membrane lipids & cholesterol metabolism...the complex regulation of cholesterol biosynthesis...

Membrane Lipids & Cholesterol Metabolism

Learning Objectives

1. Know the synthesis of triacylglycerols.

2. How Are Acylglycerols and Compound Lipids Produced?

3. What cause the Respiratory Distress Syndrome and Tay-Sachs Disease ?

4. How is cholesterol synthesized ?

5. Understand the regulation of cholesterol metabolism ?

Phosphatidate Is a Common Intermediate in the Synthesis of Phospholipids and

Triacylglycerols

These acylations are catalyzed by glycerol phosphate acyltransferase. In most phosphatidates, the fatty acyl chain attached to the C-1 atom is saturated, whereas the one attached to the C-2 atom is unsaturated.

DA glycerol is acylated to a triacylglycerol in a reaction that is catalyzed by diglyceride acyltransferase. The liver is the primary site of triacylglycerol synthesis. From the liver, the triacylglycerols are transported to the muscles for energy conversion or to the adipocytes for storage.

How Are Acylglycerols and Compound Lipids Produced?

phosphatidyl choline

In mammals, a pathway that utilizes choline obtained from the diet ends in the synthesis of the phosphatidyl choline the most common phospholipid in these organisms. In this case, choline is activated in a series of reactions analogous to those in the activation of ethanolamine. The liver possesses an enzyme, phosphatidyl ethanolamine methyltransferase, that synthesizes phosphatidyl choline from phosphatidyl ethanolamine.

Sphingolipids Are Synthesized from Ceramide

Respiratory Distress Syndrome and Tay-Sachs Disease Result from the

Disruption of Lipid Metabolism

Respiratory distress syndrome is a pathological condition resulting

from a failure in the biosynthetic pathway for dipalmitoyl phosphatidyl choline. This phospholipid, in conjunction with specific proteins and other phospholipids, is found in the extracellular fluid that surrounds the alveoli of the lung, where it decreases the surface tension of the fluid to prevent lung collapse at the end of the expiration phase of breathing.

Premature infants may suffer from respiratory distress syndrome because their immature lungs do not synthesize enough dipalmitoyl phosphatidyl choline ( Surfactant ).

Tay-Sachs disease

It is caused by a failure of lipid degradation: an inability to degrade gangliosides. Gangliosides are found in highest concentration in the nervous system, particularly in gray matter, where they constitute 6% of the lipids.

Gangliosides are normally degraded inside lysosomes by the sequential removal of their terminal sugars but, in Tay-Sachs disease, this degradation does not occur. As a consequence, neurons become enormously swollen with lipid-filled lysosomes . An affected infant displays weakness and retarded psychomotor skills before 1 year of age. The child is demented and blind by age 2 and usually dead before age 3.

Tay-Sachs disease can be diagnosed in the course of fetal development. Amniotic fluid is obtained by amniocentesis and assayed for β-N-acetylhexosaminidase activity.

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Cholesterol

"Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted an almost hypnotic fascination for scientists from the most diverse areas of science and medicine.

The very property that makes it useful in cell membranes, namely its absolute insolubility in water, also makes it lethal."

-Michael Brown and Joseph Goldstein

Nobel Lectures (1985)

Cholesterol Carbon Numbering

• The synthesis of mevalonate is the committed step in cholesterol formation. The enzyme catalyzing this irreversible step,

3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase), is an important control site in cholesterol biosynthesis.

HMG-CoA reductase is an integral membrane protein in the endoplasmic reticulum

How Is Cholesterol Produced?

Fates of 3-Hydroxy-3-Methylglutaryl CoA

Bile Salts

• (1ry.bile salt)

Deoxycholic acid (secondary bile acid)

Steroid Hormones

Vitamin D Is Derived from Cholesterol by the Ring-Splitting Activity of Light

Cholesterol is also the precursor of vitamin D, which plays an essential role in the control of calcium and phosphorus metabolism.

7-Dehydrocholesterol (provitamin D3) is photolyzed by the ultraviolet light of sunlight to provitamin D3,which spontaneously isomerizes to vitamin D3

Vitamin D Synthesis

The Complex Regulation of Cholesterol Biosynthesis Takes Place at Several

Levels

Cholesterol can be obtained from the diet or it can be synthesized de novo. An adult on a low-cholesterol diet typically synthesizes about 800 mg of cholesterol per day. The liver is the major site of cholesterol synthesis in mammals, although the intestine also forms significant amounts. The rate of cholesterol formation by these organs is highly responsive to the cellular level of cholesterol. This feedback regulation is mediated primarily by changes in the amount and activity of

3-hydroxy-3-methylglutaryl CoA reductase.

The Absence of the LDL Receptor Leads to Hypercholesteremia and

Atherosclerosis

The results of Brown and Goldstein's pioneering studies of familial hypercholesterolemia revealed the physiologic importance of the LDL receptor. The total concentration of cholesterol and LDL in the plasma is markedly elevated in this genetic disorder, which results from a mutation at a single autosomal locus. The cholesterol level in the plasma of homozygotes is typically 680 mg /dl, compared with 300 mg /dl in heterozygotes.

Lovastatin A Competitive Inhibitor of HMG-CoA Reductase. The part of the structure that resembles the 3-hydroxy-3-methylglutaryl moiety is shown in red.

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