Bioc 460 Spring 1999
Lecture 36 - Chapter 27

- Sphingolipids and Tay Sachs
- Cholesterol biosynthesis
- Metabolism of dietary fats

Ceramide is the precursor of sphingomyelin and gangliosides. Sphingolipids are derived from the condensation of palmitoyl CoA and serine which forms sphingosine. Sphingolipids are constituents of neuronal tissue. Sphingolipids with containing carbohydrate components such as glucose and galactose, are called gangliosides.

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Figure 27.6

Figure 27.7

Inherited genetic diseases effecting sphingolipid metabolism have been identified. The first such disease characterized is called Tay Sachs disease which results from a defect in the enzyme hexoseaminidase A. Complete absence of this enzymes results in the accumulation of the ganglioside GM2 which builds up in the brain and causes death by the age of 5 years old.

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Tay Sachs is recessive genetic disease which occurs at a higher carrier frequency in Americans of Jewish decent (3%), than in non-Jewish Americans (0.03%). Carriers contain one normal gene copy of hexoseaminidase A and one defective gene. A single gene copy is sufficient to protect carriers against the disease, however, offspring of two carriers have a 25% chance of inheriting Tay Sachs disease. Genetic screening can be used to identify carriers and for testing fetuses in utero. There is no treatment currently available for Tay Sachs disease and it is considered a terminal illness.

RLM 36.1

Do you think Tay Sachs disease will some day be treated using modern molecular genetics? How?

All 27 carbon atoms of cholesterol are derived from acetyl CoA. Squalene a C30 hydrocarbon is an intermediate in the cholesterol biosynthesis pathway. Radiosotope labeling experiments, and metabolic studies in bacteria, were used to elucidate the cholesterol biosynthetic pathway.

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The synthesis of mevalonate from 3-hydroxy-3-methyl-glutaryl CoA requires the enzyme HMG CoA Reductase which is the key regulated enzyme in the cholesterol biosynthetic pathway. Cholesterol biosynthesis takes place in the cytosol of liver cells and involves the sequential addition of 5C units (isopentenyl pyrophosphate) up to squalene (C30). This pathway consumes ATP and NADPH (we won't worry about the net reaction!).

Figure 27.11

Figure 27.12

Figure 27.13

Figure 27.15

Figure 27.16

Bile salts are highly effective biological detergents that solubilize dietary lipids in the small intestine. Bile salts are derived from cholesterol. One way to treat high serum cholesterol is to remove bile salts using oral dose resins. The decrease in intestinal bile salts stimulates the conversion of cholesterol to bile salts in the liver.

Figure 27.17

HMG CoA Reductase plays a key role in setting the rate of cholesterol synthesis in the liver. Cholesterol is derived from the diet and from de novo synthesis in the liver. Normally, when dietary sources of cholesterol are high, the enzyme is inhibited. HMG CoA reductase is controlled in four major ways:

1. HMG CoA reductase gene expression is regulated.
2. The rate of translation of HMG CoA reductase mRNA is regulated.
3. The HMG CoA reductase protein level is controlled by degradation.
4. Enzyme activity is inhibited by phosphorylation (AMP-activated protein kinase).

Cholesterol and triglycerides are carried in the blood by lipoprotein particles. These macromolecular aggregates solubilize hydrophobic lipids and provide cell targeting signals. Depending on the function, and protein+lipid components, plasma lipoproteins can be divided into several distinct classes.

Table 27.1

Dietary fats and cholesterol are transported out of the small intestine by large lipoprotein particles called chylomicrons. Another important lipoprotein is Low Density Lipoprotein (LDL) which is the main carrier of cholesterol to the peripheral tissues. LDL receptor proteins found on liver cells, internalize serum LDL and ultimately control the de novo synthesis of cholesterol in the liver.

Figure 27.19

Figure 27.20

Figure 27.21

Figure 27.23

There are basically four key steps in the uptake of LDL particles by liver cells:

1. Apolipoprotein B-100 on the LDL particle binds to the LDL receptor on liver cells.
2. The LDL receptor complex is internalized by endocytosis forming a vesicle.
3. The LDL-containing vesicles fuse with lysosomes inside the cytosol to initiate degradation.
4. The unesterified cholesterol can be used by the cell or stored for release later.

The absence of LDL receptor in humans leads to familial hypercholesterolemia and atherosclerosis. Lovastatin is a therapeutic drug used to inhibit de novo cholesterol biosynthesis by inhibiting the committed step catalyzed by HMG CoA Reductase. Atherosclerosis and high levels of serum cholesterol lead to severe cardiovascular disease and death.

Figure 27.24

Figure 27.25

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Department of Biochemistry The University of Arizona Spring 1999  RLM@u.arizona.edu cusanovi@u.arizona.edu http://www.biochem.arizona.edu/classes/bioc460/spring/springindex.html All contents copyright © 1999. All rights reserved.