S
 -Adenosylmethionine–responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in
 Mycobacterium
 tuberculosis

Bandyopadhyay, Parijat; Pramanick, Ishika; Biswas, Rupam; Subramanian, Sabarinath Peruvemba; Sreedharan, Sreesa; Singh, Shalini; Rajmani, Raju S; Laxman, Sunil; Dutta, Somnath; Singh, Amit

doi:10.1126/sciadv.abo0097

Cited by 14 publications

(13 citation statements)

References 87 publications

(99 reference statements)

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“…S27). These features are also consistent with observations of Mycobacterium tuberculosis CBS ( 28 ). In addition, a molecule of PO 4 , which is part of PLP, was found in the active site of monomer A of our cCBS-cc structure after structural refinement.…”

Section: Discussionsupporting

confidence: 92%

Inhibition of fungal pathogenicity by targeting the H ₂ S-synthesizing enzyme cystathionine β-synthase

et al. 2022

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The global emergence of antifungal resistance threatens the limited arsenal of available treatments and emphasizes the urgent need for alternative antifungal agents. Targeting fungal pathogenic functions is an appealing alternative therapeutic strategy. Here, we show that cystathionine β-synthase (CBS), compared with cystathionine γ-lyase, is the major enzyme that synthesizes hydrogen sulfide in the pathogenic fungus Candida albicans . Deletion of CBS leads to deficiencies in resistance to oxidative stress, retarded cell growth, defective hyphal growth, and increased β-glucan exposure, which, together, reduce the pathogenicity of C. albicans . By high-throughput screening, we identified protolichesterinic acid, a natural molecule obtained from a lichen, as an inhibitor of CBS that neutralizes the virulence of C. albicans and exhibits therapeutic efficacy in a murine candidiasis model. These findings support the application of CBS as a potential therapeutic target to fight fungal infections.

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Section: Discussionsupporting

confidence: 92%

Inhibition of fungal pathogenicity by targeting the H ₂ S-synthesizing enzyme cystathionine β-synthase

et al. 2022

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“…The transsulfuration pathway plays a central role in cell sulfur metabolism and redox regulation. Different studies have underlined the therapeutic potential of inhibiting the activity of the transsulfuration enzymes in the treatment of pathogenic infections (Bandyopadhyay et al, 2022;Gobert et al, 2019;Marciano et al, 2012;Shatalin et al, 2011Shatalin et al, , 2021. Knowledge of the threedimensional structure of these therapeutically relevant targets is crucial to guide the design of new drugs.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of the inhibition of cystathionine γ‐lyase from Toxoplasma gondii by propargylglycine and cysteine

et al. 2023

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Cystathionine γ‐lyase (CGL) is a PLP‐dependent enzyme that catalyzes the last step of the reverse transsulfuration route for endogenous cysteine biosynthesis. The canonical CGL‐catalyzed process consists of an α,γ‐elimination reaction that breaks down cystathionine into cysteine, α‐ketobutyrate, and ammonia. In some species, the enzyme can alternatively use cysteine as a substrate, resulting in the production of hydrogen sulfide (H2S). Importantly, inhibition of the enzyme and consequently of its H2S production activity, makes multiresistant bacteria considerably more susceptible to antibiotics. Other organisms, such as Toxoplasma gondii, the causative agent of toxoplasmosis, encode a CGL enzyme (TgCGL) that almost exclusively catalyzes the canonical process, with only minor reactivity to cysteine. Interestingly, the substitution of N360 by a serine (the equivalent amino acid residue in the human enzyme) at the active site changes the specificity of TgCGL for the catalysis of cystathionine, resulting in an enzyme that can cleave both the CγS and the CβS bond of cystathionine. Based on these findings and to deepen the molecular basis underlying the enzyme‐substrate specificity, we have elucidated the crystal structures of native TgCGL and the variant TgCGL‐N360S from crystals grown in the presence of cystathionine, cysteine, and the inhibitor d,l‐propargylglycine (PPG). Our structures reveal the binding mode of each molecule within the catalytic cavity and help explain the inhibitory behavior of cysteine and PPG. A specific inhibitory mechanism of TgCGL by PPG is proposed.

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“…Methionine is catalyzed into S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), homocysteine (Hcy), and cysteine (Cys), which occur primarily in the liver, kidney, small intestine, and pancreas [ 40 ]. Most of the enzymes in this metabolic reaction are hepatic-specific, including methionine adenosyltransferase, S-adenosylhomocysteinase, cystathionine β-synthase, and cystathionine γ-lyase, which belong to the methionine and folate cycles and the trans-sulfuration pathway [ 41 ]. As reported previously, methionine, which acts as a reactive oxygen-species scavenger, is implicated in caloric restriction and aging [ 42 ].…”

Section: Methionine and Its Metabolite Homocysteinementioning

confidence: 99%

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

Luo-kun

Zhang

et al. 2022

Nutrients

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Diabetic kidney disease (DKD) occurs in 25–40% of patients with diabetes. Individuals with DKD are at a significant risk of progression to end-stage kidney disease morbidity and mortality. At present, although renal function-decline can be retarded by intensive glucose lowering and strict blood pressure control, these current treatments have shown no beneficial impact on preventing progression to kidney failure. Recently, in addition to control of blood sugar and pressure, a dietary approach has been recommended for management of DKD. Amino acids (AAs) are both biomarkers and causal factors of DKD progression. AA homeostasis contributes to renal hemodynamic response and glomerular hyperfiltration alteration in diabetic patients. This review discusses the links between progressive kidney dysfunction and the metabolic homeostasis of histidine, tryptophan, methionine, glutamine, tyrosine, and branched-chain AAs. In addition, we emphasize the regulation effects of special metabolites on DKD progression, with a focus on causality and potential mechanisms. This paper may offer an optimized protein diet strategy with concomitant management of AA homeostasis to reduce the risks of DKD in a setting of hyperglycemia.

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S -Adenosylmethionine–responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in Mycobacterium tuberculosis

Cited by 14 publications

References 87 publications

Inhibition of fungal pathogenicity by targeting the H ₂ S-synthesizing enzyme cystathionine β-synthase

Inhibition of fungal pathogenicity by targeting the H ₂ S-synthesizing enzyme cystathionine β-synthase

Structural basis of the inhibition of cystathionine γ‐lyase from Toxoplasma gondii by propargylglycine and cysteine

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

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S -Adenosylmethionine–responsive cystathionine β-synthase modulates sulfur metabolism and redox balance in Mycobacterium tuberculosis

Cited by 14 publications

References 87 publications

Inhibition of fungal pathogenicity by targeting the H 2 S-synthesizing enzyme cystathionine β-synthase

Inhibition of fungal pathogenicity by targeting the H 2 S-synthesizing enzyme cystathionine β-synthase

Structural basis of the inhibition of cystathionine γ‐lyase from Toxoplasma gondii by propargylglycine and cysteine

Metabolic Homeostasis of Amino Acids and Diabetic Kidney Disease

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Inhibition of fungal pathogenicity by targeting the H ₂ S-synthesizing enzyme cystathionine β-synthase

Inhibition of fungal pathogenicity by targeting the H ₂ S-synthesizing enzyme cystathionine β-synthase