BackgroundHyperhomocysteinemia, characterized by increased plasma homocysteine level, is associated with an increased risk of atherosclerosis. On the contrary, patients with Down syndrome appear to be protected from the development of atherosclerosis. We previously found a deleterious effect of hyperhomocysteinemia on expression of DYRK1A, a Down-syndrome-associated kinase. As increased expression of DYRK1A and low plasma homocysteine level have been associated with Down syndrome, we aimed to analyze the effect of its over-expression on homocysteine metabolism in mice.Methodology/Principal FindingsEffects of DYRK1A over-expression were examined by biochemical analysis of methionine metabolites, real-time quantitative reverse-transcription polymerase chain reaction, and enzyme activities. We found that over-expression of Dyrk1a increased the hepatic NAD(P)H:quinone oxidoreductase and S-adenosylhomocysteine hydrolase activities, concomitant with decreased level of plasma homocysteine in three mice models overexpressing Dyrk1a. Moreover, these effects were abolished by treatment with harmine, the most potent and specific inhibitor of Dyrk1a. The increased NAD(P)H:quinone oxidoreductase and S-adenosylhomocysteine hydrolase activities were also found in lymphoblastoid cell lines from patients with Down syndrome.Conclusions/SignificanceOur results might give clues to understand the protective effect of Down syndrome against vascular defect through a decrease of homocysteine level by DYRK1A over-expression. They reveal a link between the Dyrk1a signaling pathway and the homocysteine cycle.

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The synthesis of 1-(tert-butoxycarbonyl)-7-[1-(tert-butoxycarbonyl)-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.5]decanes (S,S)-1a and (S,R)-1b is described. Derivatives 17a,b and 19a are prepared for use in peptide synthesis as constrained surrogates of the Pro-Leu and Gly-Leu dipeptides. The Ac-[Gly-Leu]-Met-NH(2) derivatives (S,S,S)-2a and (S,R,S)-2b, with the tripeptidic C-terminal region present in tachykinins, are also synthesized. Conformational analyses of these tripetide analogues by NMR experiments and molecular modeling calculations show that both (S,S,S)-2a and (S,R,S)-2b epimers are gamma-turn/distorted type II beta-turn mimetics.