Dataset Information

Cyclic Changes in Active Site Polarization and Dynamics Drive the 'Ping-pong' Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations.

ABSTRACT: Quinone reductases belong to the family of flavin-dependent oxidoreductases. With the redox active cofactor, flavin adenine dinucleotide, quinone reductases are known to utilize a 'ping-pong' kinetic mechanism during catalysis in which a hydride is bounced back and forth between flavin and its two substrates. However, the continuation of this catalytic cycle requires product displacement steps, where the product of one redox half-cycle is displaced by the substrate of the next half-cycle. Using improved hybrid quantum mechanical/molecular mechanical simulations, both the catalytic hydride transfer and the product displacement reactions were studied in NRH:quinone oxidoreductase 2. Initially, the self-consistent charge-density functional tight binding theory was used to describe flavin ring and the substrate atoms, while embedded in the molecular mechanically-treated solvated active site. Then, for each step of the catalytic cycle, a further improvement of energetics was made using density functional theory-based corrections. The present study showcases an integrated interplay of solvation, protonation, and protein matrix-induced polarization as the driving force behind the thermodynamic wheel of the 'ping-pong' kinetics. Reported here is the first-principles model of the 'ping-pong' kinetics that portrays how cyclic changes in the active site polarization and dynamics govern the oscillatory hydride transfer and product displacement in this enzyme.

SUBMITTER: Reinhardt CR

PROVIDER: S-EPMC6776251 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Cyclic Changes in Active Site Polarization and Dynamics Drive the 'Ping-pong' Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations.

Reinhardt Clorice R CR Hu Quin H QH Bresnahan Caitlin G CG Hati Sanchita S Bhattacharyya Sudeep S

ACS catalysis 20181114 12

Quinone reductases belong to the family of flavin-dependent oxidoreductases. With the redox active cofactor, flavin adenine dinucleotide, quinone reductases are known to utilize a 'ping-pong' kinetic mechanism during catalysis in which a hydride is bounced back and forth between flavin and its two substrates. However, the continuation of this catalytic cycle requires product displacement steps, where the product of one redox half-cycle is displaced by the substrate of the next half-cycle. Using ...[more]

PMID: 31583178

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Project description:Metastasis is the main cause of high pancreatic cancer (PaCa) mortality and trials dampening PaCa mortality rates are not satisfying. Tumor progression is driven by the crosstalk between tumor cells, predominantly cancer-initiating cells (CIC), and surrounding cells and tissues as well as distant organs, where tumor-derived extracellular vesicles (TEX) are of major importance. A strong stroma reaction, recruitment of immunosuppressive leukocytes, perineural invasion, and early spread toward the peritoneal cavity, liver, and lung are shared with several epithelial cell-derived cancer, but are most prominent in PaCa. Here, we report on the state of knowledge on the PaCIC markers Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, which all, but at different steps, are engaged in the metastatic cascade, frequently via PaCIC-TEX. This includes the contribution of PaCIC markers to TEX biogenesis, targeting, and uptake. We then discuss PaCa-selective features, where feedback loops between stromal elements and tumor cells, including distorted transcription, signal transduction, and metabolic shifts, establish vicious circles. For the latter particularly pancreatic stellate cells (PSC) are responsible, furnishing PaCa to cope with poor angiogenesis-promoted hypoxia by metabolic shifts and direct nutrient transfer via vesicles. Furthermore, nerves including Schwann cells deliver a large range of tumor cell attracting factors and Schwann cells additionally support PaCa cell survival by signaling receptor binding. PSC, tumor-associated macrophages, and components of the dysplastic stroma contribute to perineural invasion with signaling pathway activation including the cholinergic system. Last, PaCa aggressiveness is strongly assisted by the immune system. Although rich in immune cells, only immunosuppressive cells and factors are recovered in proximity to tumor cells and hamper effector immune cells entering the tumor stroma. Besides a paucity of immunostimulatory factors and receptors, immunosuppressive cytokines, myeloid-derived suppressor cells, regulatory T-cells, and M2 macrophages as well as PSC actively inhibit effector cell activation. This accounts for NK cells of the non-adaptive and cytotoxic T-cells of the adaptive immune system. We anticipate further deciphering the molecular background of these recently unraveled intermingled phenomena may turn most lethal PaCa into a curatively treatable disease.

Dataset Information

Cyclic Changes in Active Site Polarization and Dynamics Drive the 'Ping-pong' Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations.

Publications

Cyclic Changes in Active Site Polarization and Dynamics Drive the 'Ping-pong' Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations.

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