High-affinity binding of fatty acyl-CoAs and peroxisome proliferator-CoA esters to glutathione S-transferases -: Effect on enzymatic activity

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dc.contributor.authorSilva, C
dc.contributor.authorLoyola, G
dc.contributor.authorValenzuela, R
dc.contributor.authorGarcía-Huidobro, T
dc.contributor.authorMonasterio, O
dc.contributor.authorBronfman, M
dc.date.accessioned2025-01-21T01:31:50Z
dc.date.available2025-01-21T01:31:50Z
dc.date.issued1999
dc.description.abstractAcyl-CoAs an present at high concentrations within the cell, yet are strongly buffered by specific binding proteins in order to maintain a low intracellular unbound acyl-CoA concentration, compatible with their metabolic role? their importance in cell signaling, and as protection from their detergent properties. This intracellular regulation may be disrupted by nonmetabolizables acyl-CoA esters of xenobiotics, such as peroxisome proliferators, which are formed at relatively high concentration within the liver cell. The low molecular mass acyl-CoA binding protein (ACBP) and fatty acyl-CoA binding protein (FABP) have been proposed as the buffering system for fatty acyl-CoAs. Whether these proteins also bind xenobiotic-CoA is not known. Here we have identified new liver cytosolic fatty acyl-CoA and xenobiotic-CoA binding sites as glutathione S-transferase (GST), using fluorescent polarization and a acyl-etheno-CoA derivative of the peroxisome proliferator nafenopin as ligand. Rat liver GST and human liver recombinant GSTA1-1, GSTP1-1 and GSTM1-1 were used. Only class alpha rat liver GST and human GSTA1-1 bind xenobiotic-CoAs and fatty acyl-CoAs, with K-d values ranging from 200 nM to 5 mu M. One mol of acyl-CoA is bound per mol of dimeric enzyme, and no metabolization or hydrolysis was observed. Binding results in strong inhibition of rat Liver GST and human recombinant GSTA1-1 (IC50 at the nanomolar level for palmitoyl-CoA) but not GSTP1-1 and GSTM1-1. Acyl-CoAs do not interact with the GSTA1-1 substrate binding site, but probably with a different domain. Results suggest that under increased acyl-CoA concentration, as occurs after exposure to peroxisome proliferators, acyl-CoA binding to the abundant class alpha GSTs may result in strong inhibition of xenobiotic detoxification, Analysis of the binding properties of GSTs and other acyl-CoA binding proteins suggest that under increased acyl-CoA concentration GSTs would be responsible for xenobiotic-CoA binding whereas ACBP would preferentially bind fatty acyl-CoAs.
dc.fuente.origenWOS
dc.identifier.issn0014-2956
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/97152
dc.identifier.wosidWOS:000083835000015
dc.issue.numero1
dc.language.isoen
dc.pagina.final150
dc.pagina.inicio143
dc.revistaEuropean journal of biochemistry
dc.rightsacceso restringido
dc.subjectglutathione transferase
dc.subjectacyl-CoA binding
dc.subjectperoxisome proliferators
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleHigh-affinity binding of fatty acyl-CoAs and peroxisome proliferator-CoA esters to glutathione S-transferases -: Effect on enzymatic activity
dc.typeartículo
dc.volumen266
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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