Disease relevance of TRHDE

• We studied serum pyroglutamyl peptidase-II activity in 6 patients with hyperthyroidism, 18 patients with hypothyroidism, and 31 euthyroid, normal weight volunteers [1].
• Serum pyroglutamyl peptidase-II activity was elevated in patients with hypothyroidism (mean +/- SEM, 33.9 +/- 3.7 nmol/mL.h) compared to that in euthyroid, normal weight volunteers (24.5 +/- 2.8 nmol/mL.h; P < 0.05), but not that in patients with hyperthyroidism (28.3 +/- 4.1 nmol/mL.h; P = NS) [1].
• We conclude that serum pyroglutamyl peptidase-II activity is regulated by, or regulates, body weight [1].
• Because TRH [or its metabolite cyclo(His-Pro)] is believed to be an important hormone regulating appetite and metabolism, we also evaluated pyroglutamyl peptidase-II activity in 27 euthyroid patients with obesity [1].
• For the TRH-degrading ectoenzyme, a potential regulator of TRH signals at adenohypophyseal target sites, transcripts were significantly expressed only in the TRH-producing adenomas [2].

High impact information on TRHDE

• Pyroglutamyl peptidase II (PPII), a highly specific membrane-bound omegapeptidase, removes N-terminal pyroglutamyl from thyrotropin-releasing hormone (<Glu-His-Pro-NH(2)), inactivating the peptide in the extracellular space [3].
• Pyroglutamyl peptidase-II ("thyroliberinase") activity in human serum: influence of weight and thyroid status [1].
• Because pyroglutamyl peptidase-II activity in rat serum is regulated by thyroid hormone levels, we tested the hypothesis that this activity is similarly altered in humans [1].
• Inhibition of pyroglutamyl peptidase II synthesis by phorbol ester in the Y-79 retinoblastoma cell [4].
• Immunoblot experiments demonstrated a reduction in the amount of pyroglutamyl peptidase II in Y-79 membranes after long term exposure to TPA [4].

Biological context of TRHDE

• Using fluorescent in situ hybridization with the cDNA and a genomic lambda clone, respectively, we localized the TRH-DE gene to the long arm of human chromosome 12 [5].
• Specific enzymatic activity was observed after transfecting COS-7 cells with human TRH-DE cDNA yielding a Km for TRH hydrolysis of 29.7 microM [5].
• Rapid inactivation and phosphorylation of pyroglutamyl peptidase II in Y-79 human retinoblastoma cells after exposure to phorbol ester [6].
• In situ-hybridization histochemistry was used to study the TRHergic communication system by analyzing the gene expression of TRH-DE in relation to TRH and to the TRH receptors (TRH-R1 and TRH-R2) [7].

Anatomical context of TRHDE

• Incubation of TPA-activated Y-79 cell membranes with gamma-[32P]-ATP followed by immunoprecipitation revealed a time-dependent phosphorylation of a 48 kilodalton subunit of pyroglutamyl peptidase II [6].
• The specific activity of pyroglutamyl peptidase II in Y79 retinoblastoma cells was greater than the highest activity found in other cell lines by approximately one order of magnitude [8].
• Pyroglutamyl peptidase II, a highly specific thyrotropin releasing hormone (TRH)-degrading enzyme is found in highest concentration in brain where it is localized to synaptic membranes [8].

Associations of TRHDE with chemical compounds

• Pretreatment of the cells with the protein kinase C inhibitors H-7 or sphingosine prevented the inactivation of pyroglutamyl peptidase II by TPA [6].
• The stringent and tissue-specific regulation of the adenohypophyseal TRH-DE by estradiol and thyroid hormones strongly suggests that this enzyme may act as a regulatory element modulating pituitary hormone secretion [9].
• 5. Once TRH is released, it is inactivated by a narrow specificity ectoenzyme, pyroglutamyl peptidase II (PPII) [10].

Regulatory relationships of TRHDE

• Vice versa it also holds true that TRH is selectively inactivated only by TRH-DE and thus, this enzyme might be considered to be the terminator of TRH signals [7].

Analytical, diagnostic and therapeutic context of TRHDE

• Homology modeling and site-directed mutagenesis of pyroglutamyl peptidase II. Insights into omega-versus aminopeptidase specificity in the M1 family [3].
• Pyroglutamyl peptidase-II activity was positively correlated with body mass index (r2 = 0.30; P < 0.0001) [1].
• After succeeding in purifying this enzyme to homogeneity and cloning the cDNA encoding rat TRH-DE, molecular tools became available to study the expression of this enzyme by Northern blot analysis and in situ hybridization histochemistry [9].

References