scholarly journals Characterization of Apo‐Form Selective Inhibition of Indoleamine 2,3‐Dioxygenase**

ChemBioChem ◽  
2020 ◽  
Author(s):  
Rodrigo F. Ortiz‐Meoz ◽  
Liping Wang ◽  
Rosalie Matico ◽  
Anna Rutkowska‐Klute ◽  
Martha De la Rosa ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Indoleamine 2,3 Dioxygenase

scholarly journals Characterization of apo-form selective inhibition of indoleamine 2,3-dioxygenase

2018 ◽  
Author(s):  
Rodrigo Ortiz-Meoz ◽  
Liping Wang ◽  
Rosalie Matico ◽  
Anna Rutkowska ◽  
Martha De la Rosa ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Kynurenine Pathway ◽  
Cellular Systems ◽  
Inhibition Mechanism ◽  
Pharmacokinetic Parameters ◽  
Indoleamine 2,3 Dioxygenase ◽  
Disease States ◽  
Rate Limiting Step

ABSTRACTIndoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of established and novel IDO1 inhibitors remains of great interest. Comparison of a newly-developed IDO1 inhibitor (GSK5628) to the existing best-in-class compound, epacadostat (Incyte), allows us to report on a unique inhibition mechanism for IDO1. Here, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1) while epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition may help design superior inhibitors or may confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.

Characterization of class II fumarase from Schistosoma mansoni provides the molecular basis for selective inhibition

2021 ◽  
Vol 175 ◽  
pp. 406-421
Author(s):  
Iara Aimê Cardoso ◽  
Aline Kusumota Luiz de Souza ◽  
Adam Muslem George Burgess ◽  
Iain Wyllie Chalmers ◽  
Karl Francis Hoffmann ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Molecular Basis ◽  
Selective Inhibition ◽  
Class Ii

scholarly journals Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants

2018 ◽  
Vol 61 (22) ◽  
pp. 10000-10016 ◽  
Author(s):  
Martin Marek ◽  
Tajith B. Shaik ◽  
Tino Heimburg ◽  
Alokta Chakrabarti ◽  
Julien Lancelot ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Active Site ◽  
Selective Inhibition ◽  
Histone Deacetylase 8

In Vitro Cellular Muscle Calcium Metabolism. Characterization of Effects of 1,25-Dihydroxy-Vitamin D3 and 25-Hydroxy-Vitamin D3

1985 ◽  
Vol 40 (1-2) ◽  
pp. 102-108 ◽  
Author(s):  
Ana R. de Boland ◽  
Ricardo Boland
Keyword(s):  
Vitamin D ◽  
Vitamin D3 ◽  
Plasma Membranes ◽  
Selective Inhibition ◽  
Ruthenium Red ◽  
Ca Uptake ◽  
25 Hydroxy Vitamin D ◽  
Muscle Calcium

Cultures of vitamin D-deficient chick soleus muscle and 12 day-old chick embryo myoblasts were used to characterize the effects of 1,25-dihydroxy-vitamin D3 and 25-hydroxy-vitamin D3 on muscle cell Ca metabolism. Physiological amounts of both sterols increased the rate and extent of 45Ca uptake by cultures. However. 1.25(OH)2D3 was significantly more effective than 25 OHD3. The greater potency of 1,25(OH)2D3 to increase Ca uptake could be shown after various treatment intervals of cultures and using a wide concentration range of both derivatives. Information about Ca pools affected by vitamin D3 metabolites was obtained through kinetic analysis of Ca efflux in cultured myoblasts. Cytoplasmic and mitochondria Ca pools were identified on the basis of their half-times of desaturation and by selective inhibition of plasma membrane and mitochondrial Ca transport with LaCl3 and Ruthenium Red, respectively. The data suggests that 1,25(OH)2D3 acts on muscle cellular Ca by increasing Ca efflux and influx through mitochondrial and plasma membranes whereas the predominant effect of 25 OHD3 is to increase Ca influx into mitochondria.

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