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Extramural Papers of the Month

By Jerry Phelps
June 2008

Deconstructing Aflatoxin B1 Production

NIEHS grantees describe the function of polyketide synthases, enzymes involved in the synthesis of the fungal product and human carcinogen aflatoxin B1, in a paper in the April 11 issue of Science. Understanding this process and the specificity of the chemical structures created by the enzymes may lead to redesigning the enzymes for the synthesis of new molecules and drugs.

Polyketides comprise a diverse range of naturally occurring compounds with a high degree of variability in biological activities and pharmacological properties. The team used the Udwary-Merski bioinformatics algorithm to dissect one polyketide synthase known as PksA into its various domains. They then recombined the constructs in vitro and analyzed the products that were formed. Their goal was to identify the domains that control polyketide chain length, cyclization of the intermediate products and product release.

The team identified the specific domains that elongate the polyketide chain to a fixed length, drive the cyclization of the first two ring structures in aflatoxin - and finally the domain that controls cyclization of the third ring - and also mediate the release of the product. The researchers conclude that the mechanistic features they identified here should apply to catalysis in general and that the insights provided by this dissection approach enable a rational strategy for engineering these enzymes to synthesize alternative products.

Citation: Crawford JM, Thomas PM, Scheerer JR, Vagstad AL, Kelleher NL, Townsend CA.( Exit NIEHS Website. 2008. Deconstruction of iterative multidomain polyketide synthase function. Science 320(5873):243-246.

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Statin Drugs Reduce the Risk of Parkinson's Disease

Using cholesterol reducing statin drugs may decrease a person's risk for developing Parkinson's disease (PD). A new NIEHS-supported epidemiologic study of 654 subjects and controls reports that people who used statins for at least five years had about one-third the risk of PD. Study participants, with a median age of 70 years, were recruited from three rural counties in California.

The researchers were quick to point out that just because this study showed an association between lower risk and statin use, it does not prove that the cholesterol-reducing drugs prevent the devastating neurological disorder. The research team concludes that the findings are preliminary and need to be confirmed in additional well-designed studies with larger populations of subjects.

Overall about 19 percent of the subjects had taken statin drugs at some point, and there was a higher frequency of statin use in healthy adults than those with PD. The odds of having PD declined as the duration of statin use increased, with the strongest protection seen in people who had taken the drugs for longer than five years.

Lower risks were seen in people taking atorvastatin, simastatin, and lovastatin, but not pravastatin. Additional research will be carried out on the PD - cholesterol - statin use links.

Citation: Wahner AD, Bronstein JM, Bordelon YM, Ritz B.( Exit NIEHS Website 2008. Statin use and the risk of Parkinson disease.

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New Findings Contradict Aging/Mitochondrial DNA Mutation Theory

Point mutations in mitochondrial DNA do not cause aging in mice according to NIEHS-supported research that challenges the widely-held theory that mitochondrial mutation drives the aging process. In the study, mice with mitochondrial mutations 500 times higher than normal levels did not show signs of premature aging.

Previous research led to the development of the theory that accumulated mitochondrial mutations throughout life eventually cause the decline in tissue functioning associated with aging. The study authors used a new technique they described as much more sensitive to measure the accumulation of mitochondrial DNA mutations. They found that mutation frequency in mouse mitochondria is more than 10 times lower than has been previously reported, suggesting the earlier work overestimated the mutation frequency.

The authors used wild-type mice and "mutator" mice with abnormally high levels of mitochondrial mutations. Mice homozygous for the mutator gene had 2,500 times higher numbers of mitochondrial mutations than the wild-type mice and also had a reduced lifespan. However, heterozygotes had about 500 times the numbers of mitochondrial mutations, but showed no signs of premature aging.

These data suggest that wild-type mice could never accumulate enough mutations to cause aging symptoms. However, since the researchers only counted point mutations, it is possible that large mitochondrial DNA deletions could still be an underlying cause of aging.

Citation: Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, Loeb LA.( Exit NIEHS Website 2008. DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40(4):392-394.

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World Trade Center: Modeling Exposure Based on Perceived Air Pollution

At the time of the terrorist attacks on the World Trade Center and until a few weeks after the incident, there were few air pollution monitoring sites in areas of New York City exposed to the resulting pollution, making it impossible to estimate individual exposures following September 11, 2001.

To overcome this limitation, NIEHS-supported researchers at the Columbia Center for Children's Environmental Health examined the ability of a newly developed perceived-air-pollution scale and a modeled-air-pollution scale derived from it for predicting previously observed birth outcomes in pregnant women enrolled in a study just after September 11th. The women reported where they lived and worked in the four weeks following the collapse of the towers, along with information relating to the severity of air pollution in these locations.

The researchers found that both the perceived air pollution scale and the modeled scale were highly correlated with distance from the World Trade Center site. They also found that the relationships of several birth outcomes to proximity to the site were apparent when the modeled values were used as the measure of exposure to air pollution.

The team concludes that modeled air pollution values derived from perceived values may be useful in identifying high-risk areas and predicting health outcomes when traditional air pollution monitoring is not available.

Citation: Lederman SA, Becker M, Sheets S, Stein J, Tang D, Weiss L, Perera FP.( Exit NIEHS Website 2008. Modeling exposure to air pollution from the WTC disaster based on reports of perceived air pollution. Risk Anal 28(2):287-301.

(Jerry Phelps is a program analyst in the Program Analysis Branch of the NIEHS Division of Extramural Research and Training. Each month, he contributes summaries of extramural papers to the Environmental Factor.)

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