title: Cystathionine β-synthase and PGRMC1 as CO sensors.
abstract: Heme oxygenase (HO) is a mono-oxygenase utilizing heme and molecular oxygen (O2) as substrates to generate biliverdin-IXα and carbon monoxide (CO). HO-1 is inducible under stress conditions, while HO-2 is constitutive. A balance between heme and CO was shown to regulate cell death and survival in many experimental models. However, direct molecular targets to which CO binds to regulate cellular functions remained to be fully examined. We have revealed novel roles of CO-responsive proteins, cystathionine β-synthase (CBS) and progesterone receptor membrane component 1 (PGRMC1), in regulating cellular functions. CBS possesses a prosthetic heme that allows CO binding to inhibit the enzyme activity and to regulate H2S generation and/or protein arginine methylation. On the other hand, in response to heme accumulation in cells, PGRMC1 forms a stable dimer through stacking interactions of two protruding heme molecules. Heme-mediated PGRMC1 dimerization is necessary to interact with EGF receptor and cytochromes P450 that determine cell proliferation and xenobiotic metabolism. Furthermore, CO interferes with PGRMC1 dimerization by dissociating the heme stacking, and thus results in modulation of cell responses. This article reviews the intriguing functions of these two proteins in response to inducible and constitutive levels of CO with their pathophysiological implications.
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 160-8582, Japan.
authors: Yasuaki
authors: Y
authors: Kabe
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Takehiro
authors: T
authors: Yamamoto
authors: Department of Biology, Keio University School of Medicine, Yokohama 223-8521, Japan.
authors: Mayumi
authors: M
authors: Kajimura
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Yuki
authors: Y
authors: Sugiura
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Ikko
authors: I
authors: Koike
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 160-8582, Japan.
authors: Mitsuyo
authors: M
authors: Ohmura
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Takashi
authors: T
authors: Nakamura
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Admission Center, Saitama Medical University, Moroyama 350-0495, Japan.
authors: Yasuhito
authors: Y
authors: Tokumoto
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo 160-8582, Japan.
authors: Hitoshi
authors: H
authors: Tsugawa
authors: Department of Nanoparticle Translational Research, Tokyo Medical University, Tokyo 160-8402, Japan.
authors: Hiroshi
authors: H
authors: Handa
authors: Department of Medical Chemistry and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Takuya
authors: T
authors: Kobayashi
authors: Department of Biochemistry, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: gasbiology@z6.keio.jp.
authors: Makoto
authors: M
authors: Suematsu
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000737:chemistry / Q000378:metabolism*; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006712:Homocystinuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; C115296:PGRMC1 protein, human; D011980:Receptors, Progesterone; D006418:Heme; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D066246:ErbB Receptors; D003541:Cystathionine beta-Synthase; D006862:Hydrogen Sulfide
keywords: CO; Cancer chemoresistance; Cystathionine β-synthase (CBS); H(2)S; Neurovascular units; Progesterone receptor membrane component 1 (PGRMC1)