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Sex-specific dysregulation of cysteine oxidation and the methionine and folate cycles in female cystathionine gamma-lyase mice: a serendipitous model of the methylfolate trap.

Jiang H, Hurt KJ, Breen K, Stabler SP, Allen RH, Orlicky DJ, Maclean KN - Biol Open (2015)

Bottom Line: In addition to its role in the endogenous synthesis of cysteine, cystathionine gamma-lyase (CGL) is a major physiological source of the vasorelaxant hydrogen sulfide.Cgl mice of both sexes exhibited decreased expression of methylenetetrahydrofolate reductase and cysteinesulfinate decarboxylase compared to WT controls.Female Cgl mice exhibited a sex-specific induction of betaine homocysteine S-methyltransferase and methionine adenosyltransferase 1, alpha and a 70% decrease in methionine synthase expression accompanied by significantly decreased plasma methionine.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

No MeSH data available.


Related in: MedlinePlus

Methionine, folate and cysteine metabolism in mammals. (A) The transsulfuration and cysteine oxidation pathways and, methionine and folate cycles are shown. Betaine-homocysteine S-methyltransferase (BHMT), cystathionine β-synthase (CBS), cystathionine γ-lyase (CGL), cysteine dioxygenase (CDO), cysteinesulfinate decarboxylase (CSAD), glutamic-oxaloacetic transaminase (GOT), glycine N-methyltransferase (GNMT), methionine adenosyl transferase (MAT1A), methionine synthase (MTR), methylenetetrahydrofolate reductase (MTHFR), S-adenosyl homocysteine hydrolase (SAHH). (B) Cgl  female but not male mice exhibit severely elevated levels of plasma tHcy. Plasma levels of tHcy in wild type (WT) mice plus and minus treatment with the CGL specific inhibitor PPG and untreated male and female Cgl  mice. Values shown represent the mean±s.d., n=6, ***P<0.001.
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BIO013433F1: Methionine, folate and cysteine metabolism in mammals. (A) The transsulfuration and cysteine oxidation pathways and, methionine and folate cycles are shown. Betaine-homocysteine S-methyltransferase (BHMT), cystathionine β-synthase (CBS), cystathionine γ-lyase (CGL), cysteine dioxygenase (CDO), cysteinesulfinate decarboxylase (CSAD), glutamic-oxaloacetic transaminase (GOT), glycine N-methyltransferase (GNMT), methionine adenosyl transferase (MAT1A), methionine synthase (MTR), methylenetetrahydrofolate reductase (MTHFR), S-adenosyl homocysteine hydrolase (SAHH). (B) Cgl female but not male mice exhibit severely elevated levels of plasma tHcy. Plasma levels of tHcy in wild type (WT) mice plus and minus treatment with the CGL specific inhibitor PPG and untreated male and female Cgl mice. Values shown represent the mean±s.d., n=6, ***P<0.001.

Mentions: Cystathionine γ-lyase (CGL) (EC4.4.1.1) is a pyridoxal-5′-phosphate-dependent enzyme that catalyzes the γ-cleavage of cystathionine [2-amino-4-(2-amino-2-carboxy-ethyl) thio-butanoic acid] to yield cysteine, α-ketobutyrate and ammonia as the terminal reaction of the transsulfuration pathway (Fig. 1A). Deficiency of CGL causes cystathionuria which appears to be an essentially benign condition (Kraus et al., 2009). In addition to a role in endogenous cysteine synthesis, CGL catalyzes an α,β-disulfide elimination reaction that results in the production of pyruvate, ammonia and thiocysteine. This latter compound may then react with other thiol compounds to generate hydrogen sulfide (H2S). Recently, interest in the regulation of CGL has increased as data has accumulated implicating H2S as an endogenous gasotransmitter associated with multiple diseases including pancreatitis, diabetes, hypertension and septic and hemorrhagic shock (Szabó, 2007). The expression of CGL at various locations in the vasculature in isolation from CBS, has led to speculation that synthesis of H2S by this enzyme is involved in the regulation of vascular tone. Previous work demonstrating that NaHS produces significant dose-dependent decreases in the spontaneous contractility of uterine strips from pregnant rats has indicated that CGL may be specifically involved in the regulation of vascular tone and contractility during pregnancy and childbirth (Sidhu et al., 2001). A previously described Cgl mouse model (Yang et al., 2008) would seem an ideal system to investigate this hypothesis but a previous report has indicated that female Cgl mice incur severely elevated plasma total homocysteine (tHcy). This compound has the potential to form mixed disulfides with the H2S donor compound cysteine and thus interfere with studies designed to assess the potential vasorelaxant role of endogenously generated H2S (Yang et al., 2008). The reason for this female-specific biochemical anomaly and possible changes to other relevant metabolites has to date, remained uninvestigated.


Sex-specific dysregulation of cysteine oxidation and the methionine and folate cycles in female cystathionine gamma-lyase mice: a serendipitous model of the methylfolate trap.

Jiang H, Hurt KJ, Breen K, Stabler SP, Allen RH, Orlicky DJ, Maclean KN - Biol Open (2015)

Methionine, folate and cysteine metabolism in mammals. (A) The transsulfuration and cysteine oxidation pathways and, methionine and folate cycles are shown. Betaine-homocysteine S-methyltransferase (BHMT), cystathionine β-synthase (CBS), cystathionine γ-lyase (CGL), cysteine dioxygenase (CDO), cysteinesulfinate decarboxylase (CSAD), glutamic-oxaloacetic transaminase (GOT), glycine N-methyltransferase (GNMT), methionine adenosyl transferase (MAT1A), methionine synthase (MTR), methylenetetrahydrofolate reductase (MTHFR), S-adenosyl homocysteine hydrolase (SAHH). (B) Cgl  female but not male mice exhibit severely elevated levels of plasma tHcy. Plasma levels of tHcy in wild type (WT) mice plus and minus treatment with the CGL specific inhibitor PPG and untreated male and female Cgl  mice. Values shown represent the mean±s.d., n=6, ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582125&req=5

BIO013433F1: Methionine, folate and cysteine metabolism in mammals. (A) The transsulfuration and cysteine oxidation pathways and, methionine and folate cycles are shown. Betaine-homocysteine S-methyltransferase (BHMT), cystathionine β-synthase (CBS), cystathionine γ-lyase (CGL), cysteine dioxygenase (CDO), cysteinesulfinate decarboxylase (CSAD), glutamic-oxaloacetic transaminase (GOT), glycine N-methyltransferase (GNMT), methionine adenosyl transferase (MAT1A), methionine synthase (MTR), methylenetetrahydrofolate reductase (MTHFR), S-adenosyl homocysteine hydrolase (SAHH). (B) Cgl female but not male mice exhibit severely elevated levels of plasma tHcy. Plasma levels of tHcy in wild type (WT) mice plus and minus treatment with the CGL specific inhibitor PPG and untreated male and female Cgl mice. Values shown represent the mean±s.d., n=6, ***P<0.001.
Mentions: Cystathionine γ-lyase (CGL) (EC4.4.1.1) is a pyridoxal-5′-phosphate-dependent enzyme that catalyzes the γ-cleavage of cystathionine [2-amino-4-(2-amino-2-carboxy-ethyl) thio-butanoic acid] to yield cysteine, α-ketobutyrate and ammonia as the terminal reaction of the transsulfuration pathway (Fig. 1A). Deficiency of CGL causes cystathionuria which appears to be an essentially benign condition (Kraus et al., 2009). In addition to a role in endogenous cysteine synthesis, CGL catalyzes an α,β-disulfide elimination reaction that results in the production of pyruvate, ammonia and thiocysteine. This latter compound may then react with other thiol compounds to generate hydrogen sulfide (H2S). Recently, interest in the regulation of CGL has increased as data has accumulated implicating H2S as an endogenous gasotransmitter associated with multiple diseases including pancreatitis, diabetes, hypertension and septic and hemorrhagic shock (Szabó, 2007). The expression of CGL at various locations in the vasculature in isolation from CBS, has led to speculation that synthesis of H2S by this enzyme is involved in the regulation of vascular tone. Previous work demonstrating that NaHS produces significant dose-dependent decreases in the spontaneous contractility of uterine strips from pregnant rats has indicated that CGL may be specifically involved in the regulation of vascular tone and contractility during pregnancy and childbirth (Sidhu et al., 2001). A previously described Cgl mouse model (Yang et al., 2008) would seem an ideal system to investigate this hypothesis but a previous report has indicated that female Cgl mice incur severely elevated plasma total homocysteine (tHcy). This compound has the potential to form mixed disulfides with the H2S donor compound cysteine and thus interfere with studies designed to assess the potential vasorelaxant role of endogenously generated H2S (Yang et al., 2008). The reason for this female-specific biochemical anomaly and possible changes to other relevant metabolites has to date, remained uninvestigated.

Bottom Line: In addition to its role in the endogenous synthesis of cysteine, cystathionine gamma-lyase (CGL) is a major physiological source of the vasorelaxant hydrogen sulfide.Cgl mice of both sexes exhibited decreased expression of methylenetetrahydrofolate reductase and cysteinesulfinate decarboxylase compared to WT controls.Female Cgl mice exhibited a sex-specific induction of betaine homocysteine S-methyltransferase and methionine adenosyltransferase 1, alpha and a 70% decrease in methionine synthase expression accompanied by significantly decreased plasma methionine.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA.

No MeSH data available.


Related in: MedlinePlus