Transition-state mimicking inhibitors of human betaine: homocysteine S-methyltransferase
Project goals
We propose the design, synthesis and biological characterization of new inhibitors of human betaine: homocysteine S-methyltransferase (BHMT). These new inhibitors will mimic the structure of the hypothetical transition-state of substrates upon binding tothe enzyme active site. There classes of compounds mimicking the transition-state are planned to be synthesized: (i) sulfur containing compounds, (ii) phosphorus containing compounds of phosphinate, phosphonate and phosphodiester type and (iii) phosphorus containing compounds substituted by nitjrogen or sulfur containing moieties. The accent will be directed to both potency and selectivity of inhibitors towards BHMT and related enzymes, namely methionine synthase and cystathionine beta-synthetase. Potential metabolic stability of compounds will also be taken into account. The most promising inhibitors should be used in pharmacological experiments for studying the role of BHMT in vivo.
Keywords
betaine: homocysteine S-methyltransferaseinhibitorstransition-state inhibitorsphosphinatesphosphonatesthiolsthioetherssznthesis
Public support
Provider
Academy of Sciences of the Czech Republic
Programme
Grants of distinctly investigative character focused on the sphere of research pursued at present particularly in the Academy of Sciences of the Czech Republic
Call for proposals
Výzkumné granty 3 (SAV02003-A)
Main participants
Ústav organické chemie a biochemie AV ČR, v. v. i.
Contest type
VS - Public tender
Contract ID
—
Alternative language
Project name in Czech
Tranzitní stav napodobující inhibitory lidského enzymu betain: homocystein S-methyltransferázy
Annotation in Czech
Navrhujeme design, syntézu a biologickou charakterizaci nových inhibitorů lidského enzymu betain: homocystein S-methyltransferázy (BHMT). Tyto nové inhibitory budou napodobovat hypotetický tranzitní stav substrátů během jejich vazby do aktivního místa enzymu. Plánujeme syntézu tří skupin látek napodobujících tranzitní stav: (i) síru obsahující sloučeniny, (ii) fosfor obsahující sloučeniny fosfinátového, fosfonátového a fosfodiesterového typu a (iii) fosfor obsahující sloučeniny substituované skupinami obsahujícími dusík nebo síru. Důraz bude kladen jednak na potenci ale i selektivitu inhibitorů vůči BHMT a příbuzným enzymům methionin syntháze a cystathionin beta-synthetáze. V úvahu budeme brát i potencionální metabolickou stabilitu látek. Nejslibnějšíinhibitory by měly být farmakologicky testovány za účelem studia role BHMT in vivo.
Scientific branches
Completed project evaluation
Provider evaluation
U - Uspěl podle zadání (s publikovanými či patentovanými výsledky atd.)
Project results evaluation
We synthesized and characterized a series of new inhibitors of human BHMT. The most potent inhibitors were used to study intrinsic fluorescence of BHMT and tested in mice in vivo. We confirmed the role of BHMT in the metabolism of sulfur amino acids.
Solution timeline
Realization period - beginning
Jan 1, 2003
Realization period - end
Jan 1, 2005
Project status
U - Finished project
Latest support payment
—
Data delivery to CEP
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data delivery code
CEP06-AV0-IA-U/04:2
Data delivery date
Sep 26, 2007
Finance
Total approved costs
2,825 thou. CZK
Public financial support
1,629 thou. CZK
Other public sources
0 thou. CZK
Non public and foreign sources
0 thou. CZK
Basic information
Recognised costs
2 825 CZK thou.
Public support
1 629 CZK thou.
57%
Provider
Academy of Sciences of the Czech Republic
CEP
CC - Organic chemistry
Solution period
01. 01. 2003 - 01. 01. 2005