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Environmental Factor

Environmental Factor

Your Online Source for NIEHS News

April 2017

Papers of the Month

Computer models predict physicochemical properties

Scientists from the National Toxicology Program and the U.S. Environmental Protection Agency, along with their collaborators, have built new computer models that use molecular structures to estimate the physicochemical features of a wide range of chemicals. The models may provide useful tools for researchers to rapidly assess toxicity of these chemicals to humans.

The movement of substances in the body, such as pesticides, food additives, and fragrances, is determined by their physicochemical properties. Because measuring the movement of these substances in living systems is time-consuming and costly, the researchers in this study developed quantitative structure-property relationship models.

The scientists collected and curated data sets from an open source to train and validate models that predicted six key properties: solubility, melting point, boiling point, vapor pressure, octanol-water partition coefficient, and bioconcentration factor. Different modeling methods, from linear regression to machine learning, were used and their predictions compared. The new models performed better than the existing platform, and the estimated values were well matched to the experimental data, according to the authors. (QX)

CitationZang Q, Mansouri K, Williams AJ, Judson RS, Allen DG, Casey WM, Kleinstreuer NC. 2017. In silico prediction of physicochemical properties of environmental chemicals using molecular fingerprints and machine learning. J Chem Inf Model 57(1):36–49.

A third magnesium ion involved in DNA Pol Beta catalysis

A newly discovered divalent metal ion site in the DNA polymerase beta (Pol Beta) nucleotidyl transferase reaction does not promote the forward reaction, but may play a role in blocking the reverse reaction, NIEHS scientists reported.

Researchers knew that Pol Beta nucleotidyl transferase reactions used two magnesium ions, but recent work from the group found that it also boasts a third, product-associated metal in the active site. The observation sparked interest in whether this metal ion contributes to the previously defined reaction trajectory or plays a more tangential role.

The collaborative research team performed quantum mechanical-molecular mechanical calculations of the Pol Beta reaction profile to determine whether the third metal ion altered the reaction's activation barrier. An activation barrier is an energy minimum that must be achieved for a reaction to occur. Substances called catalysts lower activation barriers. The team established that the third magnesium ion did not facilitate the forward reaction by altering the activation barrier and was not required for the reaction to occur. These findings lend support to a previously published consideration that the third metal ion in question serves to inhibit the backward reaction. (AD)

CitationPerera L, Freudenthal BD, Beard WA, Pedersen LG, Wilson SH. 2017. Revealing the role of the product metal in DNA polymerase beta catalysis. Nucleic Acids Res 45(5):2736–2745.

Pol Beta uses lyase domain to search for DNA damage

DNA polymerase beta (Pol Beta) uses its lyase domain and a processive hopping mechanism to search for DNA damage, according to researchers at NIEHS. The work provides information about how Pol Beta is able to efficiently locate DNA damage hidden among the 6 billion base pairs of the human genome.

The base excision repair pathway is the body’s main defense against DNA base damage, and Pol Beta fills in the gapped DNA intermediate generated in this pathway. The researchers focused on understanding how Pol Beta locates damaged DNA. They found that it scans DNA in search of damage, and that a specific region of Pol Beta called the lyase domain is required for this searching technique. The lyase domain is positively charged and contains several lysine residues that allow Pol Beta to hop along DNA until it encounters damage. The researchers also showed that Pol Beta does not search for DNA damage in regions of DNA wrapped around histones, or nucleosomes, suggesting that the repair footprint of Pol Beta is confined to accessible and open regions of the genome. (SH)

CitationHoward MJ, Rodriguez Y, Wilson SH. 2017. DNA polymerase beta uses its lyase domain in a processive search for DNA damage. Nucleic Acids Res; doi:10.1093/nar/gkx047 [Online 23 January 2017].

Dual role of PPIP5K in sensing cellular phosphate levels

NIEHS scientists have discovered a new, dual-function role for the enzyme pentakisphosphate kinase (PPIP5K) in sensing extracellular levels of inorganic phosphate (Pi). The authors showed that PPIP5K is a rare example of a bifunctional enzyme, with separate kinase and phosphatase domains. Together, these domains regulate intracellular levels of an inositol pyrophosphate known as IP8, which is a cell signal that phosphorylates proteins and regulates their functions. PPIP5K kinase activity synthesizes IP8, and phosphatase activity degrades IP8. Using recombinant PPIP5K, the authors demonstrated that Pi inhibits phosphatase activity and stimulates kinase activity.

Using a human intestinal epithelial cell line, the authors found that intracellular IP8 levels increased in reaction to elevated levels of extracellular Pi. These findings reveal a new and important link between a signaling cascade and nutrient availability. The authors proposed that dysregulation of IP8 signaling may contribute to the mechanisms of toxicity from exposures to substances that unbalance Pi homeostasis. (MK)

CitationGu C, Nguyen HN, Hofer A, Jessen HJ, Dai X, Wang H, Shears SB. 2017. The significance of the bifunctional kinase/phosphatase activities of diphosphoinositol pentakisphosphate kinases (PPIP5Ks) for coupling inositol pyrophosphate cell-signaling to cellular phosphate homeostasis. J Biol Chem 292(11):4544–4555

Varying SIRT1 levels regulate tumor formation

SIRT1 haploinsufficiency, or low levels of protein as a result of having only one functional SIRT1 gene, can have the opposite effect of complete SIRT1 protein loss, according to NIEHS researchers and their collaborators. The scientists demonstrated that this process is dependent on the metabolism of glutamine, the most abundant amino acid in the body. The study adds to the growing body of knowledge on the origins of cancer, or oncogenesis.

SIRT1 has the capacity to both promote and suppress tumor growth. Using in vivo studies in mice and humans, as well as cell cultures, the team found that the effects are dependent on the amount of SIRT1. Haploinsufficient expression of SIRT1, which reduces SIRT1 levels, is oncogenic through enhancement of glutamine metabolism. By contrast, a complete knockout of SIRT1 is protective against cancer.

A similar dose-dependent effect can be found in overexpression models, with mild overexpression of SIRT1 protein being protective against cancer, whereas massive overexpression promotes cancer. This research has profound implications, because it highlights the importance of correctly monitoring SIRT1 levels in individuals with cancer. The overall rethinking of research that uses complete loss of protein experiments is also noteworthy. Researchers should consider including low expression models as well. (SO)

CitationRen NS, Ji M, Tokar EJ, Busch EL, Xu X, Lewis D, Li X, Jin A, Zhang Y, Wu WK, Huang W, Li L, Fargo DC, Keku TO, Sandler RS, Li X. 2017. Haploinsufficiency of SIRT1 enhances glutamine metabolism and promotes cancer development. Curr Biol 27(4):483–494.

(Anika Dzierlenga, Ph.D., is an Intramural Research Training Award [IRTA] fellow in the NIEHS Developmental and Reproductive Toxicology Group. Samantha Hall is a postbaccalaureate Cancer Research Training Award fellow in the National Cancer Institute Center for Cancer Research Laboratory of Toxicology and Toxicokinetics, housed at NIEHS. Mahita Kadmiel, Ph.D., is an IRTA fellow in the NIEHS Molecular Endocrinology Group. Simone Otto, Ph.D., is an IRTA fellow in the NIEHS Ion Channel Physiology Group. Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)

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