KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Learning Objectives

Explain information related to removal and excretion of amino groups

Answer questions about urea cycle and urea cycle defects

Answer questions about disorders of amino acid metabolism

Explain information related to propionyl-CoA carboxylase and methylmalonyl-CoA

Use knowledge of S-adenosylmethionine, folate, and cobalamin

Explain information related to specialized products derived from amino acids

Solve problems concerning heme synthesis

Use knowledge of iron transport and storage

Use knowledge of bilirubin metabolism

OVERVIEW

Protein obtained from the diet or from body protein during prolonged fasting or starvation may be used as an energy source. Body protein is catabolized primarily in muscle and in liver. Amino acids released from proteins usually lose their amino group through transamination or deamination. The carbon skeletons can be converted in the liver to glucose (glucogenic amino acids), acetyl CoA, and ketone bodies (ketogenic), or in a few cases both may be produced (glucogenic and ketogenic).

REMOVAL AND EXCRETION OF AMINO GROUPS

Excess nitrogen is eliminated from the body in the urine. The kidney adds small quantities of ammonium ion to the urine in part to regulate acid-base balance, but nitrogen is also eliminated in this process. Most excess nitrogen is converted to urea in the liver and goes through the blood to the kidney, where it is eliminated in urine.

Amino groups released by deamination reactions form ammonium ion (NH4+), which must not escape into the peripheral blood. An elevated concentration of ammonium ion in the blood, hyperammonemia, has toxic effects in the brain (cerebral edema, convulsions, coma, and death). Most tissues add excess nitrogen to the blood as glutamine by attaching ammonia to the γ-carboxyl group of glutamate. Muscle sends nitrogen to the liver as alanine and smaller quantities of other amino acids, in addition to glutamine. The figure below summarizes the flow of nitrogen from tissues to the liver or kidney for excretion.

Bridge to Pharmacology

Lactulose is metabolized to lactic acid in the GI tract by bacteria, which in turn covert ammonia (NH3) to ammonium (NH4+), interfering with absorption and treating hyperammonemia.

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Aminotransferases (Transaminases)

High-Yield

Genetic Deficiencies of the Urea Cycle

High-Yield

Phenylalanine Hydroxylase Deficiency (Phenylketonuria)

Chapter 17 ● Amino Acid Metabolism

High-Yield

Infants with classic phenylketonuria (PKU) are normal at birth but if untreated show slow development, severe mental retardation, autistic symptoms, and loss of motor control. Children may have pale skin and white-blonde hair. The neurotoxic effects relate to high levels of phenylalanine and not to the phenylketones from which the name of the disease derives. Infants are routinely screened a few days after birth for blood phenylalanine level. Treatment is a lifelong semisynthetic diet restricted in phenylalanine (small quantities are necessary because it is an essential amino acid).

Women with PKU who become pregnant must be especially careful about the phenylalanine level in their blood so as not to adversely affect neurologic development in the fetus. Infants whose phenylketonuric mothers have not maintained adequate metabolic control during pregnancy have a high risk for mental retardation (although less profound than in a child with untreated PKU), microcephaly, and low birth weight.

Albinism (1:15,000) is a group of conditions in which then normal conversion of tyrosine to melanin is altered. The most severe form is a deficiency of tyrosinase, causing an absence of pigment in the skin, hair, and eyes.

Accumulation of homogentisic acid in the blood causes its excretion in urine, after which it gradually darkens upon exposure to air. This sign of alcaptonuria is not present in all patients with the enzyme deficiency. The dark pigment also accumulates over years in the cartilage (ochronosis) and may be seen in the sclera of the eye, in ear cartilage and patients develop arthritis in adulthood, usually beginning in the third decade. Treatment is targeted to managing the symptoms.

Note

Aspartame (N-aspartylphenylala- nine methyl ester), a widely used artificial sweetener, must be strictly avoided by phenylketonurics.

Bridge to Medical Genetics

There are >100 known mutations in the gene for phenylalanine hydroxylase, causing PKU. This is an example of allelic heterogeneity.

Branched-chain ketoacid dehydrogenase, an enzyme similar to α-ketoglutarate dehydrogenase (thiamine, lipoic acid, CoA, FAD, NAD+), metabolizes branchedchain ketoacids produced from their cognate amino acids, valine, leucine, and isoleucine. In the classic form of the disease, infants are normal for the first few days of life, after which they become progressively lethargic, lose weight, and have alternating episodes of hypertonia and hypotonia, and the urine develops a characteristic odor of maple syrup. Ketosis, coma, and death ensue if not treated. Treatment requires restricting dietary valine, leucine, and isoleucine.

Valine, methionine, isoleucine, and threonine are all metabolized through the propionic acid pathway (also used for odd-carbon fatty acids). Deficiency of either enzyme results in neonatal ketoacidosis from failure to metabolize ketoacids produced from these 4 amino acids. The deficiencies may be

Note

•Propionyl CoA carboxylase deficiency involves an accumulation of propionic acid, methyl citrate, and hydroxypropionic acid.

•Methylmalonyl CoA

mutase deficiency involves an accumulation of methylmalonic acid.

Recall Question

Which of the following results from a deficiency of ornithine transcarbamoylase but not of carbamoyl phosphate synthetase?

A.Cerebral edema

B.Decreased BUN

C.Hyperammonemia

D.Increased blood glutamine

E.Orotic aciduria

Answer: E

S-ADENOSYLMETHIONINE, FOLATE, AND COBALAMIN

One-Carbon Units in Biochemical Reactions

One-carbon units in different oxidation states are required in the pathways producing purines, thymidine, and many other compounds. When a biochemical reaction requires a methyl group (methylation), S-adenosylmethionine (SAM) is generally the methyl donor.

If a 1-carbon unit in another oxidation state is required (methylene, methenyl, formyl), tetrahydrofolate (THF) typically serves as its donor.

S-Adenosylmethionine

Important pathways requiring SAM include synthesis of epinephrine and of the 7-methylguanine cap on eukaryotic mRNA. After donating the methyl group, SAM is converted to homocysteine and remethylated in a reaction catalyzed by N-methyl THF–homocysteine methyltransferase requiring both vitamin B12 and N-methyl-THF. The methionine produced is once again used to make SAM.

THF is formed from the vitamin folate through 2 reductions involving NADPH and catalyzed by dihydrofolate reductase. It picks up a 1-carbon unit from a variety of donors and enters the active 1-carbon pool. Important pathways requiring forms of THF from this pool include the synthesis of all purines and thymidine, which in turn are used for DNA and RNA synthesis during cell growth and division.

Megaloblastic anemia results from insufficient active THF to support cell division in the bone marrow. Methotrexate inhibits DHF reductase, making it a useful antineoplastic drug. Folate deficiencies may be seen during pregnancy and in alcoholism.

Additional folate may be stored as the highly reduced N5-methyl-THF. This form is referred to as the storage pool as there is only one known enzyme that uses it, and in turn moves it back into the active pool. This enzyme is N-methyl THF-homocysteine methyltransferase, which also requires vitamin B12 and is involved in regenerating SAM as a methyl donor for reactions.

Note

THB (BH4) is necessary for tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase (serotonin synthesis) and is regenerated by dihydropteridine reductase.

Clinical Correlate

Parkinson’s disease is caused by loss of dopaminergic neurons in the substantia nigra. It is treated with levodopa (L-dopa).

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