SCIENCE & TECHNOLOGY Their hypothesis faced one major difficulty: Overoxidation of cysteine to sulfinic acid had been thought to be irreversible. And why would a signaling pathway require the irreversible modification of an abundant cellular protein? The answer is that cysteine sulfinic acid 2 2 formation is not irreversible after all, according to Sue Goo Rhee, chief of the Laboratory of Cell Signaling at the National Institutes ofHealth's National Heart, Lung ELLS HAVE M I X E D F E E L I N G S tible to inactivation by H 2 0 2 , whereas its & Blood Institute in Bethesda, Md. about hydrogen peroxide: This monofunctional bacterial counterpart is by-product of metabolism is a not. The source of human peroxiredoxins' Rhee, along with associate professor of dangerous oxidant that can sensitivity, Karplus tells C&EN, is their biology H o Zoon Chae of Chonnam wreak havoc on the structure of unusual ability to stabilize a conformation National University, Kwangjoo, South cells, DNA, RNA, and proteins. But H 2 0 2 in which disulfide bond Korea, and graduate stualso plays an important role as a signal in a formation cannot occur. dent Hyun Ae Woo of number of key cellular processes, turning Ewha Womans' UniversiHuman peroxiredoxins' on (or ofr) signaling pathways by reacting ty, Seoul, South Korea, usdecreased ability to link up with protein thiol residues. Scientists have es metabolic labeling to its two cysteines leaves the now managed to turn up a few clues about show that the catalyticalone that's been oxidized what governs whether H 2 0 2 acts as Dr. ly inactive sulfinic acid to sulfenic acid susceptible Jekyll or Mr. Hyde. form of human peroxireto further oxidation by doxin is quickly reduced H 2 0 2 . Overoxidation of Human and bacterial peroxiredoxins, an to the active thiol form of this cysteine sulfenic acid abundant type of peroxidase, sop up delethe enzyme in vivo [Scito cysteine sulfinic acid interious H 2 0 2 at rates faster than other wellence, 300,653 (2003)1 activates the enzyme. known antioxidant enzymes. They do so via a pair of cysteine residues found in their The cells don't restock "But the sensitivity of active sites. Unwanted H 2 0 2 oxidizes one human peroxiredoxins to themselves with peroxof these cysteines (Cys-SH) to sulfenic acid iredoxin, and they don't overoxidation isn't neces(Cys-SOH), producing water as a by-prodsimply remove the sulfinic acid group, the sarily a limitation," Karplus tells C&EN. uct. The other cysteine then attacks its oxauthors point out. Instead, the team finds "It's also an opportunity" idized neighbor to form a disulfide bond. evidence that cysteine sulfinic acid is reThe researchers propose that human The original two-cysteine peroxiredoxin is duced to its thiol form by one or more asperoxiredoxins act as peroxide floodgates regenerated by an external reductant. yet-unidentified cellular enzymes. that, when closed, keep this dangerous celIn addition to ridding the cell of unlular oxidant away from proteins, DNA, "The fact that sulfinic acid formation is wanted H 2 0 2 , human peroxiredoxins— and RNA. When these enzymes are exa reversible process provides support for but not bacterial versions—have also been posed to a burst of H 2 0 2 intended for sigthe notion that the overoxidation of perimplicated in the regulation of peroxidenaling purposes, the floodgates open, aloxiredoxins may contribute to the regulamediated cellular signaling. lowing H 2 0 2 to accumulate sufficiently to tion of H 2 0 2 signaling," note chemical enmediate its signaling pathways. gineering professor George Georgiou and Most recently, the previously mysterigraduate student Lluis Masip of the ous switch that modulates H 2 0 2 ' s University ofTexas, Austin, in a comdual cellular roles has been shown to mentary that accompanies the two be none other than these peroxireScience papers. doxins [Science, 300,650 (2003)]. The work was carried out by a team led by But the cellular presence of an enbiochemistry and biophysics profeszymatic activity capable of reversing sor P. Andrew Karplus of Oregon cysteine oxidation has wider impliState University cations, Rhee argues. The overoxidation of methionine residues in proUsing crystallography and seteins to methionine sulfoxide has quence comparisons, Karplus' attracted much attention, he says. team—which includes former CorHuman enzymes that reverse this nell University graduate student PEROXIDE SWITCH Active peroxiredoxin modification have been suggested to Zachary A. Wood and biochemistry (Prx) contains two reduced cysteines (-SH). play a role in the repair of damaged associate professor Leslie B. Poole of One of these is oxidized by H202 to sulfenic proteins, regulation of protein funcWake Forest University's School of acid (-S0H). Disulfide bond formation followed tion, and elimination of oxidants. Medicine—suggests a mechanism for by enzymatic reduction restores the active how peroxiredoxins might distinenzyme. But if sulfenic acid persists, H202 can "By analogy, the reduction of cysguish H 2 0 2 - m e d i a t e d oxidative oxidize it further to sulfinic acid (-S02H). teine sulfinic acid could likewise serve stress from H 2 0 2 -mediated signal Sulfinic acid formation may be the cellular these cellular functions," he points transduction. They show that a huswitch that determines whether H202 acts as a out, adding that cysteine sulfinic acids man peroxiredoxin that can perform dangerous oxidant or a key cellular signal. form in other proteins, too.—AMAN DA both functions is exquisitely suscepYARNELL
DANGEROUS OXIDANT, BENEFICIAL SIGNAL
Studies shed light on how H 0 carries out its two very different cellular roles
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C & E N / MAY 2 6 , 2003
"The sensitivity of human peroxiredoxin to overoxidation isn't necessarily a limitation. It's also an opportunity/'
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