Research Director: Makoto SUEMATSU
(Professor, School of Medicine, Keio University)
Research Term: 2009-2014

Research Director: Gregg L. Semenza
(Johns Hopkins University,Institute for Cell Engineering)

While attracting great interests of researchers, researches of gas molecules in biological systems requiground-breaking breakthrough to overcome technical difficulties to mine up unidentified receptors that determine their biological actions and pathophysiology. Carbon monoxide (CO) is such a gaseous mediator generated by heme oxygenase (HO); many biological phenomena have been revealed but without identification of mechanisms for direct reception of the gas. CO generated from inducible HO-1 or from constitutive HO-2 modulates function of different heme proteins or enzymes through binding to their prosthetic ferrous heme to alter their structures, regulating biological function of cells and organs. JST ERATO Suematsu Gas Biology Project provided two distinct methodologies to overcome difficulties; advanced metabolomics and high-performance affinity nanobeads. The former technology allowed us to reveal roles of cystathionine beta-synthase (CBS). In brain, CO accounts for vasoconstrictor that inhibits H2S generated by CO-sensitive CBS in astrocytes. Since molecular oxygen (O2) is a substrate for HO, the latter mechanism contributes to hypoxic vasodilation in neurovascular units. We have recently uncovered that stress-inducible CO in and around cancer cells suppresses CBS to result in decreased methylation of PFKFB3, the enzyme regulating PFK-1, leading to a shift of glucose biotransformation from glycolysis towards pentose phosphate pathway. On the other hand, the latter technology revealed that PGRMC1/Sigma-2 receptor expressed on membrane in many cancers exerts its function through unique heme-stacking dimerization to accelerate cancer growth through the dimer interaction with EGF receptor. The project as a whole open a venue to explore receptors of the smallest class of bio-molecules and to shed light on a new horizon of GAS BIOLOGY.