A subtle change in catalyst structure can sometimes improve catalytic activity dramatically, as we found in our recent study on a-aminoxylation, tandem O-nitroso aldol/Michael reactions, and Mannich reactions catalyzed by the siloxyproline 4, a highly active proline surrogate (Scheme 1).[1] The simple introduction of a siloxy group into the proline structure leads to an increase in the catalytic activity, thus allowing a decrease in catalyst loading and shorter reaction times, without compromising the enantioselectivity, and is accompanied by broadening of the substrate scope. This higher activity can be attributed to the increased solubility of 4 in organic solvents. The fact that the substitution of a hydroxy group for a siloxy group can dramatically affect catalytic activity prompted us to investigate other catalytic systems, and these investigations led us to the diphenylprolinol silyl ether 2. The parent diphenyl-2-pyrrolidinemethanol (1, diphenylprolinol), a commercially available amino alcohol developed by Corey and co-workers, has proved to be a very useful ligand for asymmetric synthesis: B-alkylated oxazaborodine is a useful catalyst for the CBS reduction, [2] while an effective, asymmetric Lewis acid catalyst prepared from B-aryl oxazaborodine and a Brønsted acid promotes the Diels-Alder reaction of a broad range of substrates with excellent enantioselectiv-

It is now established that oxidative stress is one of the earliest, if not the earliest, change that occurs in the pathogenesis of Alzheimer's disease (AD). Consistent with this, mild cognitive impairment (MCI), the clinical precursor of AD, is also characterized by elevations in oxidative stress. Since such stress does not operate in vacuo, in this study we sought to determine whether redox-active iron, a potent source of free radicals, was elevated in MCI and preclinical AD as compared to cognitively-intact age-matched control patients. Increased iron was found at the highest levels both in the cortex and cerebellum from the pre-clinical AD/MCI cases. Interestingly, glial accumulations of redox-active iron in the cerebellum were also evident in preclinical AD patients and tended to increase as patients became progressively cognitively impaired. Our findings suggests that an imbalance in iron homeostasis is a precursor to the neurodegenerative processes leading to AD and that iron imbalance is not necessarily unique to affected regions. In fact, an understanding of iron deposition in other regions of the brain may provide insights into neuroprotective strategies. Iron deposition at the preclinical stage of AD may be useful as a diagnostic tool, using iron imaging methods, as well as a potential therapeutic target, through metal ion chelators.

Glutathione peroxidase catalyzes the reduction of hydrogen peroxide and organic hydroperoxide by glutathione and functions in the protection of cells against oxidative damage. Glutathione peroxidase exists in several forms that differ in their primary structure and localization. We have also shown that selenoprotein P exhibits a glutathione peroxidase-like activity (Saito, Y., Hayashi, T., Tanaka, A., Watanabe, Y., Suzuki, M., Saito, E., and Takahashi, K. (1999) J. Biol. Chem. 274, 2866 -2871). To understand the physiological significance of the diversity among these enzymes, a comparative study on the peroxide substrate specificity of three types of ubiquitous glutathione peroxidase (cellular glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, and extracellular glutathione peroxidase) and of selenoprotein P purified from human origins was done. The specific activities and kinetic parameters against two hydroperoxides (hydrogen peroxide and phosphatidylcholine hydroperoxide) were determined. We next examined the thiol specificity and found that thioredoxin is the preferred electron donor for selenoprotein P. These four enzymes exhibit different peroxide and thiol specificities and collaborate to protect biological molecules from oxidative stress both inside and outside the cells.

Selenoprotein P is an extracellular protein containing presumably 10 selenocysteines that are encoded by the UGA stop codon in the open reading frame of the mRNA. The function of selenoprotein P is currently unknown, although several indirect lines of evidence suggest that selenoprotein P is a free radical scavenger. We first developed a conventional procedure to isolate selenoprotein P from human plasma. Next, we investigated the reactivities of selenoprotein P against various hydroperoxides in the presence of glutathione. Although selenoprotein P reduces neither hydrogen peroxide nor tertiary butyl hydroperoxide, it does reduce phospholipid hydroperoxide such as 1-palmitoyl-2-(13-hydroperoxy-cis-9,trans-11-octadecadienoyl)-3-phosphatidylcholine hydroperoxide. Kinetic analysis demonstrated a tert-uni ping-pong mechanism, similar to those described for classical glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase. Not only glutathione, but also dithiothreitol, mercaptoethanol, cysteine, and homocysteine, were effective as reducing substances, as in the case of phospholipid hydroperoxide glutathione peroxidase. These results show that selenoprotein P functions as a phospholipid hydroperoxide glutathione peroxidase in extracellular fluids.

No abstract

A subtle change in catalyst structure can sometimes improve catalytic activity dramatically, as we found in our recent study on a-aminoxylation, tandem O-nitroso aldol/Michael reactions, and Mannich reactions catalyzed by the siloxyproline 4, a highly active proline surrogate (Scheme 1).[1] The simple introduction of a siloxy group into the proline structure leads to an increase in the catalytic activity, thus allowing a decrease in catalyst loading and shorter reaction times, without compromising the enantioselectivity, and is accompanied by broadening of the substrate scope. This higher activity can be attributed to the increased solubility of 4 in organic solvents. The fact that the substitution of a hydroxy group for a siloxy group can dramatically affect catalytic activity prompted us to investigate other catalytic systems, and these investigations led us to the diphenylprolinol silyl ether 2. The parent diphenyl-2-pyrrolidinemethanol (1, diphenylprolinol), a commercially available amino alcohol developed by Corey and co-workers, has proved to be a very useful ligand for asymmetric synthesis: B-alkylated oxazaborodine is a useful catalyst for the CBS reduction, [2] while an effective, asymmetric Lewis acid catalyst prepared from B-aryl oxazaborodine and a Brønsted acid promotes the Diels-Alder reaction of a broad range of substrates with excellent enantioselectiv-

Zinc, iron and copper are concentrated in senile plaques of Alzheimer disease. Copper and iron catalyze the Fenton-Haber-Weiss reaction, which likely contributes to oxidative stress in neuronal cells. In this study, we found that ascorbate oxidase activity and the intensity of ascorbate radicals measured using ESR spectroscopy, generated by free Cu(II), was decreased in the presence of amyloid-beta (Abeta), the major component of senile plaques. Specifically, the ascorbate oxidase activity was strongly inhibited (85% decrease) in the presence of Abeta1-16 or Abeta1-42, whereas it was only slightly inhibited in the presence of Abeta1-12 or Abeta25-35 (<20% inhibition). Ascorbate-dependent hydroxyl radical generation by free Cu(II) decreased in the presence of Abeta in the identical order of Abeta1-42, Abeta1-16 > Abeta1-12 and was abolished in the presence of 2-fold molar excess glycylhystidyllysine (GHK). Ascorbate oxidase activity and ascorbate-dependent hydroxyl radical generation by free Fe(III) were inhibited by Abeta1-42, Abeta1-16, and Abeta1-12. Although Cu(II)-Abeta shows a significant SOD-like activity, the rate constant for the reaction of superoxide with Cu(II)-Abeta was much slower than that with SOD. Overall, our results suggest that His6, His13, and His14 residues of Abeta1-42 control the redox activity of transition metals present in senile plaques.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused on amyloid-β as the major pathogenic mechanisms with the ultimate goal of using amyloid-β lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on "proteinopathies" and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.