The advanced glycation end product-lowering agent ALT-711 is a low-affinity inhibitor of thiamine diphosphokinase

Krautwald, Martina, Leech, Dale, Horne, Stacey, Steele, Megan L., Forbes, Josephine, Rahmadi, Anton, Griffith, Renate and Muench, Gerald (2011) The advanced glycation end product-lowering agent ALT-711 is a low-affinity inhibitor of thiamine diphosphokinase. Rejuvenation Research, 14 4: 383-391. doi:10.1089/rej.2010.1143


Author Krautwald, Martina
Leech, Dale
Horne, Stacey
Steele, Megan L.
Forbes, Josephine
Rahmadi, Anton
Griffith, Renate
Muench, Gerald
Title The advanced glycation end product-lowering agent ALT-711 is a low-affinity inhibitor of thiamine diphosphokinase
Journal name Rejuvenation Research   Check publisher's open access policy
ISSN 1549-1684
1557-8577
Publication date 2011-08-01
Year available 2011
Sub-type Article (original research)
DOI 10.1089/rej.2010.1143
Open Access Status Not Open Access
Volume 14
Issue 4
Start page 383
End page 391
Total pages 9
Place of publication New Rochelle, NY United States
Publisher Mary Ann Liebert, Inc. Publishers
Language eng
Formatted abstract
Advanced glycation end products (AGEs) are involved in age-related diseases, including the complications of diabetes and chronic renal impairment with arterial stiffening. Alagebrium chloride (ALT-711) is an AGE-lowering agent with beneficial effects in renal structural and functional parameters in diabetes, decreased diabetes-accelerated atherosclerosis, and age-related myocardial stiffening. ALT-711 exhibits a structural homology to thiamine, and it was suggested to interfere with thiamine metabolism. Thiamine is converted to thiamine diphosphate (TDP) by thiamine diphosphokinase (TDPK). TDP is a cofactor for pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and transketolase. A decreased activity of these enzymes due to TDP deficiency results in disorders such as beriberi and Wernicke-Korsakoff syndrome. Therefore, we investigated whether ALT-711 is an inhibitor of TDPK. Molecular modeling studies showed that ALT-711 fits into the thiamine-binding pocket of TDPK, and there are three interactions between the thiazolium ring and the enzyme, as well as parallel stacking between the phenyl ring and the indole ring of Trp222B. Enzyme kinetic experiments also showed that ALT-711 dose-dependently decreased TDPK activity with Kis, calculated by different experiments and fitting models ranging from 0.88 to 1.09mM. Fitting of the kinetic data favored mixed-mode inhibition with a major role for competitive inhibition. In summary, our results suggest that ALT-711 is a low-affinity inhibitor of TDPK, but is unlikely to interfere with thiamine metabolism at therapeutic concentrations. However, when new AGE-crosslink breakers based on thiamine are designed, care should be taken that they do not act as more potent competitive inhibitors than ALT-711.
Keyword Geriatrics & Gerontology
Geriatrics & Gerontology
GERIATRICS & GERONTOLOGY
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Mater Research Institute-UQ (MRI-UQ)
 
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