Studies on the regulation of glycoprotein biosynthesis. An investigation of the rate-limiting steps of dolichyl phosphate biosynthesis.
The possible role of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase (the rate-controlling enzyme of cholesterol biosynthesis) in regulating the rate of dolichyl phosphate biosynthesis in rat liver was investigated. Rats were either fasted 48 h or fed diets supplemented with the drug cholestyramine. The activity of HMG-CoA reductase was 5000-fold greater in liver from cholestyramine-fed rats as compared to fasted rats. The activity of dolichyl phosphate synthetase, the prenyl transferase responsible for the biosynthesis of dolichyl phosphate from farnesyl pyrophosphate and isopentenyl pyrophosphate, was similar in both nutritional conditions and was markedly less active than HMG-CoA reductase even in the fasted state. Acetate incorporation into cholesterol was 2200-fold greater in liver slices from cholestyramine-fed rats as compared to fasted rats. By contrast, acetate incorporation into dolichyl phosphate was only 6-fold higher. Further studies suggested that the levels of farnesyl pyrophosphate and isopentenyl pyrophosphate are several hundred-fold greater in liver from cholestyramine-treated rats. From these results, it is concluded that the rate of dolichyl phosphate biosynthesis in rat liver is not regulated by the activity of HMG-CoA reductase but is probably regulated at the level of dolichyl phosphate synthetase.
D000085:Acetates / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D002792:Cholestyramine Resin / Q000494:pharmacology; D004122:Dimethylallyltranstransferase / Q000378:metabolism; D004288:Dolichol Phosphates / Q000096:biosynthesis*; D005204:Farnesol / Q000031:analogs & derivatives; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000378:metabolism; D006023:Glycoproteins / Q000096:biosynthesis*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011106:Polyisoprenyl Phosphates / Q000096:biosynthesis*; D051381:Rats
D000085:Acetates; D004288:Dolichol Phosphates; D006023:Glycoproteins; D011106:Polyisoprenyl Phosphates; D002792:Cholestyramine Resin; D005204:Farnesol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D004122:Dimethylallyltranstransferase; D013186:Farnesyl-Diphosphate Farnesyltransferase