Hydroxymethylglutaryl-CoA reductase

Synthesis of endogenic cholesterol is also controlled by exogenous cholesterol supplied in food the more dietary cholesterol is digested, the less endogenic cho-lesterol is produced in the liveV. Exogenous cholesterol inhibits the activity of hydroxymethylglutaryl-CoA reductase and the cyclization of squalene to lanosterol. 

Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. The Journal of Biological Chemistry, 274, 37161-37168. 

The recent work on the stereospecificity of hydroxymethylglutaryl-CoA reductase 71 76> is particularly interesting. The reaction catalyzed by this enzyme is an important early step in the synthesis of terpenoids and steroids. The yeast enzyme and the liver enzyme both have the same stereospecificities. The overall reaction catalyzed is the reduction of hydroxymethylglutaryl CoA to mevalonic acid, as shown in scheme 1. Two molecules of NADPH are used to reduce the Co-A-bound carboxyl... 

The true biological function of liver mevaldic reductase is not clear. It is not thought to be involved in cholesterol synthesis, and because of the difference in its stereospecificity for the substrate, it is thought to be only a distant relative of the hydroxymethylglutaryl CoA reductases. But all of these enzymes have the same A stereospecifidty for the pyridine nucleotide. 

It should be noted, in this connection, that there are pyridine nucleotide dehydrogenases which catalyze redox reactions which must occur in two steps. Hydroxymethylglutaryl CoA reductase (discussed on p. 51) is one example. Another is uridine diphosphate-glucose dehydrogenase, which catalyzes the oxidation of the C—6 of the glucose (i.e., a primary alcohol) to a carboxyl group. In both cases, there are two molecules of pyridine nucleotide required, and the overall reactions are essentially irreversible. The former enzyme, with A stereospecificity for the pyridine nucleotide, catalyzes the reduction of an acyl-CoA group... 

ATP-citrate lyase Fatty acid synthase Lipoprotein lipase Hydroxymethylglutaryl-CoA reductase Phosphorylation... 

Hydroxymethylglutaryl-CoA reductase Acetyl-CoA carboxylase Triacylglycerol lipase... 

Although sterols like cholesterol are not synthesized de novo by parasitic flatworms, they do possess an active mevalonate pathway (Fig. 20.3) (reviewed in Coppens and Courtoy, 1996). This pathway has been studied in 5. mansoni, and all available evidence indicates that it is similar to the lipid metabolism seen in F. hepatica. The mevalonate pathway was shown to be used by 5. mansoni for the synthesis of dolichols for protein glycosylation, of quinones as electron transporters in the respiratory chain and of farnesyl and geranylgeranyl pyrophosphates as substrates for the isopreny-lation of proteins (Chen and Bennett, 1993 Foster et a/., 1993). A key enzyme in the mevalonate pathway is 3-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) and it was shown that the schistosomal enzyme differs from the mammalian type, both structurally and in its regulatory properties (Rajkovic et ai, 1989 Chen et at., 1991). Farnesyl pyrophosphate plays a key role in the mevalonate pathway as it is the last common substrate for the synthesis of all end products (Fig. 20.3). As mentioned already, the branch leading from farnesyl pyrophosphate via squalene to cholesterol is not operative in parasitic flatworms, whereas the other branches are active, at least in S. mansoni and probably also in F. hepatica and FI. diminuta. 

Cell line selection is one of the traditional and effective approaches to enhancing metabolite accumulation, and biochemical studies provide the fundamental information for the intentional regulation of secondary metabolism in plant cells. In a carrot suspension culture regulated by 2,4-dichlorophenoxyace-tic acid, Ozeki et al. [7] found that there was a correlation between anthocyanin synthesis and morphological differentiation for somatic embryogenesis they also demonstrated the induction and repression of phenylalanine ammonia lyase (PAL) and chalcone synthase correlated with formation of the respective mRNAs. Two biosynthetic enzymes, i. e., PAL and 3-hydroxymethylglutaryl-CoA reductase, were also related with shikonin formation in Lithospermum erythro-rhizon cultures [8]. 

Glucagon decreases cholesterol synthesis in isolated hepatocytes [131,132] apparently because it reduces the fraction of hydroxymethylglutaryl-CoA reductase in the active form [131,132], This is due to an increase in reductase kinase activity [133], However, there is no evidence that cAMP-dependent protein kinase phos-phorylates either the reductase, reductase kinase or reductase kinase kinase [134], It has been proposed that the phosphorylation state of these enzymes is indirectly controlled through changes in the activity of protein phosphatase I [132,134], This phosphatase can dephosphorylate and activate the reductase [134,135] and its activity can be controlled by a heat stable inhibitor (inhibitor 1), the activity of which is increased by cAMP-dependent phosphorylation [136,137], Since the phosphorylated forms of acetyl-CoA carboxylase, ATP-citrate lyase, pyruvate kinase, phos-phorylase, phosphorylase kinase and glycogen synthase are also substrates for protein phosphatase I [135], this mechanism could also contribute to their phosphorylation by glucagon. 

Glucagon affects hepatic lipid metabolism. A major effect is inhibition of fatty acid synthesis, which is mainly due to the phosphorylation and inhibition of acetyl-GoA carboxylase by cAMP-dependent protein kinase. ATP-citrate lyase is also phosphorylated, but it is unclear that this is involved in the inhibition of lipogene-sis. Glucagon also inhibits cholesterol synthesis apparently due to a decrease in the activity of hydroxymethylglutaryl-CoA reductase. This is thought to result from a decrease in the activity of protein phosphatase I due to the increased phosphorylation and activation of a heat stable inhibitor by cAMP-dependent protein kinase. This mechanism could also contribute to the effects of glucagon on other hepatic enzymes. 

NADPH is the electron donor in a reaction catalyzed by hydroxymethylglutaryl-CoA reductase, followed by two phosphorylation reactions involving ATP and two specific kinases, and an ATP-dependent decarboxylation. The process is summarized in Example 13.15 and Fig. 13-21. 

Narita, J.O. and Gruissem, W. (1989) Tomato hydroxymethylglutaryl-CoA reductase is required early in fruit development but not during ripening. Plant Cell, 1, 181-90. 

Rate-limiting step The enzyme hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) catalyzes an early rate-limiting step in cholesterol biosynthesis. 

---