Cystathionine β-synthase and PGRMC1 as CO sensors

Heme oxygenase (HO) is a mono-oxygenase utilizing heme and molecular oxygen (O-2) as substrates to generate biliverdin-IX alpha 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 beta-synthase (CBS) and progesterone receptor membrane component 1 (PGRMCI), 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, PGRMCI forms a stable dimer through stacking interactions of two protruding heme molecules. Heme-mediated PGRMCI dimerization is necessary to interact with EGF receptor and cytochromes P450 that determine cell proliferation and xenobiotic metabolism. Furthermore, CO interferes with PGRMCI 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. (C) 2016 Elsevier Inc. All rights reserved.