Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Abstract

Soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand nitric oxide (NO); sGC thereby acts as an amplifier in NO-driven biological signaling cascades. Because sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production, boosting sGC activity and preventing or reversing sGC inactivation are important therapeutic and pharmacologic goals. Work over the last two decades is uncovering the processes by which sGC matures to become functional, how sGC is inactivated, and how sGC is rescued from damage. A diverse group of small molecules and proteins have been implicated in these processes, including NO itself, reactive oxygen species, cellular heme, cell chaperone Hsp90, and various redox enzymes as well as pharmacologic sGC agonists. This review highlights their participation and provides an update on the processes that enable sGC maturation, drive its inactivation, or assist in its recovery in various settings within the cell, in hopes of reaching a better understanding of how sGC function is regulated in health and disease.

GAPDH is involved in the heme‐maturation of myoglobin and hemoglobin

“…GAPDH can bind heme from intracellular sources (acquired heme) 31 or bind the heme synthesized in the mitochondria. Heme bound to GAPDH constitutes the labile heme pool, 50,51 and this can be used to deliver heme to downstream target proteins to enable their heme‐maturations 35,52 . The Mb and Hb heme‐maturation processes also require an active sGCα1β1 heterodimer making cGMP and this induction maybe translational or transcriptional 27,37,40 .…”

“…Heme bound to GAPDH constitutes the labile heme pool, 50,51 and this can be used to deliver heme to downstream target proteins to enable their heme-maturations. 35,52 The Mb and Hb heme-maturation processes also require an active sGCα1β1 heterodimer making cGMP and this induction maybe translational or transcriptional. 27,37,40 GAPDH itself can deliver heme to sGCβ1 32 and thus can regulate these processes.…”

“…sGC activated by nitric oxide (NO) generated from NOS enzymes makes cGMP thereby constituting the NO-sGC-cGMP signal axis. 52 The generated cGMP acts as a second messenger to initiate a cascade of downstream events to cause vasodilation in the vasculature 52,64,65 or bronchodilation in the lungs. 66,67 Our current study has important biomedical relevance as it is focused on globin maturation.…”

NO rapidly mobilizes cellular heme to trigger assembly of its own receptor

“…This causes protein structural changes that activate cGMP production ( 13 – 16 ). The essential role that heme plays in sensing NO underscores the importance of the heme delivery and insertion steps that enable sGC to mature in cells ( 17 ). Our recent studies have illuminated parts of the sGC maturation process: After translation, the immature sGCβ subunit is heme-free and accumulates in cells in the form of a complex with the cell chaperone hsp90 ( 18 , 19 ).…”

Replacement of heme by soluble guanylate cyclase (sGC) activators abolishes heme-nitric oxide/oxygen (H-NOX) domain structural plasticity

“…The current work reveals that the association of an activator compound (heme- and NO-independent) with the sGC enzyme can be modulated reversibly by heme's redox status. In recent years, it has been shown that the sGC dimer enzyme does not exist in cells and tissues all in a heme-associated or a heme-devoid form, but these two functionally distinct forms coexist and their presence constantly reflects the cellular environment ( Stasch et al., 2006 , Stuehr et al., 2021 ; Sandner et al., 2021 , Ghosh & Stuehr, 2017 ).…”