学术报告

 

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

报告人：Makoto Suematsu MD, PhD

Dean, School of Medicine, Keio University，Japan

Leader, Global COE Program for Human Metabolomic Systems Biology，Japan

Professor, Department of Biochemistry, School of Medicine, Keio University，Japan

 

主持人： 韩晶岩教授、主任

主  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

 

地  点：逸夫楼111室

时  间： 2008年10月22日 15：30-16：50

 

继续教育I类1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