Summary for peptidase M14.005: carboxypeptidase E

Summary Gene structure Alignment Tree Sequences Sequence features Distribution Literature Human EST Mouse EST Substrates Inhibitors

 

Names
MEROPS Namecarboxypeptidase E
Other namescarboxypeptidase H, cobalt-stimulated chromaffin granule carboxypeptidase, crino carboxypeptidase B, enkephalin convertase, insulin granule-associated carboxypeptidase
Domain architecture
MEROPS Classification
Classification Clan MC >> Subclan (none) >> Family M14 >> Subfamily B >> M14.005
Holotypecarboxypeptidase E (Bos taurus), Uniprot accession P04836 (peptidase unit: 42-475), MERNUM MER0001202
History Identifier created: Handbook of Proteolytic Enzymes (1998) Academic Press, London.
Activity
Catalytic typeMetallo
PeplistIncluded in the Peplist with identifier PL00210
NC-IUBMBSubclass 3.4 (Peptidases) >> Sub-subclass 3.4.17 (Metallocarboxypeptidases) >> Peptidase 3.4.17.10
EnzymologyBRENDA database
Proteolytic eventsCutDB database (3 cleavages)
Activity statushuman: active (Fricker, 2004)
mouse: active (Gomez et al., 1999)
SpecificityCarboxypeptidase E cleaves C-terminal basic residues (Lys, Arg) from most peptides. Dipeptides are poorly cleaved; peptides with three or more residues are preferred. The P1 site is important: Xaa-Pro-Arg is very slowly cleaved; Xaa-Gly-Arg is the second slowest; and most other amino acids are cleaved with generally similar rates, although Xaa-Ala-Arg is the best substrate (Fricker & Snyder, 1982; Smyth et al., 1989).
pH optimum5.0-5.5 (Greene et al., 1992)
Substrate commentsPhysiological substrates include enkephalin-Lys-Arg and enkephalin-Arg-Arg, and all other processing intermediates generated by the action of prohormone convertases on proneuropeptides/prohormones (Zheng et al., 1994).
Inhibitor commentsNo physiological inhibitors are known. Chemical inhibitors include chelating agents (1,10-phenanthroline) and more selective agents such as guanidinoethylmercaptosuccinic acid (GEMSA). However, GEMSA inhibits several other metallo-carboxypeptidases including carboxypeptidases B (M14.003), D (XM14-001), M (M14.006), and Z (M14.012), and is not specific for carboxypeptidase E.
LocationCarboxypeptidase E is present in the secretory pathway. It is inactive in the endoplasmic reticulum and Golgi due to the neutral pH of these compartments. After sorting into secretory granules in the trans Golgi network, the decreasing pH of the maturing granules activates carboxypeptidase E where if functions in peptide biosynthesis (Fricker & Snyder, 1982; Hook & Loh, 1984; Docherty & Hutton, 1983). Carboxypeptidase E is secreted from cells along with the peptide cargo of the vesicle, but is not thought to be enzymatically active after secretion due to the stringent requirement of an acidic pH for enzyme activity.
PhysiologyInvolved in biosynthesis of many peptide hormones and neurotransmitters.
Biological aspectsCarboxypeptidase E is responsible for the final enzymatic step in the production of many neuropeptides and peptide hormones. A mouse mutation that eliminates carboxypeptidase E activity causes mice to be overweight and have behavioral problems (infertility due to inability to mate, also anxiety and depression) (Fricker & Leiter, 1999; Srinivasan et al., 2004). Mice heterozygous for the mutation in CPE (named the fat mutation (Naggert et al., 1995)) are normal in terms of body weight and behavior. Mutations in the human CPE gene have been found (Utsunomiya et al., 1998; Chen et al., 2001), but none of the mutations that reduce carboxypeptidase E activity were found in both human alleles. Therefore, mutations in carboxypeptidase E are not thought to contribute to the majority of cases of human obesity.
KnockoutA spontaneous point mutation in the coding region of the carboxypeptidase E gene results in a loss of enzymatic activity that correlates with the development of late onset obesity (Naggert et al., 1995). The protein acts as a sorting receptor as well as an enzyme, and its obliteration leads to multiple endocrine disorders including hyperproinsulinemia and infertility (Berman et al., 2001).
Pathways KEGGType I diabetes mellitus
Contributing authorsLloyd D. Fricker, Departments of Molecular Pharmacology and Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Other databases WIKIPEDIAhttp://en.wikipedia.org/wiki/Carboxypeptidase_E
Cleavage site specificity Explanations of how to interpret the following cleavage site sequence logo and specificity matrix can be found here.
Cleavage pattern-/-/fg/agrScissile bondR/-/-/- (based on 22 cleavages)
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Specificity matrix
 
Amino acid P4 P3 P2 P1 P1' P2' P3' P4'
Gly 3 2 5 5 1 0 0 0
Pro 2 2 0 1 0 0 0 0
Ala 0 0 0 5 0 0 0 0
Val 0 0 0 0 0 0 0 0
Leu 0 1 2 1 0 0 0 0
Ile 0 0 0 0 0 0 0 0
Met 3 0 0 0 0 0 0 0
Phe 0 3 6 0 0 0 0 0
Tyr 0 1 2 1 0 0 0 0
Trp 0 0 0 0 0 0 0 0
Ser 2 1 0 0 0 0 0 0
Thr 2 1 2 1 0 0 0 0
Cys 0 0 0 0 0 0 0 0
Asn 1 1 0 0 0 0 0 0
Gln 0 0 1 1 0 0 0 0
Asp 2 3 0 0 0 0 0 0
Glu 0 0 0 0 0 0 0 0
Lys 0 1 1 3 4 0 0 0
Arg 1 0 0 4 17 0 0 0
His 0 0 0 0 0 0 0 0
Mouse genetics
Gene symbol Position Megabases Ensembl Entrez gene MGI
Cpe 8:B3.1 ENSMUSG00000037852 12876 MGI:101932