Chem*4520 Metabolic Processes

Fall Semester 2000

Modified August 2000

schematic view of the enzyme citrate synthase,
with bound acetyl-CoA analog in green

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Lecture 19:

Sterol utilization.

Wed Oct 25Voet , Chapter 23, pp. 698-704.
Mathews, Van Holde: Chapter 18, pp.631-637; Chapter 19, 691-696.
Stryer:Chapter 27, pp.696-707

Plasma lipoproteins

Plasma lipoproteins are complexes formed by proteins which act as carriers of lipids in the blood stream. There are several different classes having distinct protein components recognized by specific receptors at their intended destinations:

Chylomicrons Chylomicrons are produced by intestinal cells to carry dietary triacylglycerol and cholesterol, and are taken up by liver.
VLDL/LDLVery Low Density Lipoproteins) carry triacylglycerol and cholesterol esters to peripheral tissues. The lipid content determines the density of the complex. As the triacylglycerol is shed, the density increases, and the remnants become LDL, low density lipoprotein (so-called "bad" cholesterol).
HDLHigh Density Lipoproteins act to scavenge surplus cholesterol from peripheral tissues and bring it back to the liver (so-called "good" cholesterol).

LDL and HDL

Regulation acts primarily on HMG-CoA reductase

Repression (reduced level of expression) due to binding of chylomicrons by the liver

Inhibition of activity by feedback effects from mevalonolactone and by LDL binding to LDL receptors in liver.

hmg reductase regulationThe reductase is phosphorylated and inactivated by AMP dependent protein kinase, so synthesis rates are energy sensitive. Mutation of Ser 871 causes loss of regulation by LDL feedback, indicating that LDL controls the phosphorylation in some way.

Although VLDLs are secreted by liver for uptake by peripheral tissues, there are LDL receptors on the liver as well, which allow the liver to monitor the levels of circulating cholesterol. LDL receptors act by endocytosis to transport bound LDL back into the liver. The processing of the LDL inside the liver redirects some cholesterol back to the endoplasmic reticulum, and this stream of cholesterol provides a signal for negative regulation of HMG-CoA reductase.

mevalonolactoneSome mevalonate may spontaneously cyclize to form the cyclic ester, mevalonolactone. Mevalonolactone acts as a competitive inhibitor of HMG-CoA reductase.

Increased levels of dietary cholesterol repress the expression of HMG-CoA reductase. However excessive levels of dietary cholesterol repress expression of LDL receptor also, and this has the undesired effect of cutting off the parallel negative signal acting via phosphorylation. A similar loss of control is seen in familial hypercholesterolemia, in which LDL receptor expression is reduced due to genetic factors.

Drugs may be used to reduce HMG-CoA activity in such case. Lovastatin, a fungal metabolite, is an analog of mevalonate, and acts as a competitive inhibitor of HMG-CoA reductase.


Conversion to bile acids allows removal of cholesterol from the system

cholateBile acids are synthesized in liver, and involve a variety of monooxygenase enzymes which act as hydroxylases and in C-C bond breakage via successive oxidations.

The remarkable feature of monoxygenase enzymes is their ability to act at saturated carbon at locations lacking any kind of chemical activation. The regio- and stereospecificity of these enzymes is entirely due to relative orientation of bound substrate and the O2 binding site, usually heme.

Two forms of bile acid are common in humans: cholate with 12-OH and chenodeoxycholate, lacking 12-OH.

After C-24 is oxidized to carboxylate, it is activated as a CoA derivative, then conjugated to glycine or taurine, an oxidation product of cysteamine.

These modifications substantially increase the polarity and acidity of cholate derivatives, making them effective emulsifying agents. (Deoxycholate is often used as a mild detergent for protein extraction). Bile salts are secreted into the intestine where they facilitate uptake of dietary fat. Much of the bile salts produced are recycled, but about 1 g per day may escape the body by this route. One treatment for excessive body burden of cholesterol is to ingest ion exchange resins which bind bile salts, increasing the rate of loss.


Oxidative cleavage between C-20 and C-22 of cholesterol leads to steroid hormones

pregnenoloneSteroid hormone production takes up a tiny fraction of the total body cholesterol, but is important because of the physiological function of the hormones. These reactions occur primarily in adrenal glands and gonads. Successive monooxygenase cleavages break the C-20 - C-22 bond, leaving a carbonyl at C-20.

This leaves a C21 compound, pregnenolone, which may accurately be described as the mother of all steroids (the C21 steroid carbon skeleton is given the name pregnane).


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