Catalysis of Slow C‐Terminal Processing Reactions by Carboxypeptidase H

Smyth, Derek G.; Maruthainar, K.; Darby, Nigel J.; Fricker, Lloyd D.

doi:10.1111/j.1471-4159.1989.tb07360.x

Cited by 38 publications

(11 citation statements)

References 16 publications

(13 reference statements)

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“…Peptides with X=Pro are not cleaved by the maximum amount of wild type CPE used in the present study (Fig. 5A), consistent with previous studies with proline containing peptides [Smyth et al, 1989]. To achieve equivalent hydrolysis as the peptide with X=Met, peptides with X=Gly and Trp require approximately 100-fold more wild type CPE and the other peptides present in the mixture require approximately 10-fold more CPE (Fig.…”

Section: Resultssupporting

confidence: 92%

Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity

et al. 2001

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Carboxypeptidase E (CPE) is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. One of the features of type 2 diabetes mellitus (T2DM) is an elevation in the proinsulin level and/or proinsulin/insulin molar ratio, suggesting that mutations in proinsulin processing enzymes may contribute to the development of T2DM. We scanned CPE for mutations in a collection of Ashkenazi T2DM families and identified five novel single nucleotide polymorphisms (SNPs). An SNP in the 283(rd) codon, c.847C>T, changes arginine to tryptophan (R283W). The residue Arg283 is conserved among CPE orthologs as well as most enzymatically active metallocarboxypeptidases. Of the 272 Ashkenazi T2DM pedigrees screened, we found four families segregating R283W. Within these four families, patients who inherited one copy of this variant had much earlier age of onset for T2DM. The R283W CPE protein cleaves peptide substrates with substantially lower efficiencies and is less stable at elevated temperature. In addition, the R283W CPE variant has a narrower pH optimum and is much less active at pH 6.0-6.5, indicating that the R283W CPE variant would be substantially less active than wild type CPE in the trans-Golgi network and immature secretory vesicles where the enzyme functions in vivo. To summarize, we uncovered a rare non-conservative missense mutation in CPE and demonstrated that the mutant protein has altered enzymatic properties. We predict that this mutant could cause hyperproinsulinism and diabetes in the homozygous state.

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Section: Resultssupporting

confidence: 92%

Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity

et al. 2001

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“…7). This finding is in a good agreement with a previous report showing that CPE catalyzes the conversion of ␤-endorphin 1-27 into ␤-endorphin 1-26 (43). It is possible that CPE also catalyzes the C-terminal proteolysis of acetylated ␤-endorphin 1-31, which terminates in Gln; in the absence of CPE, we found an accumulation of the latter in Cpe fat mice (Fig.…”

Section: Prodyn and Pomc Processing In Cpesupporting

confidence: 82%

Impaired Prohormone Convertases in Cpe fat/Cpe fat Mice

Berman¹,

Mzhavia²,

Polonskaia³

et al. 2001

Journal of Biological Chemistry

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. (1995) Nat. Genet. 10, 135-142). Examination of the level of neuropeptides in these mice showed a decrease in mature bioactive peptides as a result of a decrease in both carboxypeptidase and prohormone convertase activities. A defect in CPE is not expected to affect endoproteolytic processing. In this report we have addressed the mechanism of this unexpected finding by directly examining the expression of the major precursor processing endoproteases, prohormone convertases PC1 and PC2 in Cpe fat mice. We found that the levels of PC1 and PC2 are differentially altered in a number of brain regions and in the pituitary. Since these enzymes have been implicated in the generation of neuroendocrine peptides (dynorphin A-17, ␤-endorphin, and ␣-melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of these peptides in Cpe fat and wild type animals. We found a marked increase in the level of dynorphin A-17, a decrease in the level of ␣-melanocyte-stimulating hormone, and an alteration in the level of C-terminally processed ␤-endorphin. These results suggest that the impairment in the level of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activities and that this may lead to the development of obesity in these animals.

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“…CPE is specific for removing C-terminal basic residues, with no activity towards nonbasic residues (79). Apart from the requirement for C-terminal basic residues, CPE has a wide range of substrates and can efficiently remove basic residues from all known peptide processing intermediates except for those containing a proline in the penultimate position (80). The action of CPE in peptide processing is confirmed by studies on mice lacking CPE.…”

Section: Propertiesmentioning

confidence: 99%

Dissecting carboxypeptidase E: properties, functions and pathophysiological roles in disease

Qin

et al. 2017

Endocrine Connections

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Since discovery in 1982, carboxypeptidase E (CPE) has been shown to be involved in the biosynthesis of a wide range of neuropeptides and peptide hormones in endocrine tissues, and in the nervous system. This protein is produced from pro-CPE and exists in soluble and membrane forms. Membrane CPE mediates the targeting of prohormones to the regulated secretory pathway, while soluble CPE acts as an exopeptidase and cleaves C-terminal basic residues from peptide intermediates to generate bioactive peptides. CPE also participates in protein internalization, vesicle transport and regulation of signaling pathways. Therefore, in two types of CPE mutant mice, Cpefat/Cpefat and Cpe knockout, loss of normal CPE leads to a lot of disorders, including diabetes, hyperproinsulinemia, low bone mineral density and deficits in learning and memory. In addition, the potential roles of CPE and ΔN-CPE, an N-terminal truncated form, in tumorigenesis and diagnosis were also addressed. Herein, we focus on dissecting the pathophysiological roles of CPE in the endocrine and nervous systems, and related diseases.

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Catalysis of Slow C‐Terminal Processing Reactions by Carboxypeptidase H

Cited by 38 publications

References 16 publications

Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity

Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity

Impaired Prohormone Convertases in Cpe fat/Cpe fat Mice

Dissecting carboxypeptidase E: properties, functions and pathophysiological roles in disease

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