yl9193永利» 学术信息

学术信息

Biomedical Application of Metabolome Analysis: mining gaseous signal transdu…

学术报告

 

  目:Biomedical Application of Metabolome Analysis: mining gaseous signal transducers

报告人:Makoto Suematsu MD, PhD

Dean, School of Medicine, Keio UniversityJapan

Leader, Global COE Program for Human Metabolomic Systems BiologyJapan

Professor, Department of Biochemistry, School of Medicine, Keio UniversityJapan

 

主持人: 韩晶岩教授、主任

  办:北京大学医学部

          yl9193永利中西医结合教研室

          天士力微循环研究中心

 

  点:逸夫楼111

  间: 20081022 1530-1650

 

继续教育I1学分

 

 

主要内容:

Metabolome analysis1,2,3 is a new technology to grasp alterations in small molecular compounds generated by metabolic pathways of varied biological systems as a whole. We have recently combined this technology with computer-assisted biosimulation to reveal roles of hemoglobin in triggering hypoxia-inducible activation of glycolysis in human erythrocytes, suggesting usefulness of the methodology for systems biological approaches.  On the other hand, metabolome analysis allowed us to mine a novel mechanism for signal transduction through stress-inducible CO.  Serendipitous observation in metabolome analyses using capillary electrophoresis combined with mass-spectrometry (CE-MS) in heme-overloaded livers allowed us to suggest roles of cystathionine b-synthase (CBS), a heme-containing enzyme that rate-limits transsulfuration pathway and H2S generation, for a CO-responsive receptor. Studies of recombinant CBS indicated that CO binds to the prosthetic heme and stabilized the 6-coordinated CO-Fe(II)-histidine complex to inhibit the activity, while NO could hardly inhibit the enzyme, forming 5-coordinated nitrosyl heme structure. The heme-overloaded livers exhibited CO overproduction and suppressed H2S to stimulate biliary HCO3- excretion: this event was attenuated by blocking HO or by donating H2S.  Livers of heterozygous CBS-deficient mice comparably exhibited heme-elicited CO overproduction.  However, the mutant mice were unable to downregulate H2S and lacked in the increase in biliary HCO3- excretion.  Furthermore, administration of CO or pre-induction of HO-1 attenuated estradiol-induced cholestasis.  Results collected from metabolome analyses not only shed light on significance of CBS as a novel mammalian CO receptor to regulate organ functions, but suggest regulatory roles for transsulfuration pathway mediating a metabolic link between CO and H2S4. Collectively, the CE-MS serves as a potentially useful method to mine gaseous signal transduction mechanisms.

1.       Soga T, et al. J Biol Chem 2006

2.       Kinoshita A, et al. J Biol Chem 2007

3.       Tian J, et al. PNS 2005

4.       Shintani T, et al. Hepatology 2008