Lloyd Fricker

..However, studies with mutant animals that lack functional peptide-processing enzymes have facilitated the discovery of novel neuropeptides, many of which may be appropriate targets for therapeutics...

..The finding that CPD is widely distributed suggests a broad role for this enzyme in the processing of proteins that transit the secretory pathway...

..Furthermore, the increase in levels of high molecular weight enkephalin peptides in the Cpefat/Cpefat mouse suggests that CPE is required for efficient peptide processing by the endopeptidases...

..Obesity due to the Cpe(fat) mutation is not caused by increased food consumption but, rather, is a result of defective nutrient partitioning, the exact mechanism of which remains to be elucidated...

..Purified proSAAS inhibits prohormone convertase 1 activity with an IC(50) of 590 nM but does not inhibit prohormone convertase 2. Taken together, proSAAS may represent an endogenous inhibitor of prohormone convertase 1...

..These results are consistent with the model that PP2A is involved in the trafficking of proteins between a TGN recycling loop and a cell-surface recycling loop, but is not involved in the individual recycling loops...

..The quantitative peptidomics approach has provided some insights toward the answer to this question...

..In this review, peptidomics techniques are discussed along with the major findings of many recent studies and future directions for the field...

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..If mutations in CPA6 contribute to Duane syndrome, our results also suggest that Duane syndrome can be a chondrogenic rather than a myogenic or neurogenic developmental disorder...

..The overarching goals of this special issue involve defining the peptidome, identifying the current state of the field, and discussing methods to characterize the peptides, their receptors, and future needs for such measurements...

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..Taken together, the differential regulation of these peptides in the two paradigms suggests that the regulation is not due to the lower body weight but to the manner in which the paradigms achieved this lower body weight...

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..Taken together, these results provide interesting insights into endogenous neuropeptide systems that are modulated by morphine and suggest further experiments to link candidate peptides with long-term effects of morphine...

..The hot water/cold acid extraction procedure resulted in the reproducible recovery of many hypothalamic peptides, including several novel peptides...

..Taken together, these results indicate that CPE contributes, either directly or indirectly, to the production of the majority of neuropeptides...

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..The serum proteomics results indicated that Cpefat/fat and wild-type mice differed in their response to exercise...

..The finding that many peptides are substantially decreased in Cpe(fat/fat) pituitary is consistent with the broad role for carboxypeptidase E in the biosynthesis of numerous neuropeptides...

..In conclusion, both succinyl and TMAB isotopic labels are useful for quantitative peptidomics, and together these two labels provide more complete coverage of the endogenous peptides. Copyright (c) 2005 John Wiley & Sons, Ltd...

..Taken together, these findings suggest that the post-translational processing of alpha and beta hemoglobin into the hemopressins, as well as other peptides, is up-regulated in some but not all Cpe(fat/fat) mouse brain regions...

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..In the AtT-20 corticotroph cell line, CPA-5 has a perinuclear distribution. Taken together, these results are consistent with a role for CPA-5 in the intracellular processing of proopiomelanocortin-derived peptides at non-basic sites...

..The general method described in this report should be widely applicable to a large number of neuroendocrine peptides, known and novel, in a variety of regulatory paradigms...

..Taken together, these results are consistent with a role for proSAAS-derived peptides as neuropeptides that influence body weight independently of their function as inhibitors of prohormone convertase 1...

..These findings suggest that CPD domains-1 and -2 have largely redundant functions in the processing of growth factors, hormones, and neuropeptides...

..Analysis of these sites showed that while PC1/3 and PC2 have overlapping substrate preferences, there are particular cleavage site residues that distinguish peptides preferred by each PC...

..Flies that retain the short form are viable, whereas flies that are missing all forms of CPD do not survive past the early larval stages...

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..In general, the expression pattern of PC1 overlaps with that of SAAS and other proSAAS-derived peptides, consistent with the hypothesis that proSAAS functions as an endogenous PC1 inhibitor...

..These results are consistent with the acidic pH optima for peptide processing enzymes. Stable isotopic labeling with d10-Leu provides a sensitive method to examine the rate of peptide formation in neuroendocrine cell lines...

..In addition, the finding that the peptides are secreted via the regulated pathway is consistent with the proposal that they may function as neuropeptides...

..The differences in pH optima and substrate specificity between Drosophila domains 1B and 2 are similar to the differences between duck CPD domains 1 and 2, suggesting that these properties are essential to CPD function...

..Thus, the covalent attachment of palmitic acid to the Cys residues of CPD has a functional significance in the trafficking of the protein...

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..Together, these findings show that CPE is a key enzyme for pro-GnRH processing in vivo; however, the reproductive deficits in Cpe(fat/fat) males appear to be due primarily to abnormal sexual behavior...

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..Taken together, these results are consistent with a role for Nna1/CCP1 and the related CCPs in the processing of tubulin...

..Future perspectives for the regulation of these enzymes through the use of more selective and potent inhibitors are also discussed in this review and combined with earlier observations in the field...

..Taken together, these results are consistent with an important role for ECE-2 in the processing of regulatory peptides at nonclassical sites...

..Taken together, these data suggest a role for CPA6 in the regulation of neuropeptides in the extracellular environment within the olfactory bulb and other parts of the brain...

..Thirty other peptides were not substantially affected by cocaine treatment in both replicates. Taken together, the quantitative peptidomics approach provides an efficient method to screen for changes in a large number of peptides...

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..Taken together, these results suggest that CPD localization to the TGN requires both static retention involving the C-terminal domain and phosphorylation at a CK2 site, which regulates the binding of adaptor proteins...

..Taken together, the distribution of CPA6 suggests a specific role in a limited number of tissues, and it is possible that this role involves an aspect of cell migration...

..The CP on chromosome 8 is predicted to have a CPA-like specificity for C-terminal hydrophobic residues and was named CPA6. The CP on chromosome 2 is predicted to cleave substrates with C-terminal acidic residues and was named CPO...

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..Together, this concerted approach will provide important information regarding the role of CPD in the production of neuroendocrine peptides. ..

..This will provide a better understanding of the proteins, either known or novel, that interact with CPD. These studies on CPD will advance our knowledge of protein trafficking in neuroendocrine cells. ..

..The studies in this initial R21 will provide an unbiased survey of neuropeptides that are altered by food deprivation, and which may therefore be involved in regulating food intake and/or body weight. ..

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..The overall goal of this proposal is to understand the role of each domain within CPD, using a simple organism for which CPD mutants exist and which is amenable to transgenic analysis. ..

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..Taken together, these studies will provide a better understanding of the regulation of neuropeptides, both known and novel, in drug abuse. ..

..The results of these studies will provide a better understanding of the enzymes involved with peptide biosynthesis. ..

..Together, these complementary studies will provide important information on CPE, a key enzyme in the production of enkephalins and other molecules that are relevant to the biochemistry of drug abuse. ..

..The results of this multi-level analysis will provide a better understanding of the mechanisms responsible for the regulation of CPE expression and activity...