Tissue Distribution and Substrates

In addition to the structural role in the lysosome, CatA is excreted from celk as demonstrated by the isolation of CatA from the culture media of thrombin-stimulated platelets [13]. Moreover, high CatA activity has been detected in urine, probably originating fi-om renal proximal tubular cells. Therefore, human CatA is variably distributed in different tissues with liver and kidney having the highest levels [14]. 

As expected for a lysosomal carboxypeptidase, the pH optimum for the proteolytic activity of CatA is found in the acidic range at pH 5.5 [7]. In a neutral pH environment, CatA is able to function as a deamidase converting amide-blocked peptides into the acidic form [15]. Because amidation at the C-terminus is required for the activity of many small signaling peptides [16], this observation 

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Graham S. M. and Prestwich G. D. (1992) Tissue distribution and substrate specificity of an epoxide hydrase in the gypsy moth Lymantria dispar. Experentia 48, 19-21. 

Following the isolation of Oatplal, the first human OATP was cloned from human liver that showed 67% amino acid identity to Oatplal [68]. The carrier was later named OATP1A2, as it appeared to exhibit tissue distribution and substrate specificity unlike any ofthe related rat Oatps. 0ATP1A2 is composed of 670 amino acids with a predicted 12-membrane domain topology [69]. 

TABLE 6.1 Tissue distribution and substrate properties of major ABC and SLC transporters. 

Su J, Chai X, Kahn B, Napoli JL (1998) cDNA cloning, tissue distribution, and substrate characterization of... 

To Study interactions between proteins and drugs, an available tool is the Drug Absorption, Distribution, Metabolism, and Excretion (ADME) Associated Protein Database (see Table 1.5). The database contains information about relevant proteins, functions, similarities, substrates and hgands, tissue distributions, and other features of targets. Eor the understanding of pharmacokinetic (PK) and pharmacodynamic (PD) features, some available resources are listed in Table 1.5. For example, the Pharmacokinetic and Pharmacodynamic Resources site provides links to relevant software, courses, textbooks, and journals (see Note 5). For quantitative structure-activity relationship (QSAR), the QSAR Datasets site collects data sets that are available in a structural format (see Table 1.5). 

Some specific molecules that are important in protein-drug interactions have been studied extensively, including cytochrome P450 (CYP450), receptors, membrane transporters, and antibodies (see Table 1.6). Databases about these molecules may also contain information about SNP effects, tissue distribution, and interacting substrates. 

Eq. 18-38).206 The enzyme is induced both by glucocorticoids and by tryptophan.207 The related indola-mine 2,3-dioxygenase catalyzes the same reaction of L-tryptophan but also acts on D-tryptophan and other substrates. It has different tissue distribution and reg- ulatory properties208 and may play a role in... 

Table 11 Tissue Distribution and Specific Substrates for Human UDP-Glucuronosyl-transferase (UGT) Enzymes...

The MRP family of transporters is closely related and structurally similar to the MDR family (64/ 65). MRPl was initially identified in lung cellS/ which were known not to express P-gp. It has been shown to pump anionic compounds (as opposed to the cations pumped by P-gp). Substrates for MRPl include anionic natural products glutathione/ glucuronyl/ and sulfate conjugates and/ in some caseS/ neutral molecules coupled to glutathione transport without conjugation. In liver cellS/ MRPl is present on the sinusoidal surface of the hepatocyte. MRP2 is similar to MRPl/ except in its tissue distribution and localization. In liver cellS/... 

Two reactions account for the metabolic fate of about 80% of the T4 in plasma about 40% is converted to T3 via 5 -deiodination (activation), and another 40% of the T4 is converted to rT3 by 5 -deiodination (inactivation). These two reactions are catalyzed by three enzymes designated types I, II, and III iodothyronine deiodinases (Figure 33-5 and Table 33-2). Types I and II both catalyze the 5 -deiodination reaction but differ with respect to substrate specificity, tissue distribution, and regulation. Type III is a 5-deiodinase, which catalyzes the removal of iodine from position 5 of the inner ring. Type I is deiodinase selenocysteine-containing microsomal enzyme present in the liver, kidney, and thyroid, with specificity for... 

Class I aldolases of mammals and other vertebrates can be subdivided into three distinct isoenzymes.143,331 Identification of the parental aldolases A, B, and C has been made from their substrate specificities (ratio of activity towards D-fructose 1,6-bisphosphate and towards D-fructose 1-phosphate), electrophoretic mobilities, tissue distribution, and specific immunological properties. Aldolase A is the major form, present in muscle aldolase B, the predominant form in liver and kidney and aldolase C, present in brain with aldolase A. In tissues where more than one aldolase isoenzyme occurs, a hybrid form is often observed.331... 

Drug-drug interactions mediated by the CYP and P-glycoprotein system arise from the induction of the proteins or from inhibition of their function. While induction may lead to decreased bioavailability and therapeutic failure, inhibition can give rise to increased plasma levels, altered tissue distribution and in the case of nephrotoxic drugs overt dinical toxidty. As previously noted, there is considerable overlap in the substrate specificity of CYP3A4 and P-glycoprotein. Certainly at the level of the intestine, both proteins fulfill... 

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