Two enzymes in the transsulfuration pathway of homocysteine -cystathionine beta-synthase (CBS) and gamma-cystathionase (CTH)-use cysteine and/or homocysteine to produce the important signaling molecule hydrogen sulfide (H2S) and simultaneously the thioethers lanthionine, cystathionine or homolanthionine. In this study we explored whether impaired flux of substrates for H2S synthesis and/or deficient enzyme activities alter production of hydrogen sulfide in patients with homocystinurias. As an indirect measure of H2S synthesis we determined by LC-MS/MS concentrations of thioethers in plasma samples from 33 patients with different types of homocystinurias, in 8 patient derived fibroblast cell lines, and as reaction products of seven purified mutant CBS enzymes. Since chaperoned recombinant mutant CBS enzymes retained capacity of H2S synthesis in vitro it can be stipulated that deficient CBS activity in vivo may impair H2S production. Indeed, in patients with classical homocystinuria we observed significantly decreased cystathionine and lanthionine concentrations in plasma (46% and 74% of median control levels, respectively) and significantly lower cystathionine in fibroblasts (8% of median control concentrations) indicating that H2S production from cysteine and homocysteine may be also impaired. In contrast, the grossly elevated plasma levels of homolanthionine in CBS deficient patients (32-times elevation compared to median of controls) clearly demonstrates a simultaneous overproduction of H2S from homocysteine by CTH. In the remethylation defects the accumulation of homocysteine and the increased flux of metabolites through the transsulfuration pathway resulted in elevation of cystathionine and homolanthionine (857% and 400% of median control values, respectively) indicating a possibility of an increased biosynthesis of H2S by both CBS and CTH. This study shows clearly disturbed thioether concentrations in homocystinurias, and modeling using these data indicates that H2S synthesis may be increased in these conditions. Further studies are needed to confirm our findings and to explore the possible implications for pathophysiology of these disorders.

• MeSH
• alanin analogy a deriváty   metabolismus   MeSH
• cystathionin-beta-synthasa metabolismus   MeSH
• cystathionin metabolismus   MeSH
• fibroblasty metabolismus   patologie   MeSH
• homocystinurie metabolismus   patologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• sulfan metabolismus   MeSH
• sulfidy metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• chromatografie MeSH
• cystathionin metabolismus   MeSH
• cystin metabolismus   MeSH
• enzymatické testy metody   využití   MeSH
• fenylalanin izolace a purifikace   krev   MeSH
• fenylketonurie * diagnóza   MeSH
• histidin metabolismus   MeSH
• homocystinurie * krev   metabolismus   moč   MeSH
• kyseliny aminoisomáselné krev   metabolismus   moč   MeSH
• leucin metabolismus   MeSH
• lidé MeSH
• methionin metabolismus   MeSH
• plošný screening MeSH
• prolin metabolismus   MeSH
• statistika jako téma MeSH
• tyrosinemie * krev   metabolismus   MeSH
• valin krev   metabolismus   MeSH
• vrozené poruchy metabolismu aminokyselin diagnóza   patologie   prevence a kontrola   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• chromatografie metody   využití   MeSH
• cystathionin izolace a purifikace   metabolismus   MeSH
• cystin analogy a deriváty   krev   metabolismus   MeSH
• diferenciální diagnóza * MeSH
• homocystinurie * diagnóza   genetika   metabolismus   MeSH
• incest MeSH
• klinický obraz nemoci * MeSH
• lidé MeSH
• mentální retardace MeSH
• methionin krev   metabolismus   moč   MeSH
• novorozenec MeSH
• poruchy řeči MeSH
• selhání jater MeSH
• statistika jako téma MeSH
• vitamin B6 terapeutické užití   MeSH
• vrozené poruchy metabolismu aminokyselin diagnóza   etiologie   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH