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Extramural Papers of the Month

By Jerry Phelps
February 2010

Secrets of Drought Resistance Revealed

A team of NIEHS-funded scientists has discovered the three-dimensional structure of abscisic acid, a plant hormone critical for drought survival, which helps to explain the mechanism behind drought tolerance in plants.

Drought resistant plants synthesize abscisic acid when they detect dry conditions, causing changes in all parts of the plants. Seeds lie dormant in the soil, leaf pores are closed to conserve water, and growth is slowed. Plants reprogram themselves for the sole purpose of surviving.

The research team made crystals of abscisic acid bound to its protein receptor called PYR1. Using x-ray crystallography, they determined the three-dimensional structure of the complex and found that PYR1 has an open space, akin to the inside of a tin can, where abscisic acid binds. As the binding occurs, a part of the protein called "the lid" is induced to close. Structural changes to other parts of PYR1 initiate binding with other proteins, triggering processes for drought resistance.

The authors suggest that chemicals mimicking the action of abscisic acid could be developed and sprayed on crops to protect them from droughts. It may also be possible to alter crops through selective breeding or genetic manipulation to produce more abscisic acid. According to government estimates, major droughts in the U.S. in the last three years alone have caused more than $10 billion in crop losses.

Citation: Nishimura N, Hitomi K, Arvai AS, Rambo RP, Hitomi C, Cutler SR, et al( Exit NIEHS. 2009. Structural mechanism of abscisic acid binding and signaling by dimeric PYR1. Science 326(5958):1373-1379.

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Crystal Structure of Variant P450 Determined

An NIEHS grantee at the University of California, San Diego has determined the crystal structure of a genetic variant of cytochrome P450 2B6 in complex with its inhibitor. Structural insights such as this one are critical to understanding how enzymes bind to substrates and metabolize compounds, and how different genetic variations affect the enzyme's ability to initiate metabolism.

P450s are heme-containing monoxygenase enzymes. The multiple forms of cytochrome P450 metabolize a wide variety of endogenous and exogenous chemicals, including prostaglandins, steroids, drugs, and environmental chemicals. P450s interact with a variety of substrates, inhibitors, membrane lipids, and proteins that modulate their activity.

Genetic differences in the expression levels or activities of P450s are major determinants of individual responses to medications and environmental toxicants. This finding provides the first view of an important human enzyme that has been gaining in significance, as the list of compounds it interacts with has grown.

Citation: Gay SC, Shah MB, Talakad JC, Maekawa K, Roberts AG, Wilderman PR, et al( Exit NIEHS. 2010. Crystal Structure of a Cytochrome P450 2B6 Genetic Variant in Complex with the Inhibitor 4-(4-Chlorophenyl)imidazole at 2.0 A Resolution. Mol Pharmacol doi 10:1124/mol.109.062570. [Epub ahead of print]

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Lead Exposure Linked to Depression and Panic Disorders

Young adults with elevated blood lead levels are more likely to have major depression and panic disorders, according to research supported by the NIEHS.

Lead is a well-known neurotoxicant causing behavioral and learning problems in children and young adults. It has also been associated with cognitive difficulties in older adults. It is ubiquitous and is found in air, soil, dust, and water. The elimination of lead from gasoline in the late 1970s has produced dramatic decreases in the average blood lead levels of children in the U.S.

Data were analyzed from 2000 participants of the National Health and Nutrition Examination Survey (NHANES) aged 20-29. The one-fifth of the participants with the highest blood lead levels (2.11 micrograms per deciliter) were 2.3 times more likely to have major depressive disorder and nearly five times more likely to have panic disorder than the one-fifth with the lowest blood lead levels (< 0.7 micrograms per deciliter) - levels considerably lower than the national average in the 1960s-1970s.

The authors point out that low-level lead exposure disrupts brain processes involving the neurotransmitters catecholamine and serotonin. Disruptions of these processes are known to be involved in depression and panic disorders, suggesting that exposure to lead in individuals predisposed to these conditions could trigger or worsen the severity of these disorders.

Citation: Bouchard MF, Bellinger DC, Weuve J, Matthews-Bellinger J, Gilman SE, Wright RO, et al( Exit NIEHS. 2009. Blood lead levels and major depressive disorder, panic disorder, and generalized anxiety disorder in US young adults. Arch Gen Psychiatry 66(12):1313-1319.

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Genetic Risk Score for Multiple Sclerosis Developed

A large, multinational team of epidemiologists has developed a promising mathematical algorithm for predicting the likelihood of developing multiple sclerosis (MS). With additional refinement, it could become a useful tool in identifying people for early intervention or prevention efforts.

MS is a complex neurological disease, with an unknown origin, characterized by demyelination of the central nervous system,  - affecting between 2 and 150 per 100,000 people. Recent genome-wide association studies have identified a number of genetic loci involved in MS, but there is still no clear understanding of the genetic contribution to disease susceptibility. Environmental factors with convincing evidence of involvement with MS include sunshine, vitamin D, Epstein-Barr viral exposure, and smoking.

The current study employed a factor called the C statistic, which defines how well a model can differentiate between patients and controls. For clinical prediction, a C statistic of 0.8 or higher is considered useful.

In the current study involving 16 genetic loci associated with MS, the researchers used three different cohorts. The C statistics obtained ranged from 0.64 to 0.72, depending on whether gender, smoking history, and Epstein-Barr virus titers were incorporated. Although below the standard of 0.8, by incorporating other data and environmental factors, this study could lead to the development of a model that could identify individuals for early intervention efforts.

Citation: De Jager PL, Chibnik LB, Cui J, Reischl J, Lehr S, Simon KC, et al( Exit NIEHS. 2009. Integration of genetic risk factors into a clinical algorithm for multiple sclerosis susceptibility: a weighted genetic risk score. Lancet Neurol 8(12):1111-1119.

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

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