个人简介

Education Nanjing University, China, Ph.D. in Bioinorganic Chemistry, 1998 Professional Experience 2012-present: Associate Professor of Medicinal Chemistry, College of Pharmacy, University of New Mexico, Albuquerque, NM 2006-2012: Assistant Professor of Medicinal Chemistry, College of Pharmacy 2003-2005: Research Scientist, Department of Chemistry, University of Arizona, Tucson, AZ 2000 – 2002: Postdoctoral Research Associate with Professor John H. Enemark, Department of Chemistry, University of Arizona, Tucson, Arizona 1998 – 2000: Postdoctoral Fellow with Professor Yuanzhi Xu, Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang, China 1998-1999: Secretary of the 2nd Asia-Paciific EPR/ESR Symposium, Zhejiang University, China Awards and Fellowships 2007: Young Investigator Award, Gordon Research Conference on Nitric Oxide 2000 – 2002: Japan Society for the Promotion of Science Postdoctoral Fellowship (declined) 1998 – 2000: China Postdoctoral Science Foundation Postdoctoral Fellowship 1999: Asia-Pacific EPR Society Distinguished Service Award

研究领域

Chemical Biology and Biochemistry

There is still much unknown about how nitric oxide (NO) production by NO synthase (NOS) is tightly regulated. This is remarkable because deviant NO production by NOS has been implicated in an increasing number of diseases that currently lack effective treatments, including stroke and cancer. Three NOS isoforms, iNOS, eNOS and nNOS (inducible, endothelial, and neuronal NOS), achieve their key biological functions by tight regulation of interdomain electron transfer (IET) process (Fig. 1) via interdomain interactions. The long-term goal of our research is to understand the molecular mechanism of NOS enzyme catalysis, including how the interdomain interactions modulate the essential IET processes and the heme active site function. Fig. 1. Electron flow in NOS (as shown in red arrows). In eNOS/nNOS, CaM-binding facilitates IET between FAD and FMN within the reductase domain, and triggers the inter-subunit FMN-heme IET (reaction 2). We focus on investigating the mechanism of electron transfer in the NOS output state by using an integrated approach of laser flash photolysis, pulsed EPR and site-directed mutagenesis. It is proposed that the calmodulin (CaM) activation of NO synthesis in endothelial and neuronal NOS (eNOS and nNOS) requires a conformational change of the flavin mononucleotide (FMN) domain from its original electron-accepting (input) state to a new electron-donating (output) state (Fig. 2). The putative output state is envisioned as a complex between the FMN binding and oxygenase domains, thus facilitating efficient IET between the FMN and the catalytic heme in the oxygenase domain. Fig. 2. Tethered shuttle model: top: input state; bottom: putative output state. During NOS catalysis, the FMN domain plays a central role by acting as both an electron acceptor (receiving electrons from FAD) and an electron donor (to the catalytic heme center), and is proposed to undergo large conformational movements and engage in two distinct interdomain interactions in the process. The output state is envisioned as an IET-competent complex between the heme and FMN-binding domains. CaM binding to eNOS/nNOS unlocks the input state, thereby enabling the FMN domain to shuttle between the FAD and heme domains. CaM is also required for proper alignment of the FMN and heme domains in iNOS. The FMN-heme IET within the NOS output state is essential for NO synthesis. However, the mechanism of the output state formation remains unclear, which thus constitutes a critical barrier for understanding the CaM controlled NOS catalytic mechanisms more completely. The focus of our study is to investigate the mechanisms of CaM-regulated output state formation at the molecular level. Our ongoing studies will significantly improve the fundamental understanding of NOS regulation, and may provide important new insight as to how NOS might be selectively modulated for therapeutic purposes. Highlights of our recent accomplishments: We developed a new laser flash photolysis approach to directly determine the kinetics of the FMN-heme IET process. The IET rate constants can be used as a direct measure of the NOS output state formation. Our low temperature MCD data provided the first direct paramagnetic spectroscopic evidence to indicate that the docked FMN domain affects the nature of interactions between the l-Arg substrate and the catalytic heme center located in an adjacent domain in iNOS. Our pulsed EPR measurements represent the first direct determination of the distance between the heme iron of one subunit and the FMN center of the other subunit in the NOS dimer.

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Astashkin, Andrei V.; Elmore, Bradley O.; Li, Chen; Fan, Weihong; Guillemette, J. Guy; Feng, Changjian. (2012) Pulsed ENDOR determination of the arginine location in the ferrous-NO form of neuronal NOS, J. Phys. Chem. A 116, 6731-6739. Li, Wenbing; Fan, Weihong; Chen, Li; Elmore, Bradley; Piazza, Mike; Guillemette, J.; Feng, Changjian. (2012) Role of an isoform-specific serine residue in FMN–heme electron transfer in inducible nitric oxide synthase, J. Bio. Inorg. Chem. 17, 675-685. Li, Wenbing; Chen, Li; Fan, Weihong; Feng, Changjian. (2012) Comparing the temperature dependence of FMN to heme electron transfer in full length and truncated inducible nitric oxide synthase proteins, FEBS Lett. 586, 159-162. Feng, Changjian. (2012) Mechanism of nitric oxide synthase regulation: Electron transfer and interdomain interactions, Coord. Chem. Rev. 256, 393-411. Feng, Changjian; Taiakina, Valentina; Ghosh, Dipak K.; Guillemette, J. Guy; Tollin, Gordon. (2011) Intraprotein electron transfer between the FMN and heme domains in endothelial nitric oxide synthase holoenzyme, Biochim. Biophys. Acta, 1814, 1997-2002. Astashkin, Andrei V.; Fan, Weihong; Elmore, Bradley O.; Guillemette, J. Guy; Feng, Changjian. (2011) Pulsed ENDOR determination of relative orientation of g-frame and molecular frame of imidazole-coordinated heme center of iNOS, J. Phys. Chem. A 115, 10345-10352. Li, Wenbing; Fan, Weihong; Elmore, Bradley O.; Feng, Changjian. (2011) Effect of solution viscosity on intraprotein electron transfer between the FMN and heme domains in inducible nitric oxide synthase, FEBS Lett., 585, 2622-2626. Sempombe, Joseph; Galinato, Mary Grace I.; Elmore, Bradley O.; Fan, Weihong; Guillemette, J. Guy; Lehnert, Nicolai; Kirk, Martin L.; Feng, Changjian. (2011) Mutation in the flavin mononucleotide domain modulates magnetic circular dichroism spectra of the iNOS ferric cyano complex in a substrate-specific manner, Inorg. Chem. 50, 6859-6861. Feng, Changjian; Fan, Weihong; Ghosh, Dipak K.; Tollin, Gordon. (2011) Role of an isoformspecific substrate access channel residue in CO ligand accessibilities of neuronal and inducible nitric oxide synthase isoforms, Biochim. Biophys. Acta 1814, 405-408 Feng, Changjian; Fan, Weihong; Dupont, Andrea; Guillemette, J. Guy.; Ghosh, Dipak K.; Tollin, Gordon. (2010) Electron transfer in a human inducible nitric oxide synthase oxygenase/FMN construct co-expressed with the N-terminal globular domain of calmodulin, FEBS Lett. 584, 4335-4338. Astashkin, Andrei V.; Elmore, Bradley O.; Fan, Weihong; Guillemette, J. Guy.; Feng, Changjian. (2010) Pulsed EPR determination of the distance between heme iron and FMN centers in a human inducible nitric oxide synthase, J. Am. Chem. Soc. 132, 12059-12067. Feng, Changjian; Tollin, Gordon. (2009) Regulation of interdomain electron transfer in the NOS output state for NO production, Dalton Trans., 6692-6700. Invited Review. Sempombe, Joseph; Elmore, Bradley; Sun, Xi; Dupont, Andrea; Ghosh, Dipak; Guillemette, Joseph; Kirk, Martin; Feng, Changjian. (2009) Mutations in the FMN domain modulate MCD spectra of the heme site in the oxygenase domain of inducible nitric oxide synthase, J. Am. Chem. Soc. 131, 6940-6941. Sun, Xi; Pi, Jingbo; Liu, Wenlan; Hudson, Laurie; Liu, Ke Jian; Feng, Changjian. (2009) Induction of heme oxygenase 1 by arsenite inhibits cytokine-induced monocyte adhesion to human endothelial cells, Toxicol. Appl. Pharmacol. 236, 202-209. Feng, Changjian; Dupont, Andrea L.; Nahm, Nickolas J.; Spratt, Donald E.; Hazzard, James T.; Weinberg, J. Brice; Guillemette, J. Guy; Tollin, Gordon; Ghosh, Dipak K. (2009) Intraprotein electron transfer in inducible nitric oxide synthase holoenzyme, J. Biol. Inorg. Chem. 14, 133-142 Hu, Xiaohui; Feng, Changjian; Hazzard, James T.; Tollin, Gordon; Montfort, William R. (2008) Binding of YC-1 or BAY 41-2272 to soluble guanylyl cyclase induces a geminate phase in CO photolysis, J. Am. Chem. Soc. 130, 15748-15749. Feng, Changjian; Roman, Linda J.; Hazzard, James T.; Ghosh, Dipak K.; Tollin, Gordon; Masters, Bettie Sue S. (2008) Deletion of the autoregulatory insert modulates intraprotein electron transfer in rat neuronal nitric oxide synthase, FEBS Lett. 582, 2768-2772. Astashkin, Andrei V.; Johnson-Winters, Kayunta; Klein, Eric L.; Feng, Changjian; Wilson, Heather L.; Rajagopalan, K. V.; Raitsimring, Arnold M.; Enemark, John H. (2008) Structural studies of the molybdenum center of the pathogenic R160Q mutant of human sulfite oxidase by pulsed EPR spectroscopy and 17O and 33S labeling, J. Am. Chem. Soc. 130, 8471-8480. Ding, Wei; Hudson, Laurie J.; Sun, Xi; Feng, Changjian; Liu Ke Jian. (2008) As(III) inhibits ultraviolet radiation-induced cyclobutane pyrimidine dimers repair via generation of nitric oxide in human keratinocytes, Free Radic. Biol. Med. 45, 1065-1072 Feng, Changjian; Tollin, Gordon; Enemark, John H. (2007) Sulfite oxidizing enzymes, Biochim. Biophys. Acta, 1774, 527-539. Invited Review