New pathways for the biological activity of two little-understood enzymes emerge from a theoretical investigation
The enzymes, indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO), known as dioxygenases, are responsible for the cleavage of the essential amino acid, L-tryptophan. Both enzymes contain heme—a metal-containing organic ring structure—to which molecular oxygen is bound before being transferred to L-tryptophan. This important oxidation reaction releases energy into the body in all cells in mammals, but its mechanism is little understood.
Now, Hiroshi Sugimoto and colleagues at the RIKEN SPring-8 Center, Harima, in collaboration with Keiji Morokuma, Lung Wa Chung and colleagues at Kyoto University, have studied the structures of these enzymes and modeled some potential reaction pathways to better understand how they work1.
Recently, crystal structures of IDO (Fig. 1) 2 and TDO with tryptophan or similar compounds were obtained. Surprisingly, these structures showed different active sites for these enzymes compared to other heme systems. Consequently, the researchers concluded that different mechanistic pathways must also be operating for the dioxygenase reaction.
The researchers used a detailed modeling method, called Density Functional Theory, to calculate and evaluate the energy of the starting compounds, products, possible reaction intermediates and transition states. They then used comparisons to provide insight into which reaction pathways are the most energetically favorable and, therefore, which mechanism is most likely to take place in the body.
They found that one proposed mechanism involved a highly distorted transition state, which would lead to a very high energy barrier, making this route doubtful. Instead, they suggest that a new and energetically favorable mechanistic pathway explains the unusual dioxygen activation and oxidation reactions for the enzymes. This proposed mechanism is sharply distinct from other mechanisms for heme-containing oxygenases.
The enzyme-bound oxygen was found to react directly with the electron-rich indole carbon on the tryptophan via either a 2-electron (electrophilic) or 1-electron (radical) transfer pathway. Either of these reactions would lead to the formation of a low-energy intermediate making it a much more realistic possibility. Sugimoto and colleagues are now investigating exactly how oxygen binds to the heme and evaluating the contribution of the enzyme to the mechanism.
“[The research] might also be informative for rational drug design because IDO is emerging as an important new therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression,” says Sugimoto.
1. Chung, L.W., Li, X., Sugimoto, H., Shiro, Y. & Morokuma, K. Density Functional Theory Study on a Missing Piece in Understanding of Heme Chemistry: The Reaction Mechanism for Indoleamine 2,3-Dioxygenase and Tryptophan. Journal of the American Chemical Society 130, 12299–12309 (2008).
2. Sugimoto, H., Oda, S., Otsuki, T., Hino, T., Yoshida, T. & Shiro, Y. Crystal structure of human indoleamine 2,3-dioxygenase: catalytic mechanism of O2 incorporation by a heme-containing dioxygenase. Proceedings of the National Academy of Sciences USA 103, 2611–2616 (2006).
The corresponding author for this highlight is based at the RIKEN Biometal Science Laboratory
Saeko Okada | ResearchSEA
Warming ponds could accelerate climate change
21.02.2017 | University of Exeter
An alternative to opioids? Compound from marine snail is potent pain reliever
21.02.2017 | University of Utah
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
21.02.2017 | Earth Sciences
21.02.2017 | Medical Engineering
21.02.2017 | Trade Fair News