor of biochemistry and biophysics at UNC found in one study that tinkering with the circadian clock can suppress cancer growth, and in the other he and his lab team presented molecular data  suggesting why timing just might be everything with regard to delivering chemotherapy for cancer.

Both studies involve  the daily oscillatory rhythms of the cellular repair machinery. The main driver of these rhythms  is the circadian clock, which keeps the biological, behavioral and physiological processes on a  24-hour cycle.  Every cell in the body has its own internal clock, and each is synchronized by one master clock, located in a neuronal cluster in the brain. (No wonder we feel wound up sometimes.)

In the latter research, the Sancar team found that the ability of the cellular repair sytem known as nucleotide excision repair is linked to the circadian clock.  Repair ability is  at a minimum in the early morning and reaches a maximum in the evening hours. Moreover, this daily dance is due to changes in the levels of just one of six repair machinery components,  an enzyme, at different times of day.

 Of importance here is that the repair machinery in question usually fixes damage to DNA caused by chemotherapy or UV radiation exposure.  So although the study involved murine brain tissue,  chemotherapy delivery may be best early in the morning (6:00 a.m. to 10:00 a.m.).

 As to slowing the progression of cancer, Aziz Sancar explains below.  

Les Lang

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Perl Today, Tomorrow Nobel?

The aural difference between Tar Heel territory and the Hollywood hills of LA is the ubiquitous thwack of bounced basketballs in neighborhood driveways  versus the clack of computer keyboards well into the night.

 In that west coast capital of  schadenfreude, where legions of hopeful screenplay scribblers take secret delight in another’s failure,  the odds against fame and fortune, an Oscar on the mantle, are very high.  

Indeed, uncertainty with a dose of mystique abounds, driving some writers to despair, to drink, to fortune tellers, gurus,  or into the arms of those of whom it’s rumored have the contacts, power or chutzpah to make it all happen.

Not so for academic bench scientists, yes? Few , including those of the biomedical stripe,  are in it for fame and Nobel laureateship.  After all, it’s doing the work one loves.  And besides, who has time to obsess on  laurels when getting a grant, getting published, running a lab, teaching classes, preparing a paper, mentoring students, etc., etc.,  etc., round one’s days… and sleep.

But for those who might dream the big dream in a serious way,  here’s a tip worth considering: the road best traveled toward Stockholm’s big kahuna  may involve first taking home from Chapel Hill the Perl-UNC Neuroscience Prize.

Since its inception in 2001,  four of eight Perl prize recipients have received Nobel gold. 

Really. Amazing, you say.  But what is this Perl prize? Well, it’s a $10,000 award in recognition of a seminal achievement in neuroscience.

Dr. Edward R. Perl, who endowed the prize, is Sarah Graham Kenan professor of cell and molecular physiology at UNC School of Medicine. Thirty or so years ago, he was the first to prove that a particular class of nerve cells (now called nociceptors) responds to stimuli that are perceived as painful. These cells now are targets of extensive efforts to find drugs that block their function.

Previous Perl prize awardees were David Julius from the University of California at San Francisco; Roderick MacKinnon from Rockefeller University; Linda Buck from the Fred Hutchinson Cancer Research Center in Seattle; Richard Axel from Columbia University; Roger Tsien from the UC San Diego; Roger Nicoll from UC San Francisco; Rob Malenka from Stanford; and Huda Y. Zoghbi of Baylor College of Medicine. 

Of this list, MacKinnon, Buck, Axel and Tsien were subsequently awarded the Nobel Prize for their pioneering efforts.

No research slouches here. Take Tsien, who was last year’s Nobel winner for chemistry. Back in 2005, the  selection team for the 5th UNC-Perl previously noted the wide variety of tools he developed for optically monitoring stucture and function of cells and molecules in the nervous system, including calcium indicator dyes, genetically coded protein biosensors and modifications to green fluorescent protein, or GFP.

Given the Perl prize numbers, bookies who annually tout the Nobel may perk up their ears and their odds. In a few weeks or so, the 9th Perl winner will be announced.  (You’ll read all about it here.)

And in September, the Stockholm short  list just may carry another winner of the Perl.

Les Lang

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