KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Table I-17-2. Folate versus Vitamin B12 Deficiency

SPECIALIZED PRODUCTS DERIVED FROM AMINO ACIDS

Table I-17-3. Products of Amino Acids

HEME SYNTHESIS

Heme synthesis occurs in almost all tissues because heme proteins include not only hemoglobin and myoglobin but all the cytochromes (electron transport chain, cytochrome P-450, cytochrome b5), as well as the enzymes catalase, peroxidase, and the soluble guanylate cyclase stimulated by nitric oxide. The pathway producing heme, as shown below, is controlled independently in different tissues. In liver, the rate-limiting enzyme δ-aminolevulinate synthase (ALA) is repressed by heme.

Chapter 17 ● Amino Acid Metabolism

Bridge to Pathology

Vitamin B12 deficiency causes demyelination of the posterior columns and lateral corticospinal tracts in the spinal cord.

Part I ● Biochemistry

Note

Compounds with an “-ogen” suffix, such as urobilinogen, are colorless substances. In the presence of oxygen, they spontaneously oxidize, forming a conjugated double-bond network in the compounds. These oxidized compounds are highly colored substances and have an “-in” suffix (e.g., porphobilin, urobilin).

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Figure I-17-5. Heme Synthesis

This late-onset autosomal dominant disease exhibits variable expression. Many heterozygotes remain symptom-free throughout their lives. Signs and symptoms, when present, include:

•Abdominal pain, often resulting in multiple laparoscopies (scars on abdomen)

•Anxiety, paranoia, and depression

Deficiencies of other enzymes in the heme pathway produce porphyrias in which photosensitivity is a common finding. Chronic inflammation to overt blistering and shearing in exposed areas of the skin characterize these porphyrias. The most common is porphyria cutanea tarda (deficiency of uroporphyrinogen decarboxylase), an autosomal dominant condition with late onset. β-Carotene is often administered to porphryia patients with photosensitivity to reduce the production of reactive oxygen species.

Porphyria cutanea tarda

A 35-year-old man was becoming very sensitive to sunlight and often detected persistent rashes and blisters throughout areas of his body that were exposed to the sun. He also observed that drinking excessive alcohol with his friends after softball games worsened the incidence of the recurrent blisters and sunburns. He became even more concerned after he noticed his urine became a red-brown tint if he did not flush the toilet.

Porphyria cutanea tarda is an adult-onset hepatic porphyria in which hepatocytes are unable to decarboxylate uroporphyrinogen in heme synthesis. The uroporphyrin spills out of the liver and eventually into urine, giving rise to the characteristic red-wine urine if it is allowed to stand, a hallmark of porphyrias. Hepatotoxic substances, such as excessive alcohol or iron deposits, can exacerbate the disease. Skin lesions are related to high circulating levels of porphyrins.

ALA synthase, the rate-limiting enzyme, requires pyridoxine (vitamin B6). Deficiency of pyridoxine is associated with isoniazid therapy for tuberculosis and may cause sideroblastic anemia with ringed sideroblasts.

The last enzyme in the pathway, heme synthase (ferrochelatase), introduces the Fe2+ into the heme ring. Deficiency of iron produces a microcytic hypochromic anemia.

Bridge to Pharmacology

Barbiturates are hydroxylated by the microsomal cytochrome P-450 system in the liver to facilitate their efficient elimination from the body. Administration of the barbiturates results in stimulation of cytochrome P-450 synthesis, which in turn reduces heme levels. The reduction in heme lessens the repression of ALA synthase, causing more porphyrin precursor synthesis. In porphyrias, the indirect production of more precursors by the barbiturates exacerbates the disease.

Part I ● Biochemistry

Clinical Correlate

The failure of ferrochelatase to insert Fe2+ into protoporphyrin IX to form heme, such as in lead poisoning or iron deficiency anemia, results in the nonenzymatic insertion of Zn2+ to form zinc-protoporphyrin. This complex is extremely fluorescent and is easily detected.

Note

Anemia is an important topic on the exam. Compare and contrast all anemias (differential diagnosis).

Bridge to Pathology

Hemochromatosis is an inherited, autosomal recessive disease (prevalence 1/200) generally seen in men age >40 and in older women. The disease is characterized by a daily intestinal absorption of 2–3 mg of iron compared with the normal 1 mg. Over 20–30 years, the disease results in levels of 20–30 grams of iron in the body (normal 4 grams). Hemosiderin deposits are found in the liver, pancreas, skin, and joints.

Lead inactivates many enzymes including ALA dehydraseMEDIUMand ferrochelataseYIELD (heme synthase), and can produce a microcytic sideroblastic anemia with ringed sideroblasts in the bone marrow. Other symptoms include:

•Coarse basophilic stippling of erythrocytes

•Headache, nausea, memory loss

•Abdominal pain, diarrhea (lead colic)

•Lead lines in gums

•Lead deposits in abdomen and epiphyses of bone seen on radiograph

•Neuropathy (claw hand, wrist-drop)

•Increased urinary ALA

•Increased free erythrocyte protoporphyrin

Vitamin B6 deficiency, iron deficiency, and lead poisoning all can cause anemia.

Table I-17-4. Vitamin B6 Deficiency, Iron Deficiency, and Lead Poisoning

IRON TRANSPORT AND STORAGE

Iron (Fe3+) released from hemoglobin in the histiocytes is bound to ferritin and then transported in the blood by transferrin, which can deliver it to tissues for synthesis of heme. Important proteins in this context are:

•Ferroxidase (also known as ceruloplasmin, a Cu2+ protein) oxidizes Fe2+ to Fe3+ for transport and storage.

•Transferrin carries Fe3+ in blood.

Part I ● Biochemistry

Clinical Correlate

Excessive RBC destruction in hemolytic anemia results in excessive conversion of bilirubin to urobilinogen in the intestine. Higher-than-normal absorption of the urobilinogen and its subsequent excretion in the urine results in a deeper-colored urine.

Clinical Correlate

At very high levels, lipid-soluble bilirubin may cross the blood-brain barrier and precipitate in the basal ganglia, causing irreversible brain damage (kernicterus).

Bilirubin and Jaundice

High-Yield