Insights into the Regulatory Domain of Cystathionine Beta-Synthase: Characterization of Six Variant Proteins

Mendes, Marisa I.; Santos, Ana Sofia; Smith, Desirée E.C.; Lino, Paulo Roque; Colaço, Henrique G.; Almeida, Isabel Tavares de; Vicente, João B.; Salomons, Gajja S.; Rivera, Isabel; Blom, Henk J.; Leandro, Paula

doi:10.1002/humu.22616

Cited by 17 publications

(22 citation statements)

References 33 publications

(51 reference statements)

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“…An increasing number of structural and functional data have been reported over the past few years to elucidate the molecular mechanism of CBS activation by AdoMet (11,12,26,30,31). Two AdoMet-binding sites with different affinity and distinct functional and structural roles have been proposed (26).…”

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confidence: 99%

S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase

Vicente

Colaço

Sarti

et al. 2016

Journal of Biological Chemistry

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Cystathionine ␤-synthase (CBS) is a key enzyme in human (patho)physiology with a central role in hydrogen sulfide metabolism. The enzyme is composed of a pyridoxal 5-phosphate-binding catalytic domain, flanked by the following two domains: a heme-binding N-terminal domain and a regulatory C-terminal domain binding S-adenosyl-L-methionine (AdoMet). CO or NO ⅐ binding at the ferrous heme negatively modulates the enzyme activity. Conversely, AdoMet binding stimulates CBS activity. Here, we provide experimental evidence for a functional communication between the two domains. We report that AdoMet binding significantly enhances CBS inhibition by CO. Consistently, we observed increased affinity (ϳ5-fold) and faster association (ϳ10-fold) of CO to the ferrous heme at physiological AdoMet concentrations. NO ⅐ binding to reduced CBS was also enhanced by AdoMet, although to a lesser extent (ϳ2-fold higher affinity) as compared with CO. Importantly, CO and NO ⅐ binding was unchanged by AdoMet in a truncated form of CBS lacking the C-terminal regulatory domain. These unprecedented observations demonstrate that CBS activation by AdoMet puzzlingly sensitizes the enzyme toward inhibition by exogenous ligands, like CO and NO ⅐ . This further supports the notion that CBS regulation is a complex process, involving the concerted action of multiple physiologically relevant effectors.

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confidence: 99%

S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase

Vicente

Colaço

Sarti

et al. 2016

Journal of Biological Chemistry

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“…Mutations of CBS gene could impair folding and stability of the protein, which lead to substantially decreased CBS activity . Deficiency of CBS activity can lead to an increase in Hcy . The down‐regulation of CBS induced by promoter hypermethylation of CBS would enhance Hcy levels; subsequently, the excessive Hcy would influence the normal methylation of CBS gene …”

Section: Discussionmentioning

confidence: 99%

“…22,23 Deficiency of CBS activity can lead to an increase in Hcy. 24,25 The down-regulation of CBS induced by promoter hypermethylation of CBS would enhance Hcy levels; subsequently, the excessive Hcy would influence the normal methylation of CBS gene. 26 The difference in CBS promoter methylation levels was statistically significant only in males.…”

Section: Discussionmentioning

confidence: 99%

CBS gene polymorphism and promoter methylation‐mediating effects on the efficacy of folate therapy in patients with hyperhomocysteinemia

Zhao

Zhang

et al. 2020

The Journal of Gene Medicine

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Background A decrease in cystathionine beta‐synthase (CBS) enzyme activity could lead to hyperhomocysteinemia (HHcy). Studies have revealed that DNA methylation has a mediating effect on the development of diseases. The present study aimed to explore CBS promoter methylation‐mediating effects on the efficacy of folate treatment for HHcy. Methods HHcy patients were treated with folate (5 mg/day) for 90 days and then divided into a failure group (Hcy ≥ 15 μmol/l) and a success group (Hcy < 15 μmol/l) according to post‐treatment plasma Hcy levels. Genotyping of CBS gene (rs2851391 and rs706209) in patients (n = 638) was detected using a MassArray system (Sequenom, San Diego, CA, USA). The baseline DNA methylation levels of patients (n = 299) were detected using MethylTarget™ technology (Genesky Biotechnologies Inc., Shanghai, China). Results The CBS rs2851391 TC + CC genotype was related to a 57% reduction of failure risk in HHcy treatment compared to the TT genotype (95% confidence interval [CI] = 0.19–0.97). The CBS rs706209 CT + TT genotype had a 2.97‐fold increased risk of failure to treatment compared to the CC genotype (95% CI = 1.52–5.80). After adjustment for confounding factors, the odds ratio (95% CI) for the risk of failure in HHcy treatment in total and male patients was 0.55 (0.32–0.93) and 0.34 (0.16–0.69), respectively, for patients with higher methylation levels (≥ methylation median). Additionally, baseline CBS promoter methylation mediated 33.39% of the effect of rs2851391 on the efficacy of folate treatment for HHcy (ACME [average causal mediation effects]: –0.05, 95% CI = –0.11 to 0.00, p = 0.046). Conclusions The present study indicates that CBS gene polymorphism and promoter methylation could affect the efficacy of HHcy. There were potentially causal effects of genetic, epigenetic variations at the CBS rs2851391 locus on the efficacy of HHcy therapy with folate.

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“…These transporters have high affinity for glutamine transport, but this AA was present in similar concentrations in the uterine lumen of both groups. In contrast, regardless of a similar abundance of the transporter SLC7A11 between groups on D4 and D7, cystathionine, a product of serine and homocysteine condensation by cystathionine β-synthase [58], and valine were present in greater concentrations in the uterine washings of cows from the LF-LCL group compared to cows from the SF-SLC group. In a third scenario, SLC6A14 and one of its transporting targets, valine, were stimulated in the LF-LCL group.…”

Section: Discussionmentioning

confidence: 99%

Evidence of endometrial amino acid metabolism and transport modulation by peri-ovulatory endocrine profiles driving uterine receptivity

França

Silva

Pugliesi

et al. 2017

J Animal Sci Biotechnol

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BackgroundIn beef cattle, changes in the periovulatory endocrine milieu are associated with fertility and conceptus growth. A large preovulatory follicle (POF) and the resulting elevated concentrations of progesterone (P4) during diestrus positively affect pregnancy rates. Amino acids (AA) are important components of maternally derived secretions that are crucial for embryonic survival before implantation. The hypothesis is that the size of the POF and the concentration of P4 in early diestrus modulate the endometrial abundance of SLC transcripts related to AA transport and metabolism and subsequently impact luminal concentrations of AA. The follicle growth of Nelore cows was manipulated to produce two experimental groups: large POF and CL (LF-LCL group) and small POF and CL (SF-SCL group). On Day 4 (D4; Experiment 1) and Day 7 (D7; Experiment 2) after GnRH-induced ovulation (GnRH treatment = D0), the animals were slaughtered and uterine tissues and uterine washings were collected. qRT-PCR was used to evaluate the expression levels of AA transporters in D4 and D7 endometrial tissues. The concentrations of AA were quantified in D4 and D7 uterine washings by HPLC.ResultsTranscript results show that, on D4, SLC6A6, SLC7A4, SLC17A5, SLC38A1, SLC38A7 and SCLY and on D7 SLC1A4, SLC6A1, SLC6A14, SLC7A4, SLC7A7, SLC7A8, SLC17A5, SLC38A1, SLC38A7, SLC43A2 and DDO were more abundant in the endometria of cows from the LF-LCL group (P < 0.05). In addition, concentrations of AA in the uterine lumen were influenced by the endocrine profiles of the mother. In this context, D4 uterine washings revealed that greater concentrations of taurine, alanine and α-aminobutyric acid were present in SF-SCL (P < 0.05). In contrast, lower concentrations of valine and cystathionine were quantified on D7 uterine washings from SF-SCL cows (P < 0.05).ConclusionThe present study revealed an association between the abundance of transcripts related to AA transport and metabolism in the endometrium and specific periovulatory endocrine profiles related to the receptive status of the mother. Such insights suggest that AAs are involved in uterine function to support embryo development.

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Insights into the Regulatory Domain of Cystathionine Beta-Synthase: Characterization of Six Variant Proteins

Cited by 17 publications

References 33 publications

S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase

S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase

CBS gene polymorphism and promoter methylation‐mediating effects on the efficacy of folate therapy in patients with hyperhomocysteinemia

Evidence of endometrial amino acid metabolism and transport modulation by peri-ovulatory endocrine profiles driving uterine receptivity

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