Cystathionine β-synthase and PGRMC1 as CO sensors

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• 作者：Yasuaki Kabe^a ; ^b ; Takehiro Yamamoto^a ; Mayumi Kajimura^c ; Yuki Sugiura^a ; Ikko Koike^a ; Mitsuyo Ohmura^a ; ^b ; Takashi Nakamura^a ; Yasuhito Tokumoto^a ; ^d ; Hitoshi Tsugawa^a ; ^b ; Hiroshi Handa^e ; Takuya Kobayashi^f ; Makoto Suematsu^a ; ^{gasbiology@z6.keio.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CO ; Cystathionine β-synthase (CBS) ; Progesterone receptor membrane component 1 (PGRMC1) ; Neurovascular units ; H2S ; Cancer chemoresistance
• 刊名：Free Radical Biology and Medicine
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：99
• 期：Complete
• 页码：333-344
• 全文大小：3904 K

文摘

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.