Lysosomal enzymes synthesis

The answer is D. As this patient ages, a variety of skeletal defects and short stature that are consistent with a lysosomal storage disease (mucolipidosis), either I-cell disease or pseudo-Hurler polydystrophy, are developing. Both diseases arise from a deficiency of an enzyme involved in synthesis of the Man-6-P marker on lysosomal enzymes. Such misaddressed proteins are secreted rather than trafficked to the lysosomes. The degradative function of lysosomes is impaired as a result and the organelles tend to accumulate waste products (hence, the term storage disease ). It is these inclusion bodies or dense structures that would be visible by microscopic examination of the patient s cells in a biopsy specimen. 

Mechanism of Action An adrenocortical steroid that inhibits the accumulation of inflammatory cells at inflammation sites, phagocytosis, lysosomal enzyme release and synthesis, and release of mediators of inflammation. Therapeutic Effect Prevents or suppresses cell-mediated immune reactions. Decreases or prevents tissue response to inflammatory process. 

It acts peripherally by inhibiting the synthesis of prostaglandins by reversible inhibition of cyclooxygenase. Inhibition of the migration of leukocytes to an inflammatory site and inhibition of the release of lysosomal enzymes may also be involved in the antiinflammatory action. 

Chloroquine and hydroxychloroquine are used mainly in malaria (see Chapter 52) and in the rheumatic diseases. The mechanism of the antiinflammatory action of these drugs in rheumatic diseases is unclear. The following mechanisms have been proposed suppression of T-lymphocyte responses to mitogens, decreased leukocyte chemotaxis, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, and the trapping of free radicals. 

The chemotactic peptides are also active in the stimulation of release of O and in the release of lysosomal contents Directed locomotion by PMNs is stimulated by a family of tri-, tetra-, and dipeptides which have in common formylated methionine as the first amino acid. Since formylated methionine is the initiator to which other amino acids are added in the synthesis of bacterial protein, small peptides which commence with formylated methionine are likely to be liberated proteolytically at sites of bacterial infection, possibly explaining their great potency as chematoxins. Using superoxide-dependent chemiluminescence (see below) as a measure of synthesis of O , Hatch et al. showed a hierarchy of potency of FMLP > FMP > FMV > FMA. Becker et al. measured the formation of O in suspensions of rabbit PMNs and found that the hierarchy of potency was the same for stimulation of the formation of O7 as it was for stimulation of release of lysosomal enzymes, namely... 

Vaes, G. On the mechanism of bone resorption the action of PTH on the excretion and synthesis of lysosomal enzymes and the extracellular release of acid bone cells. J. Cell. Biol. 39. 676 (1968)... 

The I-cell patient has proved invaluable for elucidation of the complex nature of intracellular packaging and sorting of lysosomal enzymes. The physiological importance of this signal-mediated pathway is evident in that fibroblasts from patients with I-cell disease and pseudo-Hurler polydystrophy secrete rather than target most of their lysosomal enzymes. Thus, the molecular theme of I-cell disease is that of faulty lysosomal targeting, the inability to transport (i.e., sort) lysosomal enzymes from their site of synthesis to the lysosome. 

Figure 17-5. Synthesis of the mannose 6-phosphate recognition marker. R represents the high-mannose oligosaccharide of newly synthesized lysosomal enzymes. Reaction 1 is catalyzed by UDP-A,-acetylglucosamine lysosomal enzyme Ar-acetylglucosaminyl-1 -phosphotransferase. Reaction 2 is catalyzed by iV-acetylglucosamine-l-phosphodiester-iV-ace tylgluco saminidase.

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