Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation

Collman, James P.; Ghosh, Santanu; Dey, Abhishek; Decréau, Richard A.

doi:10.1073/pnas.0904082106

Cited by 146 publications

(149 citation statements)

References 39 publications

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“…This notion is consistent with previous studies indicating that pharmacologic inhibition of HO increases basal O 2 consumption in the liver (52) and that an increase in endogenous CO, by enzyme induction inhibits cellular respiration through its inhibitory effect on cytochrome c oxidase (53). H 2 S also might modulate mitochondrial respiration through reversible inhibition of cytochrome c oxidase (54); however, at least in the present study, basal H 2 S levels in the brain are unchanged in HO-2-null mice compared with WT mice (Fig. 3E), possibly due to compensatory changes in endogenous H 2 S production from other enzymes in the transsulfuration pathway (27).…”

Section: Discussionsupporting

confidence: 81%

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Morikawa

Kajimura

Nakamura

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

235

230

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Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H 2 S formed by cystathionine β-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H 2 S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2-null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.gas biology | neurovascular unit | energy metabolism | gasotransmitter T he cerebral circulation is maintained by autoregulation, which prevents marked alterations in response to changes in blood pressure, whereas functional hyperemia links blood flow to neural activity (1). Blood flow regulation in the brain is modulated by O 2 (2), with increased cerebral blood flow in response to hypoxia critical for protecting the brain against diverse insults. Such regulation also participates in functional hyperemia, as demonstrated by functional MRI investigations indicating a transient decrease in O 2 levels preceding activation of blood flow in response to neuronal firing (3).Alterations in cerebral blood flow in response to hypoxia and neural activity are mediated via several neurotransmitter systems, with prominent involvement of the gaseous mediator nitric oxide (NO) (1, 2). In response to glutamate acting on NMDA receptors, neuronal NO synthase (nNOS) is activated by increases in intracellular calcium, with the generated NO stimulating soluble guanylyl cyclase, thereby increasing cGMP levels to dilate blood vessels (4). Functional hyperemia is decreased by ∼50% in rats in response to inhibition of nNOS (5). Another gaseous mediator, CO (6-8), is also vasoactive. In some blood vessel systems (e.g., liver sinusoids), CO causes vasodilation, and inhibition of its biosynthetic enzyme HO-2 leads to vasoconstriction (9-13). However, in the cerebral circulation, CO elicits vasoconstriction. Thus, HO inhibitors cause cerebral vasodilation, an effect reversed by CO (14). This action of CO cannot be readily explained by previously identified CO receptors, such as soluble guanylyl cyclase (6-12, 15) or potassium channels (13, 16), both of which mediate vasodilation. The CO and NO systems interface; thus, the vasodilatory actions of HO inhibitors are partially reversed by inhibitors of NOS (14). A third gaseous mediator, H 2 S, is also vasoactive, eliciting vasodilation in both the peripheral and cerebral circulation (17-21). H 2 S can be physiologically ...

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Section: Discussionsupporting

confidence: 81%

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Morikawa

Kajimura

Nakamura

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

235

230

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“…Using exogenous H 2 S, we demonstrated that it promotes H 2 O 2 killing by specifically damaging heme-containing proteins, especially the CAT KatB, even though it is able to induce the protective OxyR regulon, as described in other bacterial species (3). Such an inhibitory effect on heme-containing proteins such as Cco (mitochondrial aa 3 type), myoglobin, and hemoglobin by H 2 S is well documented in eukaryotes (44)(45)(46). In general, the reaction between these proteins and H 2 S induced modification of the heme component, reversibly inhibiting activity (46,47).…”

Section: Discussionmentioning

confidence: 82%

A Matter of Timing: Contrasting Effects of Hydrogen Sulfide on Oxidative Stress Response in Shewanella oneidensis

Wan

et al. 2015

J Bacteriol

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Hydrogen sulfide (H 2 S), well known for its toxic properties, has recently become a research focus in bacteria, in part because it has been found to prevent oxidative stress caused by treatment with some antibiotics. H 2 S has the ability to scavenge reactive oxygen species (ROS), thus preventing oxidative stress, but it is also toxic, leading to conflicting reports of its effects in different organisms. Here, with Shewanella oneidensis as a model, we report that the effects of H 2 S on the response to oxidative stress are time dependent. When added simultaneously with H 2 O 2 , H 2 S promoted H 2 O 2 toxicity by inactivating catalase, KatB, a hemecontaining enzyme involved in H 2 O 2 degradation. Such an inhibitory effect may apply to other heme-containing proteins, such as cytochrome cbb 3 oxidase. When H 2 O 2 was supplied 20 min or later after the addition of H 2 S, the oxidative-stress-responding regulator OxyR was activated, resulting in increased resistance to H 2 O 2 . The activation of OxyR was likely triggered by the influx of iron, a response to lowered intracellular iron due to the iron-sequestering property of H 2 S. Given that Shewanella bacteria thrive in redox-stratified environments that have abundant sulfur and iron species, our results imply that H 2 S is more important for bacterial survival in such environmental niches than previously believed. IMPORTANCE Previous studies have demonstrated that H 2 S is either detrimental or beneficial to bacterial cells. While it can act as a growth-inhibiting molecule by damaging DNA and denaturing proteins, it helps cells to combat oxidative stress. Here we report that H 2 S indeed has these contrasting biological functions and that its effects are time dependent. Immediately after H 2 S treatment, there is growth inhibition due to damage of heme-containing proteins, at least to catalase and cytochrome c oxidase. In contrast, when added a certain time later, H 2 S confers an enhanced ability to combat oxidative stress by activating the H 2 O 2 -responding regulator OxyR. Our data reconcile conflicting observations about the functions of H 2 S.

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“…Oxygen consumption is obligatory during H 2 S metabolism, and 1 mol of oxygen is consumed for every mol of H 2 S oxidized along the electron transport chain (53 (82). It is important to note that sulfide oxidation in the mitochondria appears to take priority over oxidation of other carbon-based substrates, ensuring its efficient removal (24). This plus the fact that the capacity of cells to oxidize sulfide appears to be considerably greater than the estimated rate of sulfide production (24) ensures that intracellular H 2 S concentrations are very low.…”

Section: Metabolism (Inactivation)mentioning

confidence: 99%

The therapeutic potential of hydrogen sulfide: separating hype from hope

Olson

2011

American Journal of Physiology-Regulatory, Integrative and Comp

162

154

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Hydrogen sulfide (H2S) has become the hot new signaling molecule that seemingly affects all organ systems and biological processes in which it has been investigated. It has also been shown to have both proinflammatory and anti-inflammatory actions and proapoptotic and anti-apoptotic effects and has even been reported to induce a hypometabolic state (suspended animation) in a few vertebrates. The exuberance over potential clinical applications of natural and synthetic H2S-“donating” compounds is understandable and a number of these function-targeted drugs have been developed and show clinical promise. However, the concentration of H2S in tissues and blood, as well as the intrinsic factors that affect these levels, has not been resolved, and it is imperative to address these points to distinguish between the physiological, pharmacological, and toxicological effects of this molecule. This review will provide an overview of H2S metabolism, a summary of many of its reported “physiological” actions, and it will discuss the recent development of a number of H2S-donating drugs that show clinical potential. It will also examine some of the misconceptions of H2S chemistry that have appeared in the literature and attempt to realign the definition of “physiological” H2S concentrations upon which much of this exuberance has been established.

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Using a functional enzyme model to understand the chemistry behind hydrogen sulfide induced hibernation

Abstract: The toxic gas H2S is produced by enzymes in the body. At

Cited by 146 publications

References 39 publications

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway

A Matter of Timing: Contrasting Effects of Hydrogen Sulfide on Oxidative Stress Response in Shewanella oneidensis

The therapeutic potential of hydrogen sulfide: separating hype from hope

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