Emerging roles of cystathionine β-synthase in various forms of cancer

Ascenção, Kelly; Szabó, Csaba

doi:10.1016/j.redox.2022.102331

Cited by 55 publications

(53 citation statements)

References 427 publications

(961 reference statements)

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“…In both cultured cancer cell lines and tissues in vivo, we find that cystathionine is robustly labeled from serine, while cysteine labeling is slow or absent, even when exogenous cystine is removed from the culture system. CBS is considered the rate limiting enzyme of transsulfuration, and its activity is positively regulated by S-adenosylmethionine availability to promote entry of homocysteine into the transsulfuration pathway (Ascenção and Szabo, 2022). However, our results demonstrate that the second step of transsulfuration mediated by CSE is likely to restriction de novo cysteine synthesis in vitro as well as in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…While this stroma can account for half of the tumor cellularity, it is unlikely to completely account for the complete absence of cysteine synthesis and CBS/CSE expression we observe in the GEMMs. In contrast to HCC, low expression of CBS in PDAC is associated with better outcomes (Ascenção and Szabo, 2022). In addition to their role in cysteine synthesis, CBS and CSE play a role in hydrogen sulfide (H2S) generation, which can be toxic in high concentrations (Ascenção and Szabo, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to HCC, low expression of CBS in PDAC is associated with better outcomes (Ascenção and Szabo, 2022). In addition to their role in cysteine synthesis, CBS and CSE play a role in hydrogen sulfide (H2S) generation, which can be toxic in high concentrations (Ascenção and Szabo, 2022). Thus, tumors in which adequate cysteine is supplied from other pathways may downregulate these enzymes to limit the other metabolic consequences of these enzymes.…”

Section: Discussionmentioning

confidence: 99%

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The Origin of Cysteine and its Catabolism in Mammalian Tissues and Tumors

Yoon

Combs

Falzone

et al. 2022

Preprint

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Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and is an essential contributor to redox metabolism. While cultured cells are highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and the cancer that arise from them using stable isotope 13C-serine and 13C-cystine tracing. We found that de novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue. In tumors, cysteine synthesis was either inactive or downregulated during tumorigenesis. By contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. Differences in cysteine catabolism were evident across tumor types, including glutathione synthesis. Thus, cystine is a major contributor to the cysteine pool in tumors and cysteine catabolic pathways are differentially active across tumor types.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Origin of Cysteine and its Catabolism in Mammalian Tissues and Tumors

Yoon

Combs

Falzone

et al. 2022

Preprint

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“…Based on disease scenarios, different delivery approaches can be utilized to apply H 2 S donors-of-choice to patients to reach optimal results. The readers may refer to a few recent reviews on the different types of H 2 S donors and their potential clinical applications [ 8 , 9 , 10 , 11 , 15 ]. To write this review, we performed a literature search on recent publications related to H 2 S donors and the molecular and cellular responses after the treatment of H 2 S donors in in vitro and in vivo disease models.…”

Section: Introductionmentioning

confidence: 99%

Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter

et al. 2022

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Hydrogen sulfide has been recently identified as the third biological gasotransmitter, along with the more well studied nitric oxide (NO) and carbon monoxide (CO). Intensive studies on its potential as a therapeutic agent for cardiovascular, inflammatory, infectious and neuropathological diseases have been undertaken. Here we review the possible direct targets of H2S in mammals. H2S directly interacts with reactive oxygen/nitrogen species and is involved in redox signaling. H2S also reacts with hemeproteins and modulates metal-containing complexes. Once being oxidized, H2S can persulfidate proteins by adding -SSH to the amino acid cysteine. These direct modifications by H2S have significant impact on cell structure and many cellular functions, such as tight junctions, autophagy, apoptosis, vesicle trafficking, cell signaling, epigenetics and inflammasomes. Therefore, we conclude that H2S is involved in many important cellular and physiological processes. Compounds that donate H2S to biological systems can be developed as therapeutics for different diseases.

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“…Therefore, it has been proposed that reversible competitive CBS inhibitors might act as pharmacological chaperones and rescue proper folding of certain CBS mutants [8]. On the other end of the CBS activity scale, increased expression of CBS results in an increased biogenesis of H 2 S. Upregulation of CBS and consequent overproduction of H 2 S stimulate mitochondrial electron transport, enhance cellular bioenergetics and increase proliferation in multiple types of cancer [9][10][11]. However, systemic and chronic overexpression of CBS due to additional copy of CBS gene in trisomy 21 (Down syndrome, DS) elevates the cellular levels of H 2 S to toxic levels, which (on the background of a variety of additional biochemical misalignments caused by additional gene triplications in this condition) suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and aerobic ATP generation [12].…”

Section: Introductionmentioning

confidence: 99%

H2S biogenesis by cystathionine beta-synthase: mechanism of inhibition by aminooxyacetic acid and unexpected role of serine

Petrosino

Zuhra

Kopec

et al. 2022

Cell. Mol. Life Sci.

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Cystathionine beta-synthase (CBS) is a pivotal enzyme of the transsulfuration pathway responsible for diverting homocysteine to the biosynthesis of cysteine and production of hydrogen sulfide (H2S). Aberrant upregulation of CBS and overproduction of H2S contribute to pathophysiology of several diseases including cancer and Down syndrome. Therefore, pharmacological CBS inhibition has emerged as a prospective therapeutic approach. Here, we characterized binding and inhibitory mechanism of aminooxyacetic acid (AOAA), the most commonly used CBS inhibitor. We found that AOAA binds CBS tighter than its respective substrates and forms a dead-end PLP-bound intermediate featuring an oxime bond. Surprisingly, serine, but not cysteine, replaced AOAA from CBS and formed an aminoacrylate reaction intermediate, which allowed for the continuation of the catalytic cycle. Indeed, serine rescued and essentially normalized the enzymatic activity of AOAA-inhibited CBS. Cellular studies confirmed that AOAA decreased H2S production and bioenergetics, while additional serine rescued CBS activity, H2S production and mitochondrial function. The crystal structure of AOAA-bound human CBS showed a lack of hydrogen bonding with residues G305 and Y308, found in the serine-bound model. Thus, AOAA-inhibited CBS could be reactivated by serine. This difference may be important in a cellular environment in multiple pathophysiological conditions and may modulate the CBS-inhibitory activity of AOAA. In addition, our results demonstrate additional complexities of using AOAA as a CBS-specific inhibitor of H2S biogenesis and point to the urgent need to develop a potent, selective and specific pharmacological CBS inhibitor.

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Emerging roles of cystathionine β-synthase in various forms of cancer

Cited by 55 publications

References 427 publications

The Origin of Cysteine and its Catabolism in Mammalian Tissues and Tumors

The Origin of Cysteine and its Catabolism in Mammalian Tissues and Tumors

Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter

H2S biogenesis by cystathionine beta-synthase: mechanism of inhibition by aminooxyacetic acid and unexpected role of serine

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