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  1. Book ; Thesis: Proteolyse in den extraembryonalen Kompartimenten der Japanischen Wachtel

    Gerhartz, Bernd

    1995  

    Author's details Bernd Gerhartz
    Language German
    Size 109 S, Ill., graph. Darst
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Techn. Univ., Diss.--München, 1995
    Database Former special subject collection: coastal and deep sea fishing

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  2. Book ; Thesis: Proteolyse in den extraembryonalen Kompartimenten der Japanischen Wachtel

    Gerhartz, Bernd

    1995  

    Author's details Bernd Gerhartz
    Language German
    Size 109 S, Ill., graph. Darst
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Techn. Univ., Diss.--München, 1995
    Database Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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  3. Article: A quantitative homogeneous assay for fragile X mental retardation 1 protein.

    Schutzius, Gabi / Bleckmann, Dorothee / Kapps-Fouthier, Sandra / di Giorgio, Francesco / Gerhartz, Bernd / Weiss, Andreas

    Journal of neurodevelopmental disorders

    2013  Volume 5, Issue 1, Page(s) 8

    Abstract: Background: Hypermethylation of the fragile X mental retardation 1 gene FMR1 results in decreased expression of FMR1 protein FMRP, which is the underlying cause of Fragile X syndrome - an incurable neurological disorder characterized by mental ... ...

    Abstract Background: Hypermethylation of the fragile X mental retardation 1 gene FMR1 results in decreased expression of FMR1 protein FMRP, which is the underlying cause of Fragile X syndrome - an incurable neurological disorder characterized by mental retardation, anxiety, epileptic episodes and autism. Disease-modifying therapies for Fragile X syndrome are thus aimed at treatments that increase the FMRP expression levels in the brain. We describe the development and characterization of two assays for simple and quantitative detection of FMRP protein.
    Method: Antibodies coupled to fluorophores that can be employed for time-resolved Förster's resonance energy transfer were used for the development of homogeneous, one-step immunodetection. Purified recombinant human FMRP and patient cells were used as control samples for assay development.
    Results: The assays require small sample amounts, display high stability and reproducibility and can be used to quantify endogenous FMRP in human fibroblasts and peripheral blood mononuclear cells. Application of the assays to FXS patient cells showed that the methods can be used both for the characterization of clinical FXS patient samples as well as primary readouts in drug-discovery screens aimed at increasing endogenous FMRP levels in human cells.
    Conclusion: This study provides novel quantitative detection methods for FMRP in FXS patient cells. Importantly, due to the simplicity of the assay protocol, the method is suited to be used in screening applications to identify compounds or genetic interventions that result in increased FMRP levels in human cells.
    Language English
    Publishing date 2013-04-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2487174-6
    ISSN 1866-1955 ; 1866-1947
    ISSN (online) 1866-1955
    ISSN 1866-1947
    DOI 10.1186/1866-1955-5-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Physico-chemical properties of the N-terminally truncated L68Q cystatin C found in amyloid deposits of brain haemorrhage patients.

    Gerhartz, Bernd / Abrahamson, Magnus

    Biological chemistry

    2002  Volume 383, Issue 2, Page(s) 301–305

    Abstract: Cystatin C, a major extracellular cysteine proteinase inhibitor, is deposited as amyloid in brain haemorrhage patients with hereditary cystatin C amyloid angiopathy (HCCAA). A disease-causing mutation on the genetic level results in the substitution ... ...

    Abstract Cystatin C, a major extracellular cysteine proteinase inhibitor, is deposited as amyloid in brain haemorrhage patients with hereditary cystatin C amyloid angiopathy (HCCAA). A disease-causing mutation on the genetic level results in the substitution Leu68-->Gln (L68Q) in cystatin C, which causes protein instability. Besides carrying the L68Q substitution, cystatin C in amyloid deposits isolated from patients is N-terminally truncated by 10 amino acids. To elucidate the role of the N-terminal truncation for protein stability and aggregation properties, (delta1-10,L68Q)-cystatin C was produced in an Escherichia coli expression system and characterised. Unlike wild-type cystatin C, this variant rapidly dimerised under physiological conditions. Two unfolding intermediates of (delta1-10,L68Q)-cystatin C were identified, under the same pH and ionic strength conditions as required to form intermediates of full-length L68Q cystatin C. No evidence was found that the N-terminal truncation per se alters protein stability and leads to higher forms of aggregation. Monomeric as well as dimeric L68Q cystatin C incubated with neutrophil elastase was truncated as in HCCAA patients' amyloid. A protein variant with a thrombin cleavage site placed in front of residue Gly11 in L68Q cystatin C was constructed and used to confirm that the N-terminal segment is similarly accessible to proteinases in the monomeric and dimeric states of L68Q cystatin C. Thus, the N-terminal segment of L68Q cystatin C is exposed to proteolytic attack and does not seem to be involved in intramolecular contacts leading to dimerisation or higher-order aggregation. We conclude that the N-terminal truncation likely is an event secondary to amyloid formation, and of no relevance for the development of HCCAA.
    MeSH term(s) Cerebral Amyloid Angiopathy, Familial/genetics ; Cerebral Amyloid Angiopathy, Familial/metabolism ; Cerebral Hemorrhage/genetics ; Cerebral Hemorrhage/metabolism ; Cystatins/chemistry ; Cystatins/genetics ; Cystatins/metabolism ; Dimerization ; Electrophoresis, Polyacrylamide Gel ; Escherichia coli/genetics ; Humans ; Hydrogen-Ion Concentration ; Protein Conformation
    Chemical Substances Cystatins ; L68Q cystatin C
    Language English
    Publishing date 2002-02
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1334659-3
    ISSN 1437-4315 ; 1431-6730 ; 1432-0355
    ISSN (online) 1437-4315
    ISSN 1431-6730 ; 1432-0355
    DOI 10.1515/BC.2002.032
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors.

    Vulpetti, Anna / Randl, Stefan / Rüdisser, Simon / Ostermann, Nils / Erbel, Paul / Mac Sweeney, Aengus / Zoller, Thomas / Salem, Bahaa / Gerhartz, Bernd / Cumin, Frederic / Hommel, Ulrich / Dalvit, Claudio / Lorthiois, Edwige / Maibaum, Jürgen

    Journal of medicinal chemistry

    2017  Volume 60, Issue 5, Page(s) 1946–1958

    Abstract: Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a ... ...

    Abstract Chronic dysregulation of alternative complement pathway activation has been associated with diverse clinical disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor D is a trypsin-like serine protease with a narrow specificity for arginine in the P1 position, which catalyzes the first enzymatic reaction of the amplification loop of the alternative pathway. In this article, we describe two hit finding approaches leading to the discovery of new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification to guide rational structure-based design and NMR screening of focused and diverse fragment libraries. The wealth of information gathered by these complementary approaches enabled the identification of ligands binding to different subpockets of the latent Factor D conformation and was instrumental for understanding the binding requirements for the generation of the first known potent noncovalent reversible Factor D inhibitors.
    MeSH term(s) Catalytic Domain ; Complement Factor D/chemistry ; Drug Design ; Humans ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology
    Chemical Substances Protease Inhibitors ; CFD protein, human (EC 3.4.21.46) ; Complement Factor D (EC 3.4.21.46)
    Language English
    Publishing date 2017-02-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.6b01684
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Highly sensitive intramolecularly quenched fluorogenic substrates for renin based on the combination of L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid with 2,4-dinitrophenyl groups at various positions.

    Paschalidou, Katherine / Neumann, Ulf / Gerhartz, Bernd / Tzougraki, Chryssa

    The Biochemical journal

    2004  Volume 382, Issue Pt 3, Page(s) 1031–1038

    Abstract: The development of renin inhibitors for the treatment of hypertension requires highly sensitive substrates to evaluate potency and to characterize the mechanism of tight-binding inhibitors. A series of intramolecularly quenched fluorogenic renin ... ...

    Abstract The development of renin inhibitors for the treatment of hypertension requires highly sensitive substrates to evaluate potency and to characterize the mechanism of tight-binding inhibitors. A series of intramolecularly quenched fluorogenic renin substrates, based on the N-terminal tetradecapeptide sequence of human angiotensinogen (hTDP), was synthesized using a solid-phase technique. Incorporation of the fluorescent amino acid L-Amp [L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid] and the DNP (2,4-dinitrophenyl) group at various positions resulted in >90% quenching efficiency and strong product fluorescence. Shortening the hTDP sequence to an octapeptide from histidine in P5 to histidine in P3' (substrate 3) resulted in an acceptable k(cat)/K(m) (41000 M(-1).s(-1)) and further systematic variation gave substrate 9, DNP-Lys-His-Pro-Phe-His-Leu-Val-Ile-His-L-Amp, with a k(cat)/K(m) value of 350000 M(-1).s(-1) and 94% quenching efficiency. The free side chain of lysine, replacing the isoleucine residue at P6 position in the angiotensinogen sequence, contributed to the increased value for k(cat). The pH dependence of k(cat)/K(m) for renin and substrate 9 showed that the optimal pH is at pH 6-7. It also showed two titrating groups on the acidic side of the pH optimum, and one titrating group with a pK(a) of 7.8 on the alkaline side. The combination of good kinetic and spectroscopic properties resulted in a >20-fold improvement in the sensitivity of renin assay, compared with the commercial substrate Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg [where EDANS is 5-[(2-aminoethyl)amino]naphthalene-1-sulphonic acid and DABCYL is 4-(4-dimethylaminophenylazo)benzoic acid] (k(cat)/K(m)=268000 M(-1) x s(-1), quenching efficiency <80%). The detection limit in a microplate renin assay was 60 pM, making substrate 9 well suited for the evaluation of inhibitors at picomolar concentrations.
    MeSH term(s) Alanine/analogs & derivatives ; Alanine/chemical synthesis ; Alanine/chemistry ; Amino Acid Sequence ; Angiotensinogen/analogs & derivatives ; Angiotensinogen/chemistry ; Coumarins/chemical synthesis ; Coumarins/chemistry ; Fluorescent Dyes/chemical synthesis ; Fluorescent Dyes/chemistry ; Hydrogen-Ion Concentration ; Hydrolysis ; Kinetics ; Peptide Fragments/chemistry ; Renin/metabolism ; Spectrometry, Fluorescence ; Structure-Activity Relationship
    Chemical Substances Coumarins ; Fluorescent Dyes ; Peptide Fragments ; angiotensinogen (1-14) ; Angiotensinogen (11002-13-4) ; 2-amino-3-(7-methoxy-4-coumaryl)propionic acid (133083-29-1) ; Renin (EC 3.4.23.15) ; Alanine (OF5P57N2ZX)
    Language English
    Publishing date 2004-09-15
    Publishing country England
    Document type Evaluation Studies ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BJ20040729
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  7. Article ; Online: Aspartic proteases in drug discovery.

    Eder, Jörg / Hommel, Ulrich / Cumin, Frederic / Martoglio, Bruno / Gerhartz, Bernd

    Current pharmaceutical design

    2006  Volume 13, Issue 3, Page(s) 271–285

    Abstract: Aspartic proteases are the smallest class of human proteases with only 15 members. Over the past years, they have received considerable attention as potential targets for pharmaceutical intervention since many have been shown to play important roles in ... ...

    Abstract Aspartic proteases are the smallest class of human proteases with only 15 members. Over the past years, they have received considerable attention as potential targets for pharmaceutical intervention since many have been shown to play important roles in physiological and pathological processes. Despite numerous efforts, however, the only inhibitors for aspartic proteases currently on the market are directed against the HIV protease, an aspartic protease of viral origin. Nevertheless, several inhibitors including those targeting renin, BACE1 and gamma-secretase are in clinical or preclinical development, and some other aspartic proteases are discussed as potential drug target. The crystal structures of seven human aspartic proteases have now been solved and, together with a detailed kinetic understanding of their catalytic mechanism, this has greatly contributed to the design and discovery of novel inhibitors for this protease class. This review describes current aspartic protease drug targets and summarizes the drug discovery efforts in this field. In addition, it highlights recent developments which may lead to a new generation of aspartic protease inhibitors.
    MeSH term(s) Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/chemistry ; Animals ; Aspartic Acid Endopeptidases/antagonists & inhibitors ; Aspartic Acid Endopeptidases/chemistry ; Aspartic Acid Endopeptidases/metabolism ; Computer-Aided Design ; Drug Design ; HIV Protease/chemistry ; HIV Protease Inhibitors/pharmacology ; Humans ; Membrane Proteins/metabolism ; Models, Molecular ; Molecular Structure ; Presenilins/antagonists & inhibitors ; Presenilins/chemistry ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protein Conformation ; Renin/antagonists & inhibitors ; Renin/chemistry ; Structure-Activity Relationship
    Chemical Substances HIV Protease Inhibitors ; Membrane Proteins ; Presenilins ; Protease Inhibitors ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; HIV Protease (EC 3.4.23.-) ; signal peptide peptidase (EC 3.4.23.-) ; Renin (EC 3.4.23.15)
    Language English
    Publishing date 2006-01-23
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 1304236-1
    ISSN 1873-4286 ; 1381-6128
    ISSN (online) 1873-4286
    ISSN 1381-6128
    DOI 10.2174/138161207779313560
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Crystal structure of an activation intermediate of cathepsin E.

    Ostermann, Nils / Gerhartz, Bernd / Worpenberg, Susanne / Trappe, Jörg / Eder, Jörg

    Journal of molecular biology

    2004  Volume 342, Issue 3, Page(s) 889–899

    Abstract: Cathepsin E is an intracellular, non-lysosomal aspartic protease expressed in a variety of cells and tissues. The protease has proposed physiological roles in antigen presentation by the MHC class II system, in the biogenesis of the vasoconstrictor ... ...

    Abstract Cathepsin E is an intracellular, non-lysosomal aspartic protease expressed in a variety of cells and tissues. The protease has proposed physiological roles in antigen presentation by the MHC class II system, in the biogenesis of the vasoconstrictor peptide endothelin, and in neurodegeneration associated with brain ischemia and aging. Cathepsin E is the only A1 aspartic protease that exists as a homodimer with a disulfide bridge linking the two monomers. Like many other aspartic proteases, it is synthesized as a zymogen which is catalytically inactive towards its natural substrates at neutral pH and which auto-activates in an acidic environment. Here we report the crystal structure of an activation intermediate of human cathepsin E at 2.35A resolution. The overall structure follows the general fold of aspartic proteases of the A1 family, and the intermediate shares many features with the intermediate 2 on the proposed activation pathway of aspartic proteases like pepsin C and cathepsin D. The pro-sequence is cleaved from the protease and remains stably associated with the mature enzyme by forming the outermost sixth strand of the interdomain beta-sheet. However, different from these other aspartic proteases the pro-sequence of cathepsin E remains intact after cleavage from the mature enzyme. In addition, the active site of cathepsin E in the crystal is occupied by N-terminal amino acid residues of the mature protease in the non-primed binding site and by an artificial N-terminal extension of the pro-sequence from a neighboring molecule in the primed site. The crystal structure of the cathepsin E/pro-sequence complex, therefore, provides further insight into the activation mechanism of aspartic proteases.
    MeSH term(s) Amino Acid Sequence ; Base Sequence ; Catalytic Domain ; Cathepsin E/chemistry ; Cathepsin E/genetics ; Cathepsin E/metabolism ; Crystallography, X-Ray ; DNA, Recombinant/genetics ; Enzyme Activation ; Enzyme Precursors/chemistry ; Enzyme Precursors/genetics ; Enzyme Precursors/metabolism ; Humans ; In Vitro Techniques ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Structure, Quaternary ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
    Chemical Substances DNA, Recombinant ; Enzyme Precursors ; Recombinant Proteins ; Cathepsin E (EC 3.4.23.34)
    Language English
    Publishing date 2004-09-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2004.07.073
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  9. Article: Exploring T cell reactivity to gliadin in young children with newly diagnosed celiac disease.

    Liu, Edwin / McDaniel, Kristen / Case, Stephanie / Yu, Liping / Gerhartz, Bernd / Ostermann, Nils / Fankhauser, Gabriela / Hungerford, Valerie / Zou, Chao / Luyten, Marcel / Seidl, Katherine J / Michels, Aaron W

    Autoimmune diseases

    2014  Volume 2014, Page(s) 927190

    Abstract: Class II major histocompatibility molecules confer disease risk in Celiac disease (CD) by presenting gliadin peptides to CD4 T cells in the small intestine. Deamidation of gliadin peptides by tissue transglutaminase creates immunogenic peptides presented ...

    Abstract Class II major histocompatibility molecules confer disease risk in Celiac disease (CD) by presenting gliadin peptides to CD4 T cells in the small intestine. Deamidation of gliadin peptides by tissue transglutaminase creates immunogenic peptides presented by HLA-DQ2 and DQ8 molecules to activate proinflammatory CD4 T cells. Detecting gliadin specific T cell responses from the peripheral blood has been challenging due to low circulating frequencies and heterogeneity in response to gliadin epitopes. We investigated the peripheral T cell responses to alpha and gamma gliadin epitopes in young children with newly diagnosed and untreated CD. Using peptide/MHC recombinant protein constructs, we are able to robustly stimulate CD4 T cell clones previously derived from intestinal biopsies of CD patients. These recombinant proteins and a panel of α- and γ-gliadin peptides were used to assess T cell responses from the peripheral blood. Proliferation assays using peripheral blood mononuclear cells revealed more CD4 T cell responses to α-gliadin than γ-gliadin peptides with a single deamidated α-gliadin peptide able to identify 60% of CD children. We conclude that it is possible to detect T cell responses without a gluten challenge or in vitro stimulus other than antigen, when measuring proliferative responses.
    Language English
    Publishing date 2014-03-03
    Publishing country United States
    Document type Journal Article
    ISSN 2090-0422
    ISSN 2090-0422
    DOI 10.1155/2014/927190
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  10. Article ; Online: Gift from Nature: Cyclomarin A Kills Mycobacteria and Malaria Parasites by Distinct Modes of Action.

    Bürstner, Nathalie / Roggo, Silvio / Ostermann, Nils / Blank, Jutta / Delmas, Cecile / Freuler, Felix / Gerhartz, Bernd / Hinniger, Alexandra / Hoepfner, Dominic / Liechty, Brigitta / Mihalic, Manuel / Murphy, Jason / Pistorius, Dominik / Rottmann, Matthias / Thomas, Jason R / Schirle, Markus / Schmitt, Esther K

    Chembiochem : a European journal of chemical biology

    2015  Volume 16, Issue 17, Page(s) 2433–2436

    Abstract: Malaria continues to be one of the most devastating human diseases despite many efforts to limit its spread by prevention of infection or by pharmaceutical treatment of patients. We have conducted a screen for antiplasmodial compounds by using a natural ... ...

    Abstract Malaria continues to be one of the most devastating human diseases despite many efforts to limit its spread by prevention of infection or by pharmaceutical treatment of patients. We have conducted a screen for antiplasmodial compounds by using a natural product library. Here we report on cyclomarin A as a potent growth inhibitor of Plasmodium falciparum and the identification of its molecular target, diadenosine triphosphate hydrolase (PfAp3Aase), by chemical proteomics. Using a biochemical assay, we could show that cyclomarin A is a specific inhibitor of the plasmodial enzyme but not of the closest human homologue hFHIT. Co-crystallisation experiments demonstrate a unique binding mode of the inhibitor. One molecule of cyclomarin A binds a dimeric PfAp3Aase and prevents the formation of the enzyme⋅substrate complex. These results validate PfAp3Aase as a new drug target for the treatment of malaria. We have previously elucidated the structurally unrelated regulatory subunit ClpC1 of the ClpP protease as the molecular target of cyclomarin A in Mycobacterium tuberculosis. Thus, cyclomarin A is a rare example of a natural product with two distinct and specific modes of action.
    MeSH term(s) Acid Anhydride Hydrolases/antagonists & inhibitors ; Acid Anhydride Hydrolases/metabolism ; Antimalarials/chemistry ; Antimalarials/metabolism ; Antimalarials/pharmacology ; Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/metabolism ; Binding Sites ; Biological Products/chemistry ; Biological Products/metabolism ; Biological Products/pharmacology ; Endopeptidase Clp/antagonists & inhibitors ; Endopeptidase Clp/metabolism ; Humans ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Neoplasm Proteins/antagonists & inhibitors ; Neoplasm Proteins/metabolism ; Oligopeptides/chemistry ; Oligopeptides/metabolism ; Oligopeptides/pharmacology ; Plasmodium falciparum/drug effects ; Plasmodium falciparum/enzymology ; Plasmodium falciparum/growth & development ; Protein Binding ; Protein Structure, Tertiary
    Chemical Substances Antimalarials ; Bacterial Proteins ; Biological Products ; Neoplasm Proteins ; Oligopeptides ; cyclomarin A ; fragile histidine triad protein ; Endopeptidase Clp (EC 3.4.21.92) ; Acid Anhydride Hydrolases (EC 3.6.-)
    Language English
    Publishing date 2015-11
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2020469-3
    ISSN 1439-7633 ; 1439-4227
    ISSN (online) 1439-7633
    ISSN 1439-4227
    DOI 10.1002/cbic.201500472
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