Different roles. Describe the roles of glycerol 3-phosphate, phosphatidate, and diacylglycerol in triacylglycerol and phospholipid synthesis.

Needed supplies. How is the glycerol 3-phosphate required for phosphatidate synthesis generated?

Making fat. Write a balanced equation for the synthesis of a triacylglycerol, starting from glycerol and fatty acids.

Making a phospholipid. Write a balanced equation for the synthesis of phosphatidylethanolamine by the de novo pathway, starting from ethanolamine, glycerol, and fatty acids.

ATP needs. How many high-phosphoryl-transfer-potential molecules are required to synthesize phosphatidylethanolamine from ethanolamine and diacylglycerol? Assume that the ethanolamine is the activated component.

Identifying differences. Differentiate among sphingomyelin, a cerebroside, and a ganglioside.

Let’s count the ways. There may be 50 ways to leave your lover, but, in principle, there are only three ways to make a glycerol-based phospholipid. Describe the three pathways.

Activated donors. What is the activated reactant in each of the following biosyntheses?

No DAG, no TAG. What would be the effect of a mutation that decreased the activity of phosphatidic acid phosphatase?

Like Wilbur and Orville. Match each term with its description.

The Law of Three Stages. What are the three stages required for the synthesis of cholesterol?

Many regulations to follow. Outline the mechanisms of the regulation of cholesterol biosynthesis.

Telltale labels. What is the distribution of isotopic labeling in cholesterol synthesized from each of the following precursors?

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Too much, too soon. What is familial hypercholesterolemia and what are its causes?

Familial hypercholesterolemia. Several classes of LDL-receptor mutations have been identified as causes of this disease. Suppose that you have been given cells from patients with different mutations, an antibody specific for the LDL receptor that can be seen with an electron microscope, and access to an electron microscope. What differences in antibody distribution might you expect to find in the cells from different patients?

Breakfast conversation. You and a friend are eating breakfast together. While eating, your friend is reading the back of her cereal box and comes across the following statement: “Cholesterol plays beneficial roles in your body, making cells, hormones, and tissues.” Knowing that you are taking biochemistry, she asks if the statement makes sense. What do you reply?

A good thing. What are statins? What is their pharmacological function?

Too much of a good thing. Would the development of a “super statin” that inhibited all HMG CoA reductase activity be a useful drug? Explain.

RNA editing. A shortened version (apo B-48) of apolipoprotein B is formed by the intestine, whereas the full-length protein (apo B-100) is synthesized by the liver. A glutamine codon (CAA) is changed into a stop codon. Propose a simple mechanism for this change.

A means of entry. Describe the process of receptor-mediated endocytosis by using LDL as an example.

Inspiration for drug design. Some actions of androgens are mediated by dihydrotestosterone, which is formed by the reduction of testosterone. This finishing touch is catalyzed by an NADPH-dependent 5α-reductase. Chromosomal XY males with a genetic deficiency of this reductase are born with a male internal urogenital tract but predominantly female external genitalia. These people are usually reared as girls. At puberty, they masculinize because the testosterone level rises. The testes of these reductase-deficient men are normal, whereas their prostate glands remain small. How might this information be used to design a drug to treat benign prostatic hypertrophy, a common consequence of the normal aging process in men? A majority of men older than age 55 have some degree of prostatic enlargement, which often leads to urinary obstruction.

Drug idiosyncrasies. Debrisoquine, a β-adrenergic blocking agent, has been used to treat hypertension. The optimal dose varies greatly (20–400 mg daily) in a population of patients. The urine of most patients taking the drug contains a high level of 4-hydroxydebrisoquine. However, those most sensitive to the drug (about 8% of the group studied) excrete debrisoquine and very little of the 4-hydroxy derivative. Propose a molecular basis for this drug idiosyncrasy. Why should caution be exercised in giving other drugs to patients who are very sensitive to debrisoquine?

Removal of odorants. Many odorant molecules are highly hydrophobic and concentrate within the olfactory epithelium. They would give a persistent signal independent of their concentration in the environment if they were not rapidly modified. Propose a mechanism for converting hydrophobic odorants into water-soluble derivatives that can be rapidly eliminated.

Development difficulties. Propecia (finasteride) is a synthetic steroid that functions as a competitive and specific inhibitor of 5α-reductase, the enzyme responsible for the synthesis of dihydrotestosterone from testosterone.

In addition to its use as a treatment for benign prostatic hypertrophy (Problem 21), finasteride is also widely used to retard the development of male pattern hair loss. Pregnant women are advised to avoid handling this drug. Why is it vitally important that pregnant women avoid contact with Propecia?

Life-style consequences. Human beings and the plant Arabidopsis evolved from the same distant ancestor possessing a small number of cytochrome P450 genes. Human beings have approximately 50 such genes, whereas Arabidopsis has more than 250 of them. Propose a role for the large number of P450 isozymes in plants.

Personalized medicine. The cytochrome P450 system metabolizes many medicinally useful drugs. Although all human beings have the same number of P450 genes, individual polymorphisms exist that alter the specificity and efficiency of the proteins encoded by the genes. How could knowledge of individual polymorphisms be useful clinically?

Honeybee crisis. In 2006, there was a sudden, unexplained die-off of honeybee colonies throughout the United States. The die-off was economically significant because one-third of the human diet comes from insect-pollinated plants, and honeybees are responsible for 80% of the pollination. In October of 2006, the sequence of the honeybee genome was reported. Interestingly, the genome was found to contain far fewer cytochrome P450 genes than do the genomes of other insects. Suggest how the die-off and the paucity of P450 genes may be related.

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Missing enzyme. Congenital adrenal hyperplasia is a life-threatening condition that results from a deficiency in the P450 enzyme steroid 21-hydroxylase. This enzyme catalyzes the first step in the conversion of progesterone into cortisol and aldosterone (Figures 26.28 and 26.29). A characteristic of congenital adrenal hyperplasia is an increase in sex hormone production. Explain why this is the case.

Let the sun shine in. At a biochemical level, vitamin D functions like a steroid hormone (Chapter 31). Therefore, it is sometimes referred to as an honorary steroid. Why is vitamin D not an actual steroid?

An interfering phosphate. In the course of the overall reaction catalyzed by HMG-CoA reductase, a histidine residue protonates a coenzyme A thiolate, CoA– S⁻, generated in an earlier step.

A nearby serine residue can be phosphorylated by AMP-dependent kinase, which results in a loss of activity. Propose an explanation for why phosphorylation of the serine residue inhibits enzyme activity.

Demethylation. Methyl amines are often demethylated by cytochrome P450 enzymes. Propose a mechanism for the formation of methylamine from dimethylamine catalyzed by cytochrome P450. What is the other product?

Similarities. Compare the role of CTP in phosphoglyceride synthesis with the role of UTP in glycogen synthesis.

Hold on tight or you might be thrown to the cytoplasm. Many proteins are modified by the covalent attachment of a farnesyl (C₁₅) or a geranylgeranyl (C₂₀) unit to the carboxyl-terminal cysteine residue of the protein. Suggest why this modification might occur.

Fork in the road. 3-Hydroxy-3-methylglutaryl CoA is on the pathway for cholesterol biosynthesis. It is also a component of another pathway. Name the pathway. What determines which pathway 3-hydroxy-3-methylglutaryl CoA follows?

Requires a club membership. How is methionine metabolism related to the synthesis of phosphatidylcholine?

Drug resistance. Dichlorodiphenyltrichloroethane (DDT) is a potent insecticide rarely used today because of its effects on other forms of life. In insects, DDT disrupts sodium channel function, leading to eventual death. Mosquitos have developed resistance to DDT and other insecticides that function in a similar fashion. Suggest two means by which DDT resistance might develop.

ATP requirements. Explain how cholesterol synthesis depends on the activity of ATP-citrate lyase.

Cholesterol feeding. Mice were divided into four groups, two of which were fed a normal diet and two of which were fed a cholesterol-rich diet. HMG-CoA reductase mRNA and protein from liver were then isolated and quantified. Graph A shows the results of the mRNA isolation.

Gaucher disease. Gaucher disease, the most common lysosomal storage disease in humans, is caused by mutations in the gene encoding glucocerebrosidase (GCase), the lysosomal enzyme that degrades glucocerebrosides. The disease has a variety of symptoms depending on the severity of the disease and the person affected. Identical twins can display very different levels of severity. Symptoms include bone pain, enlarged liver, excessive fatigue, and mental retardation.

In order to better understand the disease, researchers undertook a series of experiments to characterize the nature of the defect in the enzyme. Cells were obtained from a person without the disease (control) as well as from a patient with the disease (GD). The cells were grown in culture, the enzyme was isolated, and enzyme activity of 10 μg of each sample was measured (Figure A).