Disease relevance of PSME3

• Identification of PSME3 as a Novel Serum Tumor Marker for Colorectal Cancer by Combining Two-dimensional Polyacrylamide Gel Electrophoresis with a Strictly Mass Spectrometry-based Approach for Data Analysis [1].
• Relationships between autoantibody responses to deletion mutants of Ki antigen and clinical manifestations of lupus [2].
• By using anti-Ki serum as a probe we have cloned a bovine cDNA directing the synthesis in Escherichia coli of a polypeptide immunologically indistinguishable from the authentic Ki antigen [3].
• The peptide U-81749 inhibited recombinant HIV-1 protease in vitro (inhibition constant Ki of 70 nanomolar) and HIV-1 replication in human peripheral blood lymphocytes (inhibitory concentration IC50 of 0.1 to 1 micromolar) [4].
• All inhibitors showed very high potency against HIV PR in vitro, and their Ki values ranged between 1.1 and 2.6 nM [5].

Psychiatry related information on PSME3

• The enzyme was strongly inhibited by the Kunitz inhibitor domain peptide of Alzheimer's disease amyloid protein precursor (Ki value, 0.35 nM) and by the microbial inhibitors leupeptin and anti-pain [6].

High impact information on PSME3

• Heparin (1 unit/ml) did not significantly effect inhibition of trypsin, but inhibition of XIa was 15 times greater (Ki = 25 +/- 15 pM) in the presence of heparin [7].
• PN-2/A beta PP inhibited Factor IXa with a Ki of 7.9 to 3.9 x 10(-11) M in the absence and presence of heparin, respectively [8].
• The presence of PA28gamma in coilin-containing complexes is increased by UV-C [9].
• Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28gamma-dependent manner [10].
• Here we show that a knockout of the PA28gamma gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC [10].

Chemical compound and disease context of PSME3

• Haloperidol inhibits the HIV-1 and HIV-2 proteases in a concentration-dependent fashion with a Ki of approximately 100 microM [11].
• The concentrations of inhibitors were at orders of magnitude higher than their Ki values to serine and cysteine proteases implicated in metastasis, thus ensuring a complete inhibition for tumor secreted proteases such as cathepsin B-like proteases, plasminogen activators, and plasmin [12].
• ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 microM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, </=0. 06 microM) [13].
• Inhibition constants (Ki) with purified HIV-1 protease depend strongly on the isostere in the order Phe psi Gly greater than Phe psi Ala greater than Phe psi NorVal greater than Phe psi Leu greater than Phe psi Phe and decrease with increasing length of the peptide analogue, converging to a value of 0.4 nM [14].
• Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, Ki = 0.48 microM) [15].

Biological context of PSME3

• To validate this finding, antibody to PSME3 was developed, and up-regulation in CRC was confirmed by Western blot analysis and immunohistochemistry [1].
• Screening of an adult brain cDNA library led to isolation of proteasome activator 28 subunit, PA28gamma [16].
• Moreover, endogenous PA28gamma was cleaved during not only Fas-induced apoptosis of HeLa cells, but also cisplatin-induced cell death of MCF7 cells, which are devoid of caspase-3 [16].
• Since both PA28alpha and Ki are elements of the PA28 complex and their amino acid sequences share 40.2% homology, immunoreactivity to PA28alpha was studied further [17].
• The relationship between anti-PA28alpha and Ki antibodies suggests the importance of an antigen-driven system in the induction of an autoimmune response to PA28 complex [17].

Anatomical context of PSME3

• In contrast, the PA28gamma antiserum labels the nucleus but not the nucleoli while in the cytoplasm it labels two different classes of structures identified as microtubular-like extensions and inclusion bodies that are most likely autophagosomes [18].
• This enabled us to locate the P1 residues within the reactive sites (Leu-30 for PMP-C and Arg-29 for PMP-D2 and HI), and, interestingly, variants of PMP-D2 and HI were converted into powerful inhibitors of both alpha-chymotrypsin and leukocyte elastase, the most potent elastase inhibitor obtained in this study having a Ki of 3 nM [19].
• The Ki values were lower for reactions on purified lipid than for reactions on monocyte surfaces and for reactions on resting than on endotoxin-stimulated monocytes [20].
• L-Thyroxine selectively inhibited Ca2+-calmodulin-activated myosin light chain kinases (MLC kinase) purified from rabbit skeletal muscle, chicken gizzard smooth muscle, bovine thyroid gland, and human platelet with similar Ki values (Ki = 2.5 microM) [21].
• In this paper, we show the abnormally high expression of PA28-gamma in various thyroid neoplasms [22].

Associations of PSME3 with chemical compounds

• It exists as a unique homopolymer under non-denaturing conditions. gamma-IFN was found to induce the expression of PA28 alpha and PA28 beta, whereas it caused almost complete loss of the PA28 gamma protein in cells [23].
• Proteasome activator subunit PA28 alpha and related Ki antigen (PA28 gamma) are absent from the nuclear fraction purified by sucrose gradient centrifugation [24].
• A special interaction with the "insertion loop" of thrombin (Tyr60A-Thr60I) is manifested through engagement of the hydroxyphenyl group of CtA with Trp60D as part of an "aromatic stacking chain." Biochemical inhibition data (Ki values at 37 degrees C) were obtained for CtA with thrombin and a diverse collection of serine proteases [25].
• The effector molecule, epsilon-amino hexanoic acid (epsilon Ahx; epsilon-aminocaproic acid), inhibits the overall fibrinolytic effect of rTPA in this system, with an effective Ki of approximately 1.5 mM [26].
• The sequence of the inhibitor JG-365 is Ac-Ser-Leu-Asn-Phe-psi[CH(OH)CH2N]-Pro-Ile-Val-OMe; the Ki is 0.24 nM [27].

Co-localisations of PSME3

• PA28alpha and PA28beta are co-localized in the cell whereas PA28gamma has a different distribution [18].

Other interactions of PSME3

• Finally we showed that the human chromosomal genes of PA28 alpha and PA28 gamma were located on 14q11.2 and 17q21.32-21.33, respectively [23].
• CrmA is quite selective in its ability to inhibit caspases, showing the highest affinity for interleukin-1beta-converting enzyme and the second highest for the caspase FLICE (Ki = 0.95 nM), identified as a component of the intracellular signaling complex recruited by ligation of the death receptor Fas [28].
• Therefore, dysregulation of PSME3 was masked by ANXA4 and could only be recognized by MS-based analysis but not by image analysis [1].
• OBJECTIVE: To determine the relationships between subtypes of anti-Ki antibodies and clinical manifestations of systemic lupus erythematosus [2].
• Four out of five candidate interactors identified were nuclear proteins: lamin A, splicing factor YT521-B, proteasome subunit PA28 gamma and transcription factor vav-1 [29].

Analytical, diagnostic and therapeutic context of PSME3

• Finally by developing a highly sensitive immunoassay, PSME3 could be detected in human sera and was significantly elevated in CRC patients compared with healthy donors and patients with benign bowel disease [1].
• Immunoreactivities of anti-Ki antibodies were tested by Western blotting [2].
• An inhibition test was performed by ELISA using purified Ki antigen [17].
• Selected variants, purified by trypsin affinity chromatography and reverse phase high performance liquid chromatography, potently inhibited plasma kallikrein, with apparent equilibrium dissociation constants (Ki*) ranging from approximately 75 to 300 pM [30].
• From this study, compound XIX exhibited reasonably high enzyme inhibitory activity (Ki = 15 nM) and showed antiviral activity (IC50 = 5 microM) in the cell-culture assay [31].

References