KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Bridge to Microbiology

Protozoan and multicellular parasites and many obligate parasites, such as Chlamydia, cannot synthesize purines de novo because they lack the necessary genes in the purine pathway. However, they have elaborate salvage mechanisms for acquiring purines from the host to synthesize their own nucleic acids

to grow.

Ribose 5-Phosphate

PRPP synthetase

Part I ● Biochemistry

Bridge to Pharmacology

Thiazide diuretics (hydrochlorothiazide and chlorthalidone) may cause hyperuricemia.

Bridge to Pathology

Treatment of large tumors with chemotherapeutic regimens or radiation may cause “turnor lysis syndrome” and excessive excretion of uric acid, resulting in gout. The cause of the excessive uric acid is the destruction of the cancer cell’s nucleic acid into purines undergoing turnover.

Clinical Correlate

Gout

Acute gouty arthritis, seen most commonly in males, results from precipitation of monosodium urate crystals in joints. The crystals, identified as negatively birefringent and needle-shaped, initiate neutrophil-mediated and acute inflammation, often first affecting the big toe. Chronic gout may manifest over time as tophi (deposits of monosodium urate) in soft tissue around joints, leading to chronic inflammation involving granulomas.

•Acute attacks of gout are treated with colchicine or indomethacin to reduce the inflammation.

•Chronic hyperuricemia, because of underexcretion, is treated with a uricosuric drug (probenecid).

•Overproduction of uric acid and chronic gout are treated with allopurinol.

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Adenosine deaminase (ADA) deficiency, an autosomal recessive disorder, causes a type of severe combined immunodeficiency (SCID). Lacking both B-cell and T-cell function, children are multiply infected with many organisms (Pneumocystis carinii, Candida) and do not survive without treatment. Enzyme replacement therapy and bone marrow transplantation may be used. Experimental gene therapy trials have not yet yielded completely successful cures.

High levels of dATP accumulate in red cells of ADA patients and inhibit ribonucleotide reductase, thereby inhibiting the production of other essential deoxynucleotide precursors for DNA synthesis (see Figure I-18-3). Although it is believed that the impaired DNA synthesis contributes to dysfunction of T cells and B cells, it is not known why the main effects are limited to these cell types.

Hyperuricemia may be produced by overproduction of uric acid or underexcretion of uric acid by the kidneys. Hyperuricemia may progress to acute and chronic gouty arthritis if uric acid (monosodium urate) is deposited in joints and surrounding soft tissue, where it causes inflammation. Uric acid is produced from excess endogenous purines as shown in Figure I-18-5, and is also produced from dietary purines (digestion of nucleic acid in the intestine) by intestinal epithelia. Both sources of uric acid are transported in the blood to the kidneys for excretion in urine.

Allopurinol inhibits xanthine oxidase and also can reduce purine synthesis by inhibiting PRPP amidotransferase, provided HGPRT is active (see Figure I-18-4). Hyperuricemia and gout often accompany the following conditions:

•Lesch-Nyhan syndrome (no purine salvage)

•Partial deficiency of HGPRT

•Alcoholism (lactate and urate compete for same transport system in the kidney)

•Glucose 6-phosphatase deficiency

•Hereditary fructose intolerance (aldolase B deficiency)

•Galactose 1-phosphate uridyl transferase deficiency (galactosemia)

•Mutations in PRPP synthetase that lower Km

In the last 2 diseases, phosphorylated sugars accumulate, decreasing the available Pi and increasing AMP (which cannot be phosphorylated to ADP and ATP). The excess AMP is converted to uric acid.

Lesch-Nyhan syndrome is an X-linked recessive condition involving:

•Near-complete deficiency of HGPRT activity

•Mental retardation

•Spastic cerebral palsy with compulsive biting of hands and lips

•Hyperuricemia

•Death often in first decade

Over 100 distinct mutations of the HGPRT gene located on the X chromosome have been reported to give rise to Lesch-Nyhan syndrome. These mutations include complete deletions of the gene, point mutations that result in an increased Km for hypoxanthine and guanine for the enzyme, and mutations that cause the encoded enzyme to have a short half-life.

Lesch-Nyhan Syndrome

The parents of a 9-month-old infant were concerned that their son appeared generally weak, had difficulty moving his arms and legs, repeatedly bit his lips, and frequently seemed to be in pain. The infant was brought to the pediatrician. The parents mentioned that since the baby was born, they often noticed tiny, orange-colored particles when they changed the infant’s diapers. Lab analysis of uric acid in urine was normalized to the urinary creatinine in the infant, and it was found that the amount was 3 times greater than

the normal range.

One of the earliest signs of Lesch-Nyhan syndrome is the appearance of orange crystals in diapers. They are needle-shaped sodium urate crystals. Without the salvaging of hypoxanthine and guanine by HGPRT, the purines are shunted toward the excretion pathway. This is compounded by the lack of regulatory control of the PRPP amidotransferase in the purine synthesis pathway, resulting in the synthesis of even more purines in the body. The large amounts of urate will cause crippling, gouty arthritis and urate nephropathy. Renal failure is usually the cause of death. Treatment with allopurinol will ease the amount of urate deposits formed.

Bridge to Pharmacology

Febuxostat is a nonpurine inhibitor of xanthine oxidase.

Bridge to Medical Genetics

There are a large number of known mutations in the HGPRT gene. These have varying effects on the Km for the enzyme product, generating varying degrees of severity. This concept is known as allelic heterogeneity.

Learning Objectives

Interpret scenarios about basic definitions

Use knowledge of major modes of inheritance

Understand important principles that can characterize single-gene diseases

BASIC DEFINITIONS

Chromosomes

Humans are composed of 2 groups of cells:

•Gametes. Ova and sperm cells, which are haploid, have one copy of each type of chromosome (1–22, X or Y). This DNA is transmitted to offspring.

•Somatic cells (cells other than gametes). Nearly all somatic cells are diploid, having 2 copies of each type of autosome (1–22) and either XX or XY.

Diploid cells

•Homologous chromosomes. The 2 chromosomes in each diploid pair are said to be homologs, or homologous chromosomes. They contain the same genes, but because one is of paternal origin and one is of maternal origin, they may have different alleles at some loci.

•X and Y chromosomes, or the sex chromosomes, have some homologous regions but the majority of genes are different. The regions that are homologous are sometimes referred to as pseudoautosomal regions. During meiosis-1 of male spermatogenesis, the X and Y chromosomes pair in the pseudoautosomal regions, allowing the chromosomes to segregate into different cells.

Genes

•Gene. Physically a gene consists of a sequence of DNA that encodes a specific protein (or a nontranslated RNA; for example: tRNA, rRNA, or snRNA).

•Locus. The physical location of a gene on a chromosome is termed a locus.

•Alleles. Variation (mutation) in the DNA sequence of a gene produces a new allele at that locus. Many genes have multiple alleles.

•Polymorphism. When a specific site on a chromosome has multiple alleles in the population, it is said to be polymorphic (many forms).

Note

•Gene: basic unit of inheritance

•Locus: location of a gene on a chromosome

•Allele: different forms of a gene

•Genotype: alleles found at a locus

•Phenotype: physically observable features

•Homozygote: alleles at a locus are the same

•Heterozygote: alleles at a locus are different

•Dominant: requires only one copy of the mutation to produce disease

•Recessive: requires 2 copies of the mutation to produce disease

Note

Although the term alleles is used most frequently with genes, noncoding DNA can also have alleles of specific sequences.