Reductase kinase

This enzyme [EC 2.7.1.109], also known simply as reductase kinase, catalyzes the reaction of ATP with the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (NADPH) producing ADP and the phosphorylated form of the reductase. This phosphorylation inactivates the reductase. Histones can substitute for the reductase as substrates. 

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. 

HMG-CoA reductase is phosphorylated in a reaction catalyzed by HMG-CoA reductase kinase. 

The reductase kinase (RK), which phosphorylates (and inhibits) HMG-CoA reductase, is itself controlled through phosphorylation (activated) by reductase kinase kinase (RKK). There... 

Figure 6.5 Regulation of HMG-CoA reductase. HMG-CoA reductase is active in the dephospho-rylated state phosphorylation (inhibition) is catalysed by reductase kinase, an enzyme whose activity is also regulated by phosphorylation by reductase kinase kinase. Hormones such as glucagon and adrenalin (epinephrine) negatively affect cholesterol biosynthesis by increasing the activity of the inhibitor of phosphoprotein phosphatase-1, PPI-1, (by raising cAMP levels) and so reducing the activation of HMG-CoA reductase. Conversely, insulin stimulates the removal of phosphates (and lowers cAMP levels), and thereby activates HMG-CoA reductase activity. Additional regulation of HMG-CoA reductase occurs through an inhibition of synthesis of the enzyme by elevation in intracellular cholesterol levels.

Douglas, P., Moorhead, G., Hong, Y., Morrice, N., and MacKintosh, C., 1998, Purification of a nitrate reductase kinase from Spinaceaa oleracea leaves, and its identification as a calmodulin-domain protein kinase, Planta 206 43511442. 

Dale, S., Arro, M., Becerra, B., Morrice, N.G., Boronat, A., Hardie, D.G. and Ferrer A. (1995) Bacterial expression of the catalytic domain of 3-hydroxy-3-methylglutaryl-CoA reductase (isoform hmgrl) from Arabidopsis thaliana and its inactivation by phosphorylation at ser577 by Brassica oleracea 3-hydroxy-3-methylglutaryl-CoA reductase kinase. Bur.. Biochem., 233,506-13. 

MacKintosh, R.W., Davies, S.P., Clarke, PR., Weekes, J., Gillespie, J.G., Gibb, B.J. and Hardie, D.G. (1992) Evidence for a protein kinase cascade in higher plants 3-hydroxy-3-methylglutaryl-CoA reductase kinase. Eur. ]. Biochem., 209,923-31. 

Regulation of HMG-CoA reductase by phosphorylation-dephosphorylation phosphorylation leads to loss of catalytic activity. The two phosphatases are identical and are inhibited by an inhibitor protein that is more active when phosphorylated by a cAMP-dependent protein kinase. Phosphorylation of reductase kinase is not cAMP-dependent. 

The activities of HMG-CoA reductase kinase [152] and HMG-CoA reductase phosphatase [194] rapidly respond to hormones and hormonal second messengers in a manner consistent with the observed changes in HMG-CoA reductase activity. 

AMP-dependent protein kinase is an enzyme that binds AMP and can phosphorylate both acetyl-CoA carboxylase and HMG-CoA reductase kinase. In each case, the enzyme is inactivated. 

Beg, Z.H. Stonik, J.A. Reversible inactivation of 3-hydroxy-3-metbylglutar-yl coenzyme A reductase reductase kinase and mevalonate kinase are separate enzymes. Biochem. Biophys. Res. Commun., 108, 559-566 (1982)... 

Ferrer, A. Hegardt, EG. Phosphorylation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase. Arch. Biochem. Biophys., 230, 227-237 (1984)... 

Carling, D. Clarke, P.R. Hardie, D.G. Adenosine monophosphate-activated protein kinase hydroxymethylglutaryl-CoA reductase kinase. Methods En-zymoL, 200, 362-371 (1991)... 

Ball, K.L. Dale, S. Weekes, J. Hardie, D.G. Biochemical characterization of two forms of 3-hydroxy-3-methylglutaryl-CoA reductase kinase from cauliflower (Brassica oleracia). Eur. J. Biochem., 219, 743-750 (1994)... 

Beg, Z.H. Stonik, J.A. Brewer, B. Characterization and regulation of reductase kinase, a protein kinase that modulates the enzymic activity of 3-hy-droxy-3-methylglutaryl-coenzyme A reductase. Proc. Natl. Acad. Sci. USA, 76, 4375-4379 (1979)... 

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