Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In contrast to liver, adipose tissue, and muscle, in which the diabetic state is associated with a "catabolic response," some tissues, typically the kidney and perhaps the intestinal mucosa and some vascular cell types, show an "anabolic response" to diabetes, with enhanced activity of the anabolic pathways and diminished activity of the catabolic ones. The kidney of alloxan or streptozotocin diabetic rats is hypertrophied, and shows enrichment in intracellular glycogen and abundant accumulation of glycoprotein material at the basement membrane level. Accordingly, protein synthesis and the enzymes of glucose utilization as well as those engaged in UDP sugar formation or in the hydroxylation and glycosylation processes (required for glycoprotein synthesis) show increased activity in the diabetic kidney, while the catabolic, lysosomal enzymes (cathepsin D and several glycosidases) are depressed. We observed a reduction of -24% in the activity of cathepsin D and -23% in that of galactosidase in the kidney of streptozotocin diabetic mice, as opposed to increases of +135 and +32%, respectively, found in liver. It is not known which factor(s) may be responsible for such an anabolic response of some tissues to diabetes, but persistent hyperglycemia and/or some hormonal abnormalities may be involved. The above data refer to changes in tissue enzyme content caused by induction-repression mechanisms, but rapid (activation-inhibition) effects may also occur. We observed that preincubation of slices of mouse kidney cortex for 10 min with 20.8 mmole/liter glucose resulted in a 80% activation of phosphofructokinase, as assayed in the tissue homogenate at physiological (50 mumole/liter) concentration of the substrate fructose-6-P, suggesting that hyperglycemia may be responsible for some of the metabolic changes occurring in the diabetic kidney.
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PMID:Anabolic response of some tissues to diabetes. 293 59

Microsomal-type cytochrome P450s are integral membrane proteins bound to the membrane through their N-terminal transmembrane hydrophobic segment, the signal anchor sequence. To elucidate the determinants that enable the P450s to be located in the ER, we constructed cDNAs encoding chimeric proteins in which a secretory form of carboxyesterase, carboxyesterase Sec, was connected to the N-terminus of the full-length or truncated forms of a microsomal-type P450, P450(M1), and the constructed plasmids were expressed in COS cells. Since carboxyesterase Sec is an N-glycosylated secretory protein, endo H treatment could be used to determine whether these chimeric proteins were located in the ER or not. Carboxyesterase Sec with the N-terminal 20 amino acids, containing the transmembrane region, of P450(M1), was located in the ER, as determined from the endo H sensitivity of the expressed protein and immunofluorescence staining of the cells. As the expressed protein exhibited carboxyesterase activity, it was not retained in the ER through the BiP-dependent quality control system recognizing unfolded proteins. Another chimeric protein construct in which carboxyesterase Sec was connected to the C-terminal region of rat UDP-glucuronosyltransferase (UDP-GT), that contained a double-lysin ER retention motif, was also located in the ER, as determined from the endo H sensitivity and immunofluorescence staining. On the other hand, the sugar moiety of the carboxyesterase Sec connected to the transmembrane segment of UDP-GT, Sec/GTd, was partially resistant to the endo H treatment. From the results of immunofluorescent staining and cell fractionation, it was concluded that the Sec/GTd product was located in the Golgi apparatus. These observations indicated that the N-terminal hydrophobic segment of P450(M1) is sufficient for the ER membrane retention, whereas the transmembrane segment of UDP-GT is not. To determine whether microsomal P450s are recycled between the ER and Golgi compartments or not, a DNA construct encoding cathepsin D connected to the N-terminus of P450(M1) was prepared and expressed in COS cells. The fusion protein was phosphorylated, but the phosphorylation was sensitive to alkaline phosphatase. As a control, authentic cathepsin D was subjected to phosphorylation of its oligosaccharide chain that was resistant to the alkaline phosphatase treatment. Since GlcNAc-P-transferase, which forms the alkaline phosphatase-resistant phosphodiester in the sugar chains of lysosome-targeting proteins, is located in the Golgi apparatus, it was concluded that the oligosaccharide chain of the cathepsin D portion of the fusion protein was not phosphorylated, and that the chimeric protein did not go to the Golgi apparatus.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The transmembrane region of microsomal cytochrome P450 identified as the endoplasmic reticulum retention signal. 779 74