Evidence for a functional genetic polymorphism of the human mercaptopyruvate sulfurtransferase (MPST), a cyanide detoxification enzyme

Billaut-Laden, Ingrid; Rat, Emmanuel; Allorge, Delphine; Crunelle-Thibaut, Aurélie; Cauffiez, Christelle; Chevalier, Dany; Lo-Guidice, Jean-Marc; Broly, Franck

doi:10.1016/j.toxlet.2006.02.002

Cited by 30 publications

(23 citation statements)

References 37 publications

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“…However, cyanide (2 mM) has been found to stimulate the respiratory burst of polymorphonucleates upon phagocytosis [42,43], which, if it occurred in the lung during chronic P. aeruginosa infection, may lead to an increased inflammatory response and increased tissue damage. In humans, it is thought that rhodanese (thiosulfate sulfurtransferase) and a-mercaptopyruvate sulfurtransferase contribute to the main pathway for cyanide elimination by converting it to the less toxic thiocyanate [44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa, cyanide accumulation and lung function in CF and non-CF bronchiectasis patients

Ryall¹,

Davies²,

Wilson³

et al. 2008

European Respiratory Journal

102

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In patients with cystic fibrosis (CF) and non-CF bronchiectasis, Pseudomonas aeruginosa is the most important respiratory pathogen. It is able to synthesise hydrogen cyanide, a potent inhibitor of cellular respiration.The present study investigated whether cyanide is present in the sputum of CF and non-CF bronchiectasis patients infected with P. aeruginosa, and whether the detection of cyanide affected lung function. Cyanide was measured in sputum using a cyanide ion selective electrode.Cyanide was detected in sputum from 15 out of 25 CF and non-CF bronchiectasis patients with current P. aeruginosa infection; however, it was not detected in any of the 10 patients without this organism. Maximum levels were 130 mM (mean¡SE 72¡6.6 mM). Concurrent lung function data were available on all 21 P. aeruginosa-infected CF patients; the group with measurable sputum cyanide (n511) was not different from those without (n510) on the basis of age or sex. However, those with detectable cyanide had significantly poorer lung function than those without (forced expiratory volume in one second (% predicted) 26.8¡3.8 versus 46.0¡6.7%; forced vital capacity (% pred) 44.4¡4.9 versus 60.1¡7.7%).Cyanide is detectable in sputum from cystic fibrosis and non-cystic fibrosis bronchiectasis patients infected with Pseudomonas aeruginosa, and is also associated with impaired lung function.

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa, cyanide accumulation and lung function in CF and non-CF bronchiectasis patients

Ryall¹,

Davies²,

Wilson³

et al. 2008

European Respiratory Journal

102

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“…Mercaptolactate-cysteine disulfiduria is an in-born error of metabolism caused by a defect in MST that is diagnosed by the appearance of mercaptolactate in urine as a mixed disulfide with cysteine (49). Patients also show an increased risk of neurotoxicity following exposure to cyanide, indicating that MST is important for cyanide detoxification.…”

Section: Discussionmentioning

confidence: 99%

The Mercaptopyruvate Sulfurtransferase of Trichomonas vaginalis Links Cysteine Catabolism to the Production of Thioredoxin Persulfide

Westrop

Georg

Coombs

2009

Journal of Biological Chemistry

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Trichomonas vaginalis is a protozoan parasite of humans that is able to synthesize cysteine de novo using cysteine synthase but does not produce glutathione. In this study, high pressure liquid chromatography analysis confirmed that cysteine is the major intracellular redox buffer by showing that T. vaginalis contains high levels of cysteine (ϳ600 M) comprising more than 70% of the total thiols detected. To investigate possible mechanisms for the regulation of cysteine levels in T. vaginalis, we have characterized enzymes of the mercaptopyruvate pathway. This consists of an aspartate aminotransferase (TvAspAT1), which transaminates cysteine to form 3-mercaptopyruvate (3-MP), and mercaptopyruvate sulfurtransferase (TvMST), which transfers the sulfur of 3-MP to a nucleophilic acceptor, generating pyruvate. TvMST has high activity with 3-MP as a sulfur donor and can use several thiol compounds as sulfur acceptor substrates. Our analysis indicated that TvMST has a k cat /K m for reduced thioredoxin of 6.2 ؋ 10 7 M ؊1 s ؊1 , more than 100-fold higher than that observed for ␤-mercaptoethanol and cysteine, suggesting that thioredoxin is a preferred substrate for TvMST. Thiol trapping and mass spectrometry provided direct evidence for the formation of thioredoxin persulfide as a product of this reaction. The thioredoxin persulfide could serve a biological function such as the transfer of the persulfide to a target protein or the sequestered release of sulfide for biosynthesis. Changes in MST activity of T. vaginalis in response to variation in the supply of exogenous cysteine are suggestive of a role for the mercaptopyruvate pathway in the removal of excess intracellular cysteine, redox homeostasis, and antioxidant defense.

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“…MPST catalyzes the transfer of a sulfur ion from 3-mercaptopyruvate to cyanide or other thiol compounds and may be involved in cysteine degradation and cyanide detoxification. Mutations in MPST result in a rare heritable disorder (mercaptolactate-cysteine disulfiduria) characterized by elevated levels of the mixed disulfide of 3-mercaptolactate and cysteine in the urine, 35 RBCs devoid of MPST activity, and anemia. We noted low LD (r 2 ϭ0.13) between rs855791 and rs8141597, and the latter was independently associated with MCV (Fϭ5.96; Pϭ3ϫ10 Ϫ3 ) and MCH (Fϭ4.24; Pϭ.01).…”

Section: Replicated Locimentioning

confidence: 99%

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

Ding

Shameer

Jouni

et al. 2012

Mayo Clinic Proceedings

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Objective: To identify common genetic variants influencing red blood cell (RBC) traits. Patients and Methods: We performed a genomewide association study from June 2008 through July 2011 of hemoglobin, hematocrit, RBC count, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration in 12,486 patients of European ancestry from the electronic MEdical Records and Genomics (eMERGE) network. We developed an electronic medical record-based algorithm that included individuals who had RBC measurements obtained for clinical care and excluded values measured in the setting of hematopoietic disorders, comorbid conditions, or medications known to affect RBC production or a recent history of blood loss. Results: We identified 4 new genetic loci and replicated 11 loci previously reported to be associated with one or more RBC traits in individuals of European ancestry. Notably, genes present in 3 of the 4 newly identified loci (THRB, PTPLAD1, CDT1) and in 6 of the 11 replicated loci (KLF1, ALDH8A1, CCND3, SPTA1, FBXO7, TFR2/EPO) are implicated in erythroid differentiation and regulation of cell cycle in hematopoietic stem cells. Conclusion: Genes in the erythroid differentiation and cell cycle regulation pathways influence interindividual variation in RBC indices. Our results provide insights into the molecular basis underlying variation in RBC traits.

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Evidence for a functional genetic polymorphism of the human mercaptopyruvate sulfurtransferase (MPST), a cyanide detoxification enzyme

Cited by 30 publications

References 37 publications

Pseudomonas aeruginosa, cyanide accumulation and lung function in CF and non-CF bronchiectasis patients

Pseudomonas aeruginosa, cyanide accumulation and lung function in CF and non-CF bronchiectasis patients

The Mercaptopyruvate Sulfurtransferase of Trichomonas vaginalis Links Cysteine Catabolism to the Production of Thioredoxin Persulfide

Genetic Loci Implicated in Erythroid Differentiation and Cell Cycle Regulation Are Associated With Red Blood Cell Traits

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