Hydroxymethylglutaryl-CoA lyase

P-Hydroxy-P-methylglutaryl-CoA is split by hydroxymethylglutaryl-CoA lyase into acetyl-CoA and acetoacetate ... 

Hydroxymethylglutaryl-CoA lyase 4.1.3.4 3-Hydroxybutyrate dehydrogenase 1.1.1.30 Nonenzymatic reaction... 

Fructose bisphosphate aldolase— aldolase Hydroxymethylglutaryl-CoA lyase Hydroxymethylglutaryl-CoA synthase Citrate synthase ATP-citrate lyase... 

Figure 10-5. Intrahepatic metabolism of free fatty acids (FFA). CPT I, CPT II, carnitine palmitoyltransferase I, II, respectively LCFA, long-chain fatty acid VLDL, very low-density lipoprotein. 1, Long-chain acyl-CoA synthase 2, acetoacetyl-CoA thiolase 3, hydrox-ymethylglutaryl-CoA synthase 4, hydroxymethylglutaryl-CoA lyase 5, 3-hydroxybutyrate dehydrogenase 6, acetyl-CoA carboxylase 7, fatty acid synthase 8, glycerolphosphate acyltransferase Reprinted with permission from Girard et al. (1992).

Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. The mechanism of ketone body formation is one of those pathways that doesn t look like a very good way to do things. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. We could have had an enzyme that just hydrolyzed the acetoacetyl-CoA directly to acetoacetate, but no, it s got to be done in a more complicated fashion. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. 

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

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. 

Much of the endogenous lipid that is eventually used by peripheral tissues is transported in the form of water-soluble ketone bodies, the two most important being jS-hydroxybutyrate and acetoacetate. The metabolic pathway of ketone body formation and its relationship to cholesterol biosynthesis is shown in Fig. 4.10. Four enzymes are Involved in the formation of ketone bodies, namely acetyl-CoA transferase (also known as thiolase), hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), hydroxymethyl-glutaryl-CoA lyase (HMG-CoA lyase) and jS-hy-droxybutyrate dehydrogenase. Tbe last of these catalyses the interconversion of the two principal ketone bodies. All four enzymes are present in liver, the principal site of ketone body formation. Acyl-CoAs are unable to pass through the plasmalemma, and HMG-CoA lyase thus controls the release of ketone... 

The major pathway for the formation of MVA in yeast and mammalian systems is shown in Fig. 2. Acetyl-CoA and acetoacetyl-CoA are condensed by the enzyme hydroxymethylglutaryl-CoA (HMG-CoA) synthase (HMG-CoA acetoacetyl-CoA lyase, E.C. 4.1.3.5) to form 3-hydroxy-3-methylglu-taryl-CoA (HMG-CoA). In a two-step reduction, HMG-CoA is then reduced to MVA in a reaction catalyzed by the enzyme HMG-CoA reductase. In the first step of this reaction, the CoA hemithioacetal of mevaldic acid is formed. In the second step, this compound is reduced to MVA both steps require NADPH. Hydroxymethylglutaryl-CoA reductase is an important control point in the regulation of cholesterol biosynthesis in mammalian systems. The HMG-CoA reductase enzymes from yeast and mammalian liver have been purified to homogeneity, and some of their properties have been determined. This work is covered in detail in several reviews (Beytia and Porter, 1976 Rodwell et al., 1976 Kandutsch et al., 1978). 

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