Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prolyl oligopeptidase is a large monomeric proline specific serine endopeptidase, the activity of which correlates well with different stages of depression. We have subregionally mapped human lymphocytic prolyl oligopeptidase (PREP) by FISH using a cosmid probe. The probe mapped to the long arm of chromosome 6, and the signal clustered in band q22.
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PMID:Subregional mapping of the human lymphocyte prolyl oligopeptidase gene (PREP) to human chromosome 6q22. 889 11

The therapeutic properties of lithium ions (Li+) are well known; however, the mechanism of their action remains unclear. To investigate this problem, we have isolated Li+-resistant mutants from Dictyostelium. Here, we describe the analysis of one of these mutants. This mutant lacks the Dictyostelium prolyl oligopeptidase gene (dpoA). We have examined the relationship between dpoA and the two major biological targets of lithium: glycogen synthase kinase 3 (GSK-3) and signal transduction via inositol (1,4,5) trisphosphate (IP3). We find no evidence for an interaction with GSK-3, but instead find that loss of dpoA causes an increased concentration of IP3. The same increase in IP3 is induced in wild-type cells by a prolyl oligopeptidase (POase) inhibitor. IP3 concentrations increase via an unconventional mechanism that involves enhanced dephosphorylation of inositol (1,3,4,5,6) pentakisphosphate. Loss of DpoA activity therefore counteracts the reduction in IP3 concentration caused by Li+ treatment. Abnormal POase activity is associated with both unipolar and bipolar depression; however, the function of POase in these conditions is unclear. Our results offer a novel mechanism that links POase activity to IP3 signalling and provides further clues for the action of Li+ in the treatment of depression.
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PMID:Loss of a prolyl oligopeptidase confers resistance to lithium by elevation of inositol (1,4,5) trisphosphate. 1032 20

A group of serine peptidases, the prolyl oligopeptidase family, cannot hydrolyze peptides containing more than about 30 residues. This group is unrelated to the classical trypsin and subtilisin families, and includes dipeptidyl peptidase IV, acylaminoacyl peptidase and oligopeptidase B, in addition to the prototype prolyl oligopeptidase. The recent crystal structure determination of prolyl oligopeptidase (80 kDa) has shown that the enzyme contains a peptidase domain with an alpha/beta hydrolase fold, and its catalytic triad is covered by the central tunnel of an unusual seven-bladed beta-propeller. This domain operates as a gating filter, excluding large, structured peptides from the active site. The binding mode of substrates and the catalytic mechanism differ from that of the classical serine peptidases in several features. The members of the family are important targets of drug design. Prolyl oligopeptidase is involved in amnesia, depression and blood pressure control, dipeptidyl peptidase IV in type 2 diabetes and oligopeptidase B in trypanosomiasis.
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PMID:The prolyl oligopeptidase family. 1191 48

Manic-depression, or bipolar affective disorder, is a prevalent mental disorder with a global impact. Mood stabilizers have acute and long-term effects and at a minimum are prophylactic for manic or depressive poles without detriment to the other. Lithium has significant effects on mania and depression, but may be augmented or substituted by some antiepileptic drugs. The biochemical basis for mood stabilizer therapies or the molecular origins of bipolar disorder is unknown. One approach to this problem is to seek a common target of all mood stabilizers. Lithium directly inhibits two evolutionarily conserved signal transduction pathways. It both suppresses inositol signaling through depletion of intracellular inositol and inhibits glycogen synthase kinase-3 (GSK-3), a multifunctional protein kinase. A number of GSK-3 substrates are involved in neuronal function and organization, and therefore present plausible targets for therapy. Valproic acid (VPA) is an antiepileptic drug with mood-stabilizing properties. It may indirectly reduce GSK-3 activity, and can up-regulate gene expression through inhibition of histone deacetylase. These effects, however, are not conserved between different cell types. VPA also inhibits inositol signaling through an inositol-depletion mechanism. There is no evidence for GSK-3 inhibition by carbamazepine, a second antiepileptic mood stabilizer. In contrast, this drug alters neuronal morphology through an inositol-depletion mechanism as seen with lithium and VPA. Studies on the enzyme prolyl oligopeptidase and the sodium myo-inositol transporter support an inositol-depletion mechanism for mood stabilizer action. Despite these intriguing observations, it remains unclear how changes in inositol signaling underlie the origins of bipolar disorder.
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PMID:Search for a common mechanism of mood stabilizers. 1282 61

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.
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PMID:Serum activity of prolyl endopeptidase, but not of dipeptidyl peptidase IV, is decreased by immunotherapy with IFN-alpha in high-risk melanoma patients. 1529 52

Prolyl oligopeptidase is implicated in the metabolism of neuropeptides and is involved in amnesia and depression. It contains a peptidase and an unusual beta-propeller domain that excludes large peptides and proteins from the active site. The propeller consists of seven blades not closed by a "Velcro" between the first and last blades. The propeller domain was expressed as a stable, soluble protein, P(7). Its conformational identity with that of the native propeller was verified by circular dichroism and digestion with trypsin. Differential scanning calorimetry, kinetic denaturation with urea and equilibrium denaturation with guanidinium chloride have shown that the propeller is more stable than the parent prolyl oligopeptidase. The deletion of the seventh blade of P(7) led to a stable structure, a six-bladed propeller, P(6), which immediately dimerized, in contrast with the monomeric P(7). Addition of an 11 amino acid residue extension to the C terminus of P(6) also produced a dimer, whereas the P(6) labelled with a His-tag at the N terminus displayed a monomer structure. The stability of P(6) and its variants was lower than that of P(7). The denatured propellers refolded readily. This study shows that the unclosed P(7) is a stable structure, and suggests that an opening between the peptidase and the propeller domains is more important for the substrate entry than is the putative opening between the first and seventh blades. Our results suggest that the propellers are simple, versatile structures, which can be prepared artificially.
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PMID:Unclosed beta-propellers display stable structures: implications for substrate access to the active site of prolyl oligopeptidase. 1571 71

The mood stabilizing drugs commonly used to treat bipolar disorder--lithium, valproic acid (VPA), and carbamazepine (CBZ)--limit the frequency of swings to either manic or depressive states. We previously showed that these drugs all have a common action on cultured neurons, which can be reversed by the addition of either inositol or specific inhibitors of the enzyme prolyl oligopeptidase (PO). Inhibition of PO activity is reported to enhance phosphoinositide (PIns) signaling consistent with the suggestion that mood stabilizers inhibit PIns signaling. We now report that VPA directly inhibits recombinant PO activity, which would have the opposite effect on PIns signaling. This unexpected result suggests a model that could explain the dual action of VPA in stabilizing mood: we propose that euthymic mood is dependent on stable PIns signaling and that VPA may limit mood swings to mania by decreasing PIns signaling, and that it may limit mood swings to depression by inhibiting PO and thus increasing PIns signaling.
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PMID:How can the mood stabilizer VPA limit both mania and depression? 1591 40

Prolyl oligopeptidase family enzymes regulate the activity of biologically active peptides and peptide hormones, and they are implicated in diseases, including amnesia, depression, diabetes, and trypanosomiasis. Distinctively, these enzymes hydrolyze only relatively short peptide substrates, while large structured peptides and proteins are not usually cleaved. Prolyl oligopeptidase has a C-terminal alpha/beta-hydrolase catalytic domain that is similar to lipases and esterases. An N-terminal beta-propeller domain regulates access to the buried active site, explaining the observed oligopeptidase activity. The catalytic and regulatory mechanisms have been investigated using a combination of X-ray crystallography, site-directed mutagenesis, and enzyme kinetic measurements. Crystal structures have now been determined for representative members of three of the four subfamilies and are facilitating a better understanding of the structure-function properties of these physiologically and pharmaceutically important enzymes.
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PMID:Structure-function properties of prolyl oligopeptidase family enzymes. 1667 22

Prolyl oligopeptidase (POP) is a serine endopeptidase which hydrolyzes proline-containing peptides shorter than 30 amino acids. It has been suggested that POP is associated with cognitive functions, possibly via the cleavage of neuropeptides such as substance P (SP). Recently, several studies have also linked POP to the inositol 1,4,5-triphosphate (IP(3)) signaling. However, the neuroanatomical interactions between these substances are not known. We used double-labeled immunofluorescence to determine the POP colocalization with SP, SP receptor (neurokinin-1 receptor, NK-1R) and IP(3) type 1 receptor (IP(3)R1) in the rat brain. Furthermore, since striatal and cortical GABAergic neurons are involved in SP neurotransmission, we studied the coexpression of POP, SP and GABA by triple-labeled immunofluorescence. POP was moderately present in IP(3)R1-containing cells in cortex; the colocalization was particularly high in the thalamus, hippocampal CA1 field and cerebellar Purkinje cells. Colocalization of POP with SP and NK1-receptor was infrequent throughout the brain, though some POP and SP coexpression was observed in cerebellar Purkinje cells. We also found that POP partially colocalized with SP-containing GABAergic neurons in striatum and cortex. Our findings support the view that POP is at least spatially associated with the IP(3)-signaling in the thalamus, hippocampus and cerebellar Purkinje cells. This might point to a role for POP in the regulation of long-term potentiation and/or depression. Moreover, the low degree of colocalization of POP, SP and its NK-1R suggests that a transport system is needed either for POP or SP to make hydrolysis possible and that POP may act both intra- and extracellularly.
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PMID:Spatial association of prolyl oligopeptidase, inositol 1,4,5-triphosphate type 1 receptor, substance P and its neurokinin-1 receptor in the rat brain: an immunohistochemical colocalization study. 1845 82

Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.
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PMID:Plasma activity of prolyl endopeptidase in relation to psychopathology during immunotherapy with IFN-alpha in patients with renal cell carcinoma. 1854 58


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