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The Proteasome: a Proteolytic Nanomachine of Cell Regulation and Waste Disposal
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1695 (2004) 19–31 http://www.elsevier.com/locate/bba Review The proteasome: a proteolytic nanomachine of cell regulation and waste disposal Dieter H. Wolf *, Wolfgang Hilt Institut fu¨r Biochemie, Universita¨t Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany Available online 26 October 2004 Abstract The final destination of the majority of proteins that have to be selectively degraded in eukaryotic cells is the proteasome, a highly sophisticated nanomachine essential for life. 26S proteasomes select target proteins via their modification with polyubiquitin chains or, in rare cases, by the recognition of specific motifs. They are made up of different subcomplexes, a 20S core proteasome harboring the proteolytic active sites hidden within its barrel-like structure and two 19S caps that execute regulatory functions. Similar complexes equipped with PA28 regulators instead of 19S caps are a variation of this theme specialized for the production of antigenic peptides required in immune response. Structure analysis as well as extensive biochemical and genetic studies of the 26S proteasome and the ubiquitin system led to a basic model of substrate recognition and degradation. Recent work raised new concepts. Additional factors involved in substrate acquisition and delivery to the proteasome have been discovered. Moreover, first insights in the tasks of individual subunits or subcomplexes of the 19S caps in substrate recognition and binding as well as release and recycling of polyubiquitin tags have been obtained. D 2004 Elsevier B.V. All rights reserved. -
Molecular Markers of Serine Protease Evolution
The EMBO Journal Vol. 20 No. 12 pp. 3036±3045, 2001 Molecular markers of serine protease evolution Maxwell M.Krem and Enrico Di Cera1 ment and specialization of the catalytic architecture should correspond to signi®cant evolutionary transitions in the Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St Louis, history of protease clans. Evolutionary markers encoun- MO 63110-1093, USA tered in the sequences contributing to the catalytic apparatus would thus give an account of the history of 1Corresponding author e-mail: [email protected] an enzyme family or clan and provide for comparative analysis with other families and clans. Therefore, the use The evolutionary history of serine proteases can be of sequence markers associated with active site structure accounted for by highly conserved amino acids that generates a model for protease evolution with broad form crucial structural and chemical elements of applicability and potential for extension to other classes of the catalytic apparatus. These residues display non- enzymes. random dichotomies in either amino acid choice or The ®rst report of a sequence marker associated with serine codon usage and serve as discrete markers for active site chemistry was the observation that both AGY tracking changes in the active site environment and and TCN codons were used to encode active site serines in supporting structures. These markers categorize a variety of enzyme families (Brenner, 1988). Since serine proteases of the chymotrypsin-like, subtilisin- AGY®TCN interconversion is an uncommon event, it like and a/b-hydrolase fold clans according to phylo- was reasoned that enzymes within the same family genetic lineages, and indicate the relative ages and utilizing different active site codons belonged to different order of appearance of those lineages. -
Serine Proteases with Altered Sensitivity to Activity-Modulating
(19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants. -
Arginine Enzymatic Deprivation and Diet Restriction for Cancer Treatment
Brazilian Journal of Pharmaceutical Sciences Review http://dx.doi.org/10.1590/s2175-97902017000300200 Arginine enzymatic deprivation and diet restriction for cancer treatment Wissam Zam* Al-Andalus University for Medical Sciences, Faculty of Pharmacy, Analytical and Food Chemistry, Tartous, Syrian Arab Republic Recent findings in amino acid metabolism and the differences between normal, healthy cells and neoplastic cells have revealed that targeting single amino acid metabolic enzymes in cancer therapy is a promising strategy for the development of novel therapeutic agents. Arginine is derived from dietary protein intake, body protein breakdown, or endogenous de novo arginine production and several studies have revealed disturbances in its synthesis and metabolism which could enhance or inhibit tumor cell growth. Consequently, there has been an increased interest in the arginine-depleting enzymes and dietary deprivation of arginine and its precursors as a potential antineoplastic therapy. This review outlines the most recent advances in targeting arginine metabolic pathways in cancer therapy and the different chemo- and radio-therapeutic approaches to be co-applied. Key words: Arginine-depleting enzyme/antineoplastic therapy. Dietary deprivation. INTRODUCTION variety of human cancer cells have been found to be auxotrophic for arginine, depletion of which results in Certain cancers may be auxotrophic for a particular cell death (Tytell, Neuman, 1960; Kraemer, 1964; Dillon amino acid, and amino acid deprivation is one method to et al., 2004). Arginine can be degraded by three enzymes: treat these tumors. The strategy of enzymatic degradation arginase, arginine decarboxylase and arginine deiminase of amino acids to deprive malignant cells of important (ADI). Both arginine decarboxylase and ADI are not nutrients is an established component of induction therapy expressed in mammalian cells (Morris, 2007; Miyazaki of several tumor cells. -
Of Pseudomonas Aeruginosa Cristian Gustavo Aguilera Rossi1,2, Paulino Gómez-Puertas3 and Juan Alfonso Ayala Serrano2*
Aguilera Rossi et al. BMC Microbiology (2016) 16:234 DOI 10.1186/s12866-016-0853-x RESEARCH ARTICLE Open Access In vivo functional and molecular characterization of the Penicillin-Binding Protein 4 (DacB) of Pseudomonas aeruginosa Cristian Gustavo Aguilera Rossi1,2, Paulino Gómez-Puertas3 and Juan Alfonso Ayala Serrano2* Abstract Background: Community and nosocomial infections by Pseudomonas aeruginosa still create a major therapeutic challenge. The resistance of this opportunist pathogen to β-lactam antibiotics is determined mainly by production of the inactivating enzyme AmpC, a class C cephalosporinase with a regulation system more complex than those found in members of the Enterobacteriaceae family. This regulatory system also participates directly in peptidoglycan turnover and recycling. One of the regulatory mechanisms for AmpC expression, recently identified in clinical isolates, is the inactivation of LMM-PBP4 (Low-Molecular-Mass Penicillin-Binding Protein 4), a protein whose catalytic activity on natural substrates has remained uncharacterized until now. Results: We carried out in vivo activity trials for LMM-PBP4 of Pseudomonas aeruginosa on macromolecular peptidoglycan of Escherichia coli and Pseudomonas aeruginosa. The results showed a decrease in the relative quantity of dimeric, trimeric and anhydrous units, and a smaller reduction in monomer disaccharide pentapeptide (M5) levels, validating the occurrence of D,D-carboxypeptidase and D,D-endopeptidase activities. Under conditions of induction for this protein and cefoxitin treatment, the reduction in M5 is not fully efficient, implying that LMM- PBP4 of Pseudomonas aeruginosa presents better behaviour as a D,D-endopeptidase. Kinetic evaluation of the direct D,D-peptidase activity of this protein on natural muropeptides M5 and D45 confirmed this bifunctionality and the greater affinity of LMM-PBP4 for its dimeric substrate. -
Supplemental Methods
Supplemental Methods: Sample Collection Duplicate surface samples were collected from the Amazon River plume aboard the R/V Knorr in June 2010 (4 52.71’N, 51 21.59’W) during a period of high river discharge. The collection site (Station 10, 4° 52.71’N, 51° 21.59’W; S = 21.0; T = 29.6°C), located ~ 500 Km to the north of the Amazon River mouth, was characterized by the presence of coastal diatoms in the top 8 m of the water column. Sampling was conducted between 0700 and 0900 local time by gently impeller pumping (modified Rule 1800 submersible sump pump) surface water through 10 m of tygon tubing (3 cm) to the ship's deck where it then flowed through a 156 µm mesh into 20 L carboys. In the lab, cells were partitioned into two size fractions by sequential filtration (using a Masterflex peristaltic pump) of the pre-filtered seawater through a 2.0 µm pore-size, 142 mm diameter polycarbonate (PCTE) membrane filter (Sterlitech Corporation, Kent, CWA) and a 0.22 µm pore-size, 142 mm diameter Supor membrane filter (Pall, Port Washington, NY). Metagenomic and non-selective metatranscriptomic analyses were conducted on both pore-size filters; poly(A)-selected (eukaryote-dominated) metatranscriptomic analyses were conducted only on the larger pore-size filter (2.0 µm pore-size). All filters were immediately submerged in RNAlater (Applied Biosystems, Austin, TX) in sterile 50 mL conical tubes, incubated at room temperature overnight and then stored at -80oC until extraction. Filtration and stabilization of each sample was completed within 30 min of water collection. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
B Number Gene Name Mrna Intensity Mrna
sample) total list predicted B number Gene name assignment mRNA present mRNA intensity Gene description Protein detected - Membrane protein membrane sample detected (total list) Proteins detected - Functional category # of tryptic peptides # of tryptic peptides # of tryptic peptides detected (membrane b0002 thrA 13624 P 39 P 18 P(m) 2 aspartokinase I, homoserine dehydrogenase I Metabolism of small molecules b0003 thrB 6781 P 9 P 3 0 homoserine kinase Metabolism of small molecules b0004 thrC 15039 P 18 P 10 0 threonine synthase Metabolism of small molecules b0008 talB 20561 P 20 P 13 0 transaldolase B Metabolism of small molecules chaperone Hsp70; DNA biosynthesis; autoregulated heat shock b0014 dnaK 13283 P 32 P 23 0 proteins Cell processes b0015 dnaJ 4492 P 13 P 4 P(m) 1 chaperone with DnaK; heat shock protein Cell processes b0029 lytB 1331 P 16 P 2 0 control of stringent response; involved in penicillin tolerance Global functions b0032 carA 9312 P 14 P 8 0 carbamoyl-phosphate synthetase, glutamine (small) subunit Metabolism of small molecules b0033 carB 7656 P 48 P 17 0 carbamoyl-phosphate synthase large subunit Metabolism of small molecules b0048 folA 1588 P 7 P 1 0 dihydrofolate reductase type I; trimethoprim resistance Metabolism of small molecules peptidyl-prolyl cis-trans isomerase (PPIase), involved in maturation of b0053 surA 3825 P 19 P 4 P(m) 1 GenProt outer membrane proteins (1st module) Cell processes b0054 imp 2737 P 42 P 5 P(m) 5 GenProt organic solvent tolerance Cell processes b0071 leuD 4770 P 10 P 9 0 isopropylmalate -
Table 6. Putative Genes Involved in the Utilization of Carbohydrates in G
Table 6. Putative genes involved in the utilization of carbohydrates in G. thermodenitrificans NG80-2 genome Carbohydrates* Enzymes Gene ID Glycerol Glycerol Kinase GT1216 Glycerol-3-phosphate dehydrogenase, aerobic GT2089 NAD(P)H-dependent glycerol-3-phosphate dehydrogenase GT2153 Enolase GT3003 2,3-bisphosphoglycerate-independentphosphoglycerate mutase GT3004 Triosephosphate isomerase GT3005 3-phosphoglycerate kinase GT3006 Glyceraldehyde-3-phosphate dehydrogenase GT3007 Phosphoglycerate mutase GT1326 Pyruvate kinase GT2663 L-Arabinose L-arabinose isomerase GT1795 L-ribulokinase GT1796 L-ribulose 5-phosphate 4-epimerase GT1797 D-Ribose Ribokinase GT3174 Transketolase GT1187 Ribose 5-phosphate epimerase GT3316 D-Xylose Xylose kinase GT1756 Xylose isomerase GT1757 D-Galactose Galactokinase GT2086 Galactose-1-phosphate uridyltransferase GT2084 UDP-glucose 4-epimerase GT2085 Carbohydrates* Enzymes Gene ID D-Fructose 1-phosphofructokinase GT1727 Fructose-1,6-bisphosphate aldolase GT1805 Fructose-1,6-bisphosphate aldolase type II GT3331 Triosephosphate isomerase GT3005 D-Mannose Mannnose-6 phospate isomelase GT3398 6-phospho-1-fructokinase GT2664 D-Mannitol Mannitol-1-phosphate dehydrogenase GT1844 N-Acetylglucosamine N-acetylglucosamine-6-phosphate deacetylase GT2205 N-acetylglucosamine-6-phosphate isomerase GT2204 D-Maltose Alpha-1,4-glucosidase GT0528, GT1643 Sucrose Sucrose phosphorylase GT3215 D-Trehalose Alpha-glucosidase GT1643 Glucose kinase GT2381 Inositol Myo-inositol catabolism protein iolC;5-dehydro-2- GT1807 deoxygluconokinase -
An Investigation on Catalysis of Acylaminoacyl Peptidases
An investigation on catalysis of acylaminoacyl peptidases PhD Thesis András László Kiss Doctorate School of Biology School leader: Prof. Anna Erdei Structural Biochemistry Programme Programme leader: Prof. László Gráf Supervisor: Prof. László Polgár Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences Budapest 2007 1. Introduction Serine peptidases contain two residues at the active site in addition to the catalytic triad (His, Asp, Ser), which form a cavity called “oxyanion hole” that accommodates the negatively charged oxyanion in the transition state of the catalysis and donate two H- bonds. Enzymes of the prolyl oligopeptidase (POP) family (acylaminoacyl peptidase, prolyl oligopeptidase, dipeptidyl peptidase IV and oligopeptidase B) are extensively studied. These enzymes are larger than classical serine peptidases and are composed of a peptidase domain with an α/β hydrolase fold and a β-propeller domain. POP and oligopeptidase B are monomeric enzymes and endopeptidases, while the exopeptidase acylaminoacyl peptidase and dipeptidyl peptidase IV are tetrameric and dimeric enzymes, respectively. Acylaminoacyl peptidase (AAP) cleaves acylated amino acids from the N-terminus of the N-acylated peptides that plays important role in many biological and disease processes. Human AAP is encoded by the DNF15S2 locus on the short arm of chromosome 3 at the region 21, which suffers deletions in small cell lung carcinomas, and renal carcinomas, resulting in deficiency in the expression of the enzyme. Acylaminoacyl peptidase is also supposed to be involved in the degradation of oxidatively damaged proteins in cells and can be associated with various diseases where damaged proteins aggregate. Its involvement in cataract formation and in the breakdown of immunogenic formylmethionyl-peptides in the digestive tract after bacterial attack was also suggested. -
High-Resolution Mass Spectrometry-Based Approaches for the Detection and Quantification of Peptidase Activity in Plasma
molecules Article High-Resolution Mass Spectrometry-Based Approaches for the Detection and Quantification of Peptidase Activity in Plasma Elisa Maffioli 1,2 , Zhenze Jiang 3, Simona Nonnis 1,2 , Armando Negri 1,2, Valentina Romeo 1, Christopher B. Lietz 3, Vivian Hook 3,4, Giuseppe Ristagno 5, Giuseppe Baselli 6, Erik B. Kistler 7,8 , Federico Aletti 9, Anthony J. O’Donoghue 3,* and Gabriella Tedeschi 1,2,* 1 Department of Veterinary Medicine, University of Milano, 20133 Milano, Italy; elisa.maffi[email protected] (E.M.); [email protected] (S.N.); [email protected] (A.N.); [email protected] (V.R.) 2 Centre for Nanostructured Materials and Interfaces (CIMAINA), University of Milano, 20133 Milano, Italy 3 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA; [email protected] (Z.J.); [email protected] (C.B.L.); [email protected] (V.H.) 4 Department of Neurosciences, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA 5 Department of Pathophysiology and Transplantation, University of Milan, 20133 Milan, Italy; [email protected] 6 Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, 20133 Milan, Italy; [email protected] 7 Department of Anesthesiology & Critical Care, University of California San Diego, La Jolla, CA 92093, USA; [email protected] 8 Department of Anesthesiology & Critical Care, VA San Diego HealthCare System, San Diego, CA 92161, USA 9 Department of Bioengineering, University of California San Diego, La Jolla, CA 92093, USA; [email protected] * Correspondence: [email protected] (A.J.O.); [email protected] (G.T.); Tel.: +1-8585345360 (A.J.O.); +39-02-50318127 (G.T.) Academic Editor: Paolo Iadarola Received: 28 July 2020; Accepted: 4 September 2020; Published: 6 September 2020 Abstract: Proteomic technologies have identified 234 peptidases in plasma but little quantitative information about the proteolytic activity has been uncovered. -
(12) Patent Application Publication (10) Pub. No.: US 2006/0110747 A1 Ramseier Et Al
US 200601 10747A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0110747 A1 Ramseier et al. (43) Pub. Date: May 25, 2006 (54) PROCESS FOR IMPROVED PROTEIN (60) Provisional application No. 60/591489, filed on Jul. EXPRESSION BY STRAIN ENGINEERING 26, 2004. (75) Inventors: Thomas M. Ramseier, Poway, CA Publication Classification (US); Hongfan Jin, San Diego, CA (51) Int. Cl. (US); Charles H. Squires, Poway, CA CI2O I/68 (2006.01) (US) GOIN 33/53 (2006.01) CI2N 15/74 (2006.01) Correspondence Address: (52) U.S. Cl. ................................ 435/6: 435/7.1; 435/471 KING & SPALDING LLP 118O PEACHTREE STREET (57) ABSTRACT ATLANTA, GA 30309 (US) This invention is a process for improving the production levels of recombinant proteins or peptides or improving the (73) Assignee: Dow Global Technologies Inc., Midland, level of active recombinant proteins or peptides expressed in MI (US) host cells. The invention is a process of comparing two genetic profiles of a cell that expresses a recombinant (21) Appl. No.: 11/189,375 protein and modifying the cell to change the expression of a gene product that is upregulated in response to the recom (22) Filed: Jul. 26, 2005 binant protein expression. The process can improve protein production or can improve protein quality, for example, by Related U.S. Application Data increasing solubility of a recombinant protein. Patent Application Publication May 25, 2006 Sheet 1 of 15 US 2006/0110747 A1 Figure 1 09 010909070£020\,0 10°0 Patent Application Publication May 25, 2006 Sheet 2 of 15 US 2006/0110747 A1 Figure 2 Ester sers Custer || || || || || HH-I-H 1 H4 s a cisiers TT closers | | | | | | Ya S T RXFO 1961.