Redox regulation and reaction mechanism of human cystathionine-β-synthase: a PLP-dependent hemesensor protein

Banerjee, Ruma; Zou, Cheng

doi:10.1016/j.abb.2004.08.037

Cited by 213 publications

(197 citation statements)

References 65 publications

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“…Thus, deletion of the regulatory domains in dhPPase favorably changed its K m1 value (Table 3). A similar deletion in cystathionine ␤-synthase increased k cat but not K m (41,42). The concept of autoinhibition is also consistent with the diminished activity (1-3 orders of magnitude) of CBS domain-containing PPases compared with their close homologs lacking CBS domains (5) as well as their ability to be activated by ATP.…”

Section: Discussionmentioning

confidence: 99%

Cystathionine β-Synthase (CBS) Domains Confer Multiple Forms of Mg2+-dependent Cooperativity to Family II Pyrophosphatases

Salminen

Anashkin

Lahti

et al. 2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Cystathionine β-Synthase (CBS) Domains Confer Multiple Forms of Mg2+-dependent Cooperativity to Family II Pyrophosphatases

Salminen

Anashkin

Lahti

et al. 2014

Journal of Biological Chemistry

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“…In fact, there is considerable evidence showing that mitochondria efficiently oxidize H 2 S [reviewed in Olson (121)]. Sulfide:quinone oxidoreductase (SQR), 3-MST, rhodanase (Rde), thiosulfate reductase (TR), sulfur dioxygenase (ETHE1), and sulfite oxidase (SO) are mitochondrial enzymes that oxidize H 2 S to sulfate (SO 4 2 -) for subsequent excretion. Sulfite (SO 3 2 -) and thiosulfate (S 2 O 3 2 -) are intermediates.…”

Section: Metabolic Relationships Between H 2 S and Omentioning

confidence: 99%

“…Sulfur transferase (ST) transfers the other persulfide and forms thiosulfate (S 2 O 3 2 -). H 2 S may be regenerated from thiosulfate by 3-MST or rhodanase (Rde), or the thiosulfate may be oxidized to sulfate (SO 4 2 -) by the sequential actions of thioredoxin (Trx) reductase (TRD) in combination with glutathione (GSH) and sulfite oxidase (SO). Oxidation of H 2 S donates electrons to the respiratory chain (Q, III, IV) that has been shown in invertebrates and mammals to result in ATP production and O 2 consumption.…”

Section: Effectors Of H 2 S Metabolismmentioning

confidence: 99%

Hydrogen sulfide as an oxygen sensor

Olson

2013

Clinical Chemistry and Laboratory Medicine

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Significance: Although oxygen (O 2 )-sensing cells and tissues have been known for decades, the identity of the O 2 -sensing mechanism has remained elusive. Evidence is accumulating that O 2 -dependent metabolism of hydrogen sulfide (H 2 S) is this enigmatic O 2 sensor. Recent Advances: The elucidation of biochemical pathways involved in H 2 S synthesis and metabolism have shown that reciprocal H 2 S/O 2 interactions have been inexorably linked throughout eukaryotic evolution; there are multiple foci by which O 2 controls H 2 S inactivation, and the effects of H 2 S on downstream signaling events are consistent with those activated by hypoxia. H 2 S-mediated O 2 sensing has been demonstrated in a variety of O 2 -sensing tissues in vertebrate cardiovascular and respiratory systems, including smooth muscle in systemic and respiratory blood vessels and airways, carotid body, adrenal medulla, and other peripheral as well as central chemoreceptors. Critical Issues: Information is now needed on the intracellular location and stoichometry of these signaling processes and how and which downstream effectors are activated by H 2 S and its metabolites. Future Directions: Development of specific inhibitors of H 2 S metabolism and effector activation as well as cellular organelle-targeted compounds that release H 2 S in a timeor environmentally controlled way will not only enhance our understanding of this signaling process but also provide direction for future therapeutic applications. Antioxid. Redox Signal. 22, 377-397.

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“…C ystathionine b-synthase (CBS) is a pyridoxal 5¢-phosphate (PLP)-dependent hemeprotein (2,33) which catalyzes the first steps in the trans-sulfuration pathway that converts homocysteine to cysteine, the limiting reagent in the synthesis of the antioxidant, glutathione (GSH). Alternatively, CBS can catalyze the condensation of cysteine and homocysteine or the condensation of two moles of cysteine to produce hydrogen sulfide (H 2 S) (6,45), a signaling molecule with cytoprotective effects (19)(20)(21)24).…”

Section: Introductionmentioning

confidence: 99%

S-Glutathionylation Enhances Human Cystathionine β-Synthase Activity Under Oxidative Stress Conditions

Niu

Yadav

Adamec

et al. 2015

Antioxidants & Redox Signaling

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Aims: Cystathionine b-synthase (CBS) catalyzes the first and rate-limiting step in the two-step trans-sulfuration pathway that converts homocysteine to cysteine. It is also one of three major enzymes responsible for the biogenesis of H 2 S, a signaling molecule. We have previously demonstrated that CBS is activated in cells challenged by oxidative stress, but the underlying molecular mechanism of this regulation has remained unclear. Results: Here, we demonstrate that S-glutathionylation of CBS enhances its activity *2-fold in vitro. Loss of this post-translational modification in the presence of dithiothreitol results in reversal to basal activity. Cys346 was identified as the site for S-glutathionylation by a combination of mass spectrometric, mutagenesis, and activity analyses. To test the physiological relevance of S-glutathionylation-dependent regulation of CBS, HEK293 cells were oxidatively challenged with peroxide, which is known to enhance the trans-sulfuration flux. Under these conditions, CBS glutathionylation levels increased and were correlated with a *3-fold increase in CBS activity. Innovation: Collectively, our results reveal a novel post-translational modification of CBS, that is, glutathionylation, which functions as an allosteric activator under oxidative stress conditions permitting enhanced synthesis of both cysteine and H 2 S. Conclusions: Our study elucidates a molecular mechanism for increased cysteine and therefore glutathione, synthesis via glutathionylation of CBS. They also demonstrate the potential for increased H 2 S production under oxidative stress conditions, particularly in tissues where CBS is a major source of H 2 S. Antioxid. Redox Signal. 22,[350][351][352][353][354][355][356][357][358][359][360][361]

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Redox regulation and reaction mechanism of human cystathionine-β-synthase: a PLP-dependent hemesensor protein

Cited by 213 publications

References 65 publications

Cystathionine β-Synthase (CBS) Domains Confer Multiple Forms of Mg2+-dependent Cooperativity to Family II Pyrophosphatases

Cystathionine β-Synthase (CBS) Domains Confer Multiple Forms of Mg2+-dependent Cooperativity to Family II Pyrophosphatases

Hydrogen sulfide as an oxygen sensor

S-Glutathionylation Enhances Human Cystathionine β-Synthase Activity Under Oxidative Stress Conditions

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