Brain pyruvate and 2-oxoglutarate dehydrogenase complexes are mitochondrial targets of the CoA ester of the Refsum disease marker phytanic acid.
Pyruvate and 2-oxoglutarate dehydrogenase complexes are strongly inhibited by phytanoyl-CoA (IC(50) approximately 10(-6)-10(-7) M). Palmitoyl-CoA is 10-fold less potent. Phytanic or palmitic acids have no inhibitory effect up to 0.3 mM. At the substrate saturation, the acyl-CoA's affect the first and second enzymatic components of the 2-oxoglutarate dehydrogenase complex, while the third component is inhibited only at a low saturation with its substrate dihydrolipoamide. Thus, key regulatory branch points of mitochondrial metabolism are targets of a cellular derivative of phytanic acid. Decreased activity of the complexes might therefore contribute to neurological symptoms upon accumulation of phytanic acid in Refsum disease.
Bunik
Victoria I
VI
School of Bioinformatics and Bioengineering and AN Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Russian Federation. bunik@belozersky.msu.ru
Raddatz
Günter
G
Wanders
Ronald J A
RJ
Reiser
Georg
G
D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D003065:Coenzyme A / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D008958:Models, Molecular; D010831:Phytanic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D051381:Rats; D012035:Refsum Disease / Q000201:enzymology / Q000378:metabolism*
D015415:Biomarkers; C089917:phytanoyl-coenzyme A; D010831:Phytanic Acid; D019289:Pyruvic Acid; D007655:Ketoglutarate Dehydrogenase Complex; D003065:Coenzyme A