Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.4.22.62 (
caspase-9
)
7,507
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
L-Histidine decarboxylase (
HDC
) is the rate-limiting enzyme for histamine synthesis in mammals. Although accumulating evidence has indicated the post-translational processing of
HDC
, it remains unknown what kinds of proteases are involved. We investigated the processing of
HDC
in a mouse mastocytoma, P-815, using a lentiviral expression system.
HDC
was expressed as a 74-kDa precursor form, which is cleaved to yield the 55- and 60-kDa forms upon treatment with butyrate. Alanine-scanning mutations revealed that two tandem aspartate residues (Asp(517)-Asp(518), Asp(550)-Asp(551)) are critical for the processing. Treatment with butyrate caused an increase in the enzyme activity of the cells expressing the wild type
HDC
, but not in the cells expressing the processing-incompetent mutant. An increase in histamine synthesis by butyrate was accompanied by formation of the 55- and 60-kDa form of
HDC
. In addition, the in vitro translated 74-kDa form of
HDC
was found to undergo a limited cleavage by purified human
caspase-9
, whereas the alanine-substituted mutants were not. Processing and enzymatic activation of
HDC
in P-815 cells was enhanced in the presence of a Zn(2+) chelator, TPEN. Although treatment with butyrate and TPEN drastically augmented the protease activity of caspase-3, and -9, no apoptotic cell death was observed. Both enzymatic activation and processing of
HDC
were completely suppressed by a pan-caspase inhibitor, partially but significantly by a specific inhibitor for
caspase-9
, but not by a caspase-3 inhibitor. These results suggest that, in P-815 cells, histamine synthesis is augmented through the post-translational cleavage of
HDC
, which is mediated by
caspase-9
.
...
PMID:Activation of histidine decarboxylase through post-translational cleavage by caspase-9 in a mouse mastocytoma P-815. 1736 Jul 17
In the mammalian species studied so far, the
L-histidine decarboxylase
(HDC) enzyme responsible for histamine biosynthesis has been shown to undergo post-translational processing. The processing is best characterized for the mouse enzyme, where di-asparate DD motifs mediate the production of active ~55 and ~60 kDa isoforms from the ~74 kDa precursor in a
caspase-9
dependent manner. The identification of conserved di-aspartate motifs at similar locations in the rat and human HDC protein sequences has led to proposals that these may represent important processing sites in these species also. Here we used transfected Cos7 cells to demonstrate that the rat and human HDC proteins undergo differential processing compared to each other, and found no evidence to suggest that conserved di-aspartate motifs are required absolutely for processing in this cell type. Instead we identified SKD and EEAPD motifs that are important for caspase-6 dependent production of ~54 and ~59 kDa isoforms in the rat and human proteins, respectively. The addition of staurosporine, which is known to pharmacologically activate caspase enzymes, increased processing of the human HDC protein. We propose that caspase-dependent processing is a conserved feature of mammalian HDC enzymes, but that proteolysis may involve different enzymes and occur at diverse sites and sequences.
...
PMID:Differential processing of mammalian L-histidine decarboxylase enzymes. 2450 57
