HMG Co A reductase- 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is an important control site in cholesterol biosynthesis, this enzyme catalyzes the formation of Mevalonate, the committed step in cholesterol biosynthesis. HMG-CoA reductase is an integral membrane protein in the endoplasmic reticulum and spans the membrane. The active site for this enzyme is found on the cytosolic side of the membrane.
The enzyme catalyzes the irreversible step,
Regulation of HMG co A reductase/ cholesterol Biosynthesis- HMG CoA reductase is controlled in multiple ways:
This regulation is mediated primarily by changes in the amount and activity of 3-hydroxy-3-methylglutaryl CoA reductase.
A) Regulation of enzyme activity-
1) Feed back inhibition -HMG-CoA reductase in liver is inhibited by Mevalonate, the immediate product of the pathway, and by cholesterol, the main product. The rate of cholesterol formation is highly responsive to the cellular level of cholesterol.
2) Covalent modification Insulin or thyroid hormone increases HMG-CoA reductase activity, whereas glucagon or glucocorticoids decrease it. Activity is reversibly modified by phosphorylation-dephosphorylation mechanisms, some of which may be cAMP-dependent and therefore immediately responsive to glucagon. Phosphorylation decreases the activity of the reductase. This enzyme, like acetyl CoA carboxylase(which catalyzes the committed step in fatty acid synthesis, is switched off by an AMP-activated protein kinase. Thus, cholesterol synthesis ceases when the ATP level is low. (Insulin causes dephosphorylation, while glucagon causes phosphorylation).
3) Effect of statins-Becausethe enzyme HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis,this enzyme is the target for many cholesterol lowering drugs. Statins act by inhibiting HMG-CoA reductase and up-regulating LDL receptor activity. Examples currently in use include atorvastatin, simvastatin, fluvastatin, and pravastatin.
B) Regulation of concentration of HMG Co A reductase- The concentration of HMG Co A Reductase is regulated by three main mechanisms-
i)The rate of synthesis of reductase mRNA(Transcription ) – Transcription of HMG Co A reductase gene is controlled by the sterol regulatory element binding protein (SREBP).
SREBPs are a family of proteins that regulate the transcription of a range of genes involved in the cellular uptake and metabolism of cholesterol and other lipids. This transcription factor binds to a short DNA sequence called the sterol regulatory element(SRE) on the 5’ side of the reductase gene. In its inactive state, the SREBP is anchored to the endoplasmic reticulum or nuclear membrane. When cholesterol levels fall, the protein is released from its association with the membrane by two specific proteolytic cleavages. The released protein migrates to the nucleus and binds the SRE of the HMG-CoA reductase gene, as well as several other genes in the cholesterol biosynthetic pathway, to enhance transcription.Low concentrations of cholesterol increase the level of mRNA for HMG-CoA reductase, whereas high concentrations of cholesterol decrease the mRNA level.
When cholesterol levels rise, the proteolytic release of the SREBP is blocked, and the SREBP in the nucleus is rapidly degraded. These two events halt the transcription of the genes of the cholesterol biosynthetic pathways. It is feed back regulation.Dietary cholesterol also decreases the endogenous cholesterol synthesis. However, it is only hepatic synthesis that is inhibited by dietary cholesterol. .
ii)The rate of translation of reductase mRNA -is inhibited by non sterol metabolites derived from Mevalonate as well as by dietary cholesterol. Reverse occurs when Mevalonate concentration is low, hence translation is enhanced and amount ofHMG Co A reductase is increased.
iii) The degradation of the reductase is stringently controlled. In response to increasing concentrations of sterols such as cholesterol, the enzyme becomes more susceptible to proteolysis. A combination of these three regulatory devices can regulate the amount of enzyme over a 200-fold range.
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