Prodynorphin Processing by Proprotein Convertase 2

Day, Robert; Lazure, Claude; Basak, Ajoy; Boudreault, Alain; Limperis, Paul; Dong, Weijia; Lindberg, Iris

doi:10.1074/jbc.273.2.829

Cited by 128 publications

(55 citation statements)

References 51 publications

(44 reference statements)

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“…A number of studies (both in vitro as well as in vivo) implicate PC1 and PC2 in ProDyn processing (12)(13)(14). Studies using mice lacking PC2 activity (PC2 K/O) show a complete lack of Dyn A-8 and substantially reduced levels of Dyn A-17 and Dyn B-13 (13,14).…”

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confidence: 99%

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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confidence: 99%

Impaired Prohormone Convertases in Cpe fat/Cpe fat Mice

Berman¹,

Mzhavia²,

Polonskaia³

et al. 2001

Journal of Biological Chemistry

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“…These results suggest that although PC1 is able to process prodynorphin at monobasic sites, the efficiency of processing at this site is substantially lower than the processing at dibasic sites. Recent studies have shown that purified PC2 is able to process prodynorphin efficiently, generating dynorphin A-8 and dynorphin B-13 (Berman et al, 1997;Day et al, 1998), supporting a role for PC2 in the processing of prodynorphin at monobasic sites.…”

Section: Discussionmentioning

confidence: 99%

Specificity of the Dynorphin‐Processing Endoprotease: Comparison with Prohormone Convertases

Berman

Juliano

Devi

1999

Journal of Neurochemistry

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Abstract:The cleavage specificity of a monobasic processing dynorphin converting endoprotease is examined with a series of quench fluorescent peptide substrates and compared with the cleavage specificity of prohormone convertases. A dynorphin B-29-derived peptide, Abz-Arg-Arg-Gln-Phe-Lys-Val-Val-Thr-Arg-Ser-Glneddnp (where Abz is o-aminobenzoyl and eddnp is ethylenediamine 2,4-dinitrophenyl), that contains both dibasic and monobasic cleavage sites is efficiently cleaved by the dynorphin converting enzyme and not cleaved by two propeptide processing enzymes, furin and prohormone convertase 1. A shorter prorenin-related peptide, DnpArg-Met-Ala-Arg-Leu-Thr-Leu-eddnp, that contains a monobasic cleavage site is cleaved by the dynorphin converting enzyme and prohormone convertase 1 and not by furin. Substitution of the P1' position by Ala moderately affects cleavage by the dynorphin-processing enzyme and prohormone convertase 1. It is interesting that this substitution results in efficient cleavage by furin. The site of cleavage, as determined by matrix-assisted laser desorption/ionization time of flight mass spectrometry, is N-terminal to the Arg at the P1 position for the dynorphin converting enzyme and C-terminal to the Arg at the P1 position for furin and prohormone convertase 1. Peptides with additional basic residues at the P2 and at P4 positions also serve as substrates for the dynorphin converting enzyme. This enzyme cleaves shorter peptide substrates with significantly lower efficiency as compared with the longer peptide substrates, suggesting that the dynorphin converting enzyme prefers longer peptides that contain monobasic processing sites as substrates. Taken together, these results suggest that the cleavage specificity of the dynorphin converting enzyme is distinct but related to the cleavage specificity of the prohormone convertases and that multiple enzymes could be involved in the processing of peptide hormones and neuropeptides at monobasic and dibasic sites.

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“…The RIA against Dyn A-(1-8) has been extensively characterized (4,24). Briefly, the Dyn A-(1-8) antibody is C-terminally targeted and does not cross-react with Dyn A-(1-17) or larger forms of pro-Dyn-derived peptides.…”

Section: Methodsmentioning

confidence: 99%

“…7A). The formation of Dyn A-(1-8) is specifically due to the cleavage of its precursor Dyn A-(1-17) by SPC2 (24). The production of the Dyn A-(1-8) is an exclusive character of the ␤TC-3 cells (4), and as a consequence, inhibition of the enzyme can be monitored by analysis of this peptide in crude protein extracts by RIA.…”

Section: Identification Of Potential Targetmentioning

confidence: 99%

Silencing of SPC2 Expression Using an Engineered δ Ribozyme in the Mouse βTC-3 Endocrine Cell Line

Danjou

Bergeron

Larbi

et al. 2004

Journal of Biological Chemistry

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-(1-17) by SPC2. Moreover, a differential proteomic analysis confirmed these results and allowed identification of secretogranin II as a potential substrate of SPC2. The development of efficient, specific, and durable silencing tools, such as described in the present work, will be of great importance in elucidating the functions of the subtilaselike pro-protein convertases in regard to peptide processing and derived cellular events.

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Prodynorphin Processing by Proprotein Convertase 2

Cited by 128 publications

References 51 publications

Impaired Prohormone Convertases in Cpe fat/Cpe fat Mice

Impaired Prohormone Convertases in Cpe fat/Cpe fat Mice

Specificity of the Dynorphin‐Processing Endoprotease: Comparison with Prohormone Convertases

Silencing of SPC2 Expression Using an Engineered δ Ribozyme in the Mouse βTC-3 Endocrine Cell Line

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