Faculty Homepages
Changjian "Jim" Feng, PhD
Assistant Professor of Medicinal Chemistry and Toxicology
Department of Pharmaceutical
Sciences
Office: Multidisciplinary Research Building, second floor
mailing addres: UNM College of Pharmacy, MSC09 5360, 1 UNM, Albuquerque NM
87131-0001
Phone: 505.925.4326 | Fax: 505.925.4549
Links
Education
Nanjing University, China, Ph.D. in Bioinorganic Chemistry, 1998
Professional Experience
2006-present: Assistant Professor of Medicinal Chemistry, College of Pharmacy, University of New Mexico, Albuquerque, NM
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
Research Interests
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.
Selected Publications (Over 60 papers published in international peer-reviewed journals)
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
Feng, Changjian; Tollin, Gordon; Hazzard, James T.; Nahm, Nickolas J.; Guillemette J. Guy; Salerno, John C.; Ghosh, Dipak K. (2007) Direct measurement by laser flash photolysis of intraprotein electron transfer in a rat neuronal nitric oxide synthase, J. Am. Chem. Soc., 129, 5621-5629.
Feng, Changjian; Tollin, Gordon; Holliday, Michael A.; Thomas, Clayton; Salerno, John C.; Enemark, John H.; Ghosh, Dipak K. (2006) Intraprotein electron transfer in a two-domain construct of neuronal nitric oxide synthase: The output state in nitric oxide formation, Biochemistry 45, 6354-6362.
Feng, Changjian; Thomas, Clayton; Holliday, Michael A.; Tollin, Gordon; Salerno, John C.; Ghosh, Dipak K.; Enemark, John. H. (2006) Direct Measurement by Laser Flash Photolysis of Intramolecular Electron Transfer in a Two-Domain Construct of Murine Inducible Nitric Oxide Synthase. J. Am. Chem. Soc. 128, 3808-3811.
Feng, Changjian; Wilson, Heather L.; Tollin, Gordon; Astashkin, Andrei A; Hazzard, James T.; Rajagopalan, K. V.; Enemark, John H. (2005) The pathogenic human sulfite oxidase mutants G473D and A208D are defective in intramolecular electron transfer. Biochemistry 44, 13734 - 13743.
Astashkin, Andrei, V., Feng, Changjian, Raitsimring, Arnold, M., Enemark, John, H. (2005) "17O ESEEM evidence for exchange of the axial oxo ligand in the molybdenum center of the high pH form of sulfite oxidase." J. Am. Chem. Soc. 127, 502 - 503.
Raitsimring, Arnold M.; Kappler, Ulrike; Feng, Changjian; Astashkin, Andrei V.; Enemark, John H. (2005) Pulsed EPR studies of a bacterial sulfite-oxidizing enzyme with pH-invariant hyperfine interactions from exchangeable protons. Inorg. Chem. 44, 7283-7285.
Astashkin, Andrei V.; Hood, Brian L.; Feng, Changjian; Hille, Russ; Mendel, Ralf R.; Raitsimring, Arnold M.; Enemark, John H. (2005) Structures of the Mo(V) forms of sulfite oxidase from Arabidopsis thaliana by pulsed EPR spectroscopy. Biochemistry 44, 13274-13281.
Feng, Changjian; Kappler, Ulrike; Tollin, Gordon; Enemark, John H. (2003) Intramolecular electron transfer in a bacterial sulfite dehydrogenase. J. Am. Chem. Soc. 125, 14696 -14697.
Feng, Changjian; Wilson, Heather L.; Hurley, John K.; Hazzard, James, T.; Tollin, Gordon; Rajagopalan, K. V.; Enemark, John H. (2003) Essential role of conserved arginine 160 in intramolecular electron transfer in human sulfite oxidase. Biochemistry 42, 12235-12242.
Feng, Changjian; Wilson, Heather L.; Hurley, John K.; Hazzard, James, T.; Tollin, Gordon; Rajagopalan, K. V.; Enemark, John H. (2003) Role of conserved tyrosine 343 in intramolecular electron transfer in human sulfite oxidase. J. Biol. Chem. 278, 2913-2920.
Raitsimring, Arnold M.; Astashkin, Andrei V.; Feng, Changjian; Enemark, John. H.; Nelson, Kimberly Johnson; Rajagopalan, K. V. (2003) Pulsed EPR studies of the exchangeable proton at the molybdenum center of dimethyl sulfoxide reductase. J. Biol. Inorg. Chem. 8, 95-104.
Feng, Changjian; Kedia, Rohit V.; Hazzard, James T.; Hurley, John K.; Tollin, Gordon; Enemark, John H. (2002) Effect of solution viscosity on intramolecular electron transfer in sulfite oxidase. Biochemistry 41, 5816-5821.
Elliott, Sean J.; McElhaney, Anne E.; Feng, Changjian; Enemark, John H.; Armstrong, Fraser A. (2002) A voltammetric study of interdomain electron transfer within sulfite oxidase. J. Am. Chem. Soc. 124, 11612 -11613.
Astashkin, Andrei V.; Raitsimring, Arnold M.; Feng,
Changjian; Johnson, Jean L.; Rajagopalan, K. V.; Enemark, John H. (2002)
Pulsed EPR studies of nonexchangeable protons near the Mo (V) center of
sulfite oxidase: Direct detection of the ?-proton of the coordinated
cysteinyl residue and structural implications for the active site. J. Am.
Chem. Soc. 124, 6109-6118.
The
University of New Mexico’s Doctor of Pharmacy program is
accredited by the Accreditation Council for Pharmacy Education,
135 LaSalle Street, Suite 4100, Chicago, IL 60603-4810, TEL
(312) 664-3575 , FAX (312) 664-4652,
URL
http://www.acpe-accredit.org/
08/25/2011 09:55:57 AM -0600.