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Extramural Papers of the Month

By Jerry Phelps
August 2008

Discovery of a Shape-Shifting Protein Could Lead to Anti-Bacterial Agent

A small molecule that locks the shape of the enzyme porpholbilinogen synthase (PBGS) into an inactive form could one day form the basis of a new species-specific antibiotic, according to NIEHS-supported researchers. Their work may offer insight into ways of combating multidrug resistance.

PBGS is crucial for energy metabolism in nearly all organisms. To be activated, it must have two subunits added to the six-subunit molecule, or hexamer configuration, which makes up its basic form. The research team discovered a small molecule, Morphlock-1, which binds to the inactive form of the enzyme and locks the enzyme in a hexamer shape, thus preventing the rearrangement of the molecule and the addition of the two additional subunits required for activation.

While this study utilized a form of the enzyme found in peas, the researchers believe that this principle could apply to bacterial versions of the enzyme as well. Current research is aimed at fine tuning the structure of Morphlock-1 so that it blocks only the bacterial version of the enzyme and not other cells.

The researchers said they hope to develop a suite of drugs that will stabilize the PBGS hexamer in order to prevent bacteria from developing complete resistance to a cocktail of such compounds.

Citation: Lawrence SH, Ramirez UD, Tang L, Fazliyez F, Kundrat L, Markham GD, Jaffe EK Exit NIEHS Website. 2008. Shape shifting leads to small-molecule allosteric drug discovery. Chem Biol 15(6):586-596.

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Maternal Smoking and Receptor Gene Variant Combine to Increase Risk for Childhood Asthma

Exposure to in utero maternal smoking and childhood second-hand smoke are associated with wheezing, a common symptom of asthma, according to a new study from NIEHS-funded investigators at the University of Southern California. However, children who were homozygous for a single nucleotide polymorphism in the beta2-adrenergic receptor and who were exposed to maternal smoking in utero were three times more likely to develop asthma symptoms compared to unexposed children without the altered gene. Similar effects were evident for exposure to second-hand smoke during childhood.

Additionally, as the number of smokers increased in the home, the risk for symptoms increased for children with the gene polymorphism. The researchers examined two cohorts of children recruited in 1993 and 1996 and found similar results. The 3,128 non-Hispanic and Hispanic white children were participants in the Children's Health Study.

These results suggest that because of the high prevalence of asthma in children, intervention strategies are critically needed to reduce smoke exposures to children in general and especially those who are genetically susceptible to the adverse effects of exposure to second-hand smoke.

Citation: Wang C, Salam MT, Islam T, Wenten M, Gauderman WJ, Gilliland FD Exit NIEHS Website. 2008. Effects of in utero and childhood tobacco smoke exposure and beta2-adrenergic receptor genotype on childhood asthma and wheezing. Pediatrics 122(1):e107-114.

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Single Nucleotide Polymorphism is Associated with Neuroblastoma

Using a genome-wide association study, NIEHS-funded researchers identified an association between neuroblastoma and three common single-nucleotide polymorphisms. Homozygosity for the most significantly associated polymorphism increased the risk of neuroblastoma two-fold.

Neuroblastoma is the most common cancer in infancy, with about half of neuroblastoma cases occurring in children younger than two years old. It is a neuroendocrine cancer arising from any neural crest element of the sympathetic nervous system. Solid tumors, which take the form of a lump or mass, commonly begin in one of the adrenal glands, though they can also develop in nerve tissues in the neck, chest, abdomen or pelvis.

A genome-wide association study is an examination of genetic variation across the human genome, designed to identify genetic associations with observable traits, such as blood pressure or weight, or why some people get a disease or condition.

Additional results from the study show that children who were homozygous for the three identified polymorphisms were more likely to have metastatic disease and disease relapse. The polymorphisms could be used to identify children at risk for neuroblastoma or those who are likely to have a poor prognosis and therefore may need more aggressive treatment.

Citation: Maris JM, Mosse YP, Bradfield JP, Hou C, Monni S, Scott RH, Asgharzadeh S,Attiyeh EF, Diskin SJ, Laudenslager M, Winter C, Cole KA, Glessner JT, Kim C, Frackelton EC, Casalunovo T, Eckert AW, Capasso M, Rappaport EF, McConville C, London WB, Seeger RC, Rahman N, Devoto M, Grant SF, Li H, Hakonarson H Exit NIEHS Website. 2008. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med 358(24):2585-2593.

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Epigenetic Markers Change Over a Lifetime

New findings about the epigenetic markers on an individual's DNA may explain why some people become more susceptible to disease as they age and why individual disease risk is similar within families. NIEHS-funded researchers found that certain DNA methylation patterns or epigenetic markers change during a person's lifetime and the amount of change is similar among related people.

The research team analyzed DNA methylation in more than 200 individuals from two cohorts of subjects. Samples of DNA, taken 11 years apart, were analyzed from an Icelandic population. One third of them had significant changes in their DNA methylation; some higher, some lower. This change over time represents a proof-of-principle than an individual's epigenetics does change with age. A Salt Lake City cohort was made up of two and three generation families whose DNA was sampled 16 years apart. The results showed that DNA methylation changes tended to be similar among family members.

The authors concluded that "the implications of these results are potentially profound for population-based studies of human disease." The epigenetic changes seen over time might directly influence the onset or progression of disease and might also reflect age-related or environmental exposures.

Citation: Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP Exit NIEHS Website. 2008. Intra-individual change over time in DNA methylation with familial clustering. JAMA 299(24):2877-2883.

(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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