Synthesis and Structure-Activity Relationships of Gelatinase Inhibitors Derived from Matlystatins.

Tamaki, Koreaki; Tanzawa, Kazuhiko; Kurihara, Shinwa; Oikawa, Tetsuo; Monma, S.; Shimada, Kohei; Sugimura, Yukio

doi:10.1248/cpb.43.1883

Cited by 39 publications

(43 citation statements)

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“…The substitution Leu 3 Cys(OMeBzl) in the P 1 Ј position of the substrate improved the K m value of the substrate for MT1-MMP, a finding in agreement with x-ray data (25,29,30) and inhibitors studies (31)(32)(33)(34)(35). This suggests that in all matrixins containing a leucine residue in their S 1 Ј pocket, this pocket should be a deep cavity able to accommodate extremely long amino acid side chains.…”

Section: Discussionsupporting

confidence: 80%

“…A comparable situation is likely to occur in most other MMPs, including MT1-MMP, collagenase-2 (COL2), stromelysin-1 (ST1), stromelysin-2 (ST2), gelatinase A, and gelatinase B, due to the presence in their S 1 Ј pocket of a leucine at the same position. The high potency of several inhibitors, substituted in their P 1 Ј position by side chains longer than homophenylalanine, toward this subgroup of matrixins is consistent with this proposal (28,(31)(32)(33)(34)(35). In contrast to this subgroup of matrixins, collagenase-1 (COL1), matrilysin, and ST3 possess in their S 1 Ј…”

supporting

confidence: 77%

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Membrane Type-1 Matrix Metalloprotease and Stromelysin-3 Cleave More Efficiently Synthetic Substrates Containing Unusual Amino Acids in Their P1′ Positions

Mucha¹,

Cuniasse²,

Kannan³

et al. 1998

Journal of Biological Chemistry

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The influence of the substrate P 1 position on the specificity of two zinc matrix metalloproteases, membrane type-1 matrix metalloprotease (MT1-MMP) and stromelysin-3 (ST3), was evaluated by synthesizing a series of fluorogenic substrates of general formula dansyl-ProLeu-Ala-Xaa-Trp-Ala-Arg-NH 2 , where Xaa in the P 1 position represents unusual amino acids containing either long arylalkyl or alkyl side chains. Our data demonstrate that both MT1-MMP and ST3 cleave substrates containing in their P 1 position unusual amino acids with extremely long side chains more efficiently than the corresponding substrates with natural phenylalanine or leucine amino acids. In this series of substrates, the replacement of leucine by S-para-methoxybenzyl cysteine increased the k cat /K m ratio by a factor of 37 for MT1-MMP and 9 for ST3. The substrate with a S-paramethoxybenzyl cysteine residue in the P 1 position displayed a k cat /K m value of 1.59 10 6 M ؊1 s ؊1 and 1.67 10 4 M ؊1 s ؊1 , when assayed with MT1-MMP and ST3, respectively. This substrate is thus one of the most rapidly hydrolyzed substrates so far reported for matrixins, and is the first synthetic peptide efficiently cleaved by ST3. These unexpected results for these two matrixins suggest that extracellular proteins may be cleaved by matrixins at sites containing amino acids with unusual long side chains, like those generated in vivo by some post-translational modifications.Matrix metalloproteases (MMPs), 1 also known as matrixins, form a group of structurally related zinc endopeptidases collectively able to degrade all components of the extracellular matrix (1). MMPs are believed to be mediators of both normal and pathological tissue remodeling processes, and their increased expression has been observed in a variety of human disorders (2-4). In particular, membrane type-1 (MT1)-MMP, a progelatinase A activator (5), and stromelysin-3 (ST3), a matrixin with unusual functional properties (6), are expressed in most human carcinomas (7-9). MT1-MMP and ST3 both belong to a subgroup of MMPs which are believed to be intracellularly activated by furin or furin-like convertases, thereby suggesting that MT1-MMP and ST3 are present in tissues in an active form, in contrast to other MMPs which are secreted as inactive zymogens (10 -12). As part of a program aimed at developing therapeutic inhibitors for these two MMPs, the specificity of these enzymes in cleaving synthetic substrates has been investigated. Current data on the specificity of MT1-MMP toward the degradation of synthetic substrates are extremely limited (13), while no synthetic substrate has yet been reported to be cleaved by ST3.In contrast to MT1-MMP and ST3, several studies have been devoted to the delineation of the specificity of other matrixin family members by developing both synthetic substrates (14 -18) and inhibitors for these enzymes (19,20). Such approaches have been greatly facilitated by the resolution of the crystal structures of several MMP catalytic domains (21-27), allowing structure-based desi...

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Section: Discussionsupporting

confidence: 80%

supporting

confidence: 77%

Membrane Type-1 Matrix Metalloprotease and Stromelysin-3 Cleave More Efficiently Synthetic Substrates Containing Unusual Amino Acids in Their P1′ Positions

Mucha¹,

Cuniasse²,

Kannan³

et al. 1998

Journal of Biological Chemistry

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“…This treatment was found to reduce airway inflammation as well as airway hyperreactivity. However, it is difficult to compare our two studies directly because the inhibitor used by Kumagai et al (18) was broad spectrum in action, having reported effects on MMP-9, MMP-2, MMP-3, MMP-7, and MMP-13 (34). Because MMPs operate in a tightly regulated network with the action of one member being able to influence the action of another, the use of such an inhibitor is relatively uninformative as to the action of individual MMPs.…”

Section: Discussionmentioning

confidence: 97%

Matrix Metalloproteinase-9 Deficiency Results in Enhanced Allergen-Induced Airway Inflammation

McMillan

Kearley

Campbell

et al. 2004

The Journal of Immunology

168

133

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Matrix metalloproteinases (MMPs) are a large family of endopeptidases that proteolytically degrade extracellular matrix. Many different cells produce MMP-9, and levels have been shown to be up-regulated in patients with allergic asthma. The aim of this study was to investigate the in vivo role of MMP-9 during allergen-induced airway inflammation. Acute allergic pulmonary eosinophilia was established in MMP-9 knockout (KO) and wild-type (WT) control mice by sensitization and challenge with OVA. Cell recruitment was significantly increased in both bronchoalveolar lavage (BAL) and lung tissue compartments in MMP-9 KO mice compared with WT mice. This heightened cell recruitment was primarily due to increased eosinophils and Th2 cells in the BAL and lung tissue of MMP-9 KO mice in comparison with WT controls. Moreover, levels of the Th2 cytokines, IL-4 and IL-13, and the chemokines eotaxin/CCL11 and macrophage-derived chemokine/CCL22 were substantially increased in MMP-9 KO mice compared with WT after OVA challenge. Resolution of eosinophilia was similar between MMP-9 KO and WT mice, but Th2 cells persisted in BAL and lungs of MMP-9 KO mice for longer than in WT mice. Our results indicate that MMP-9 is critically involved in the recruitment of eosinophils and Th2 cells to the lung following allergen challenge, and suggest that MMP-9 plays a role in the development of Th2 responses to allergen.

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“…Many of these bacterial metalloproteases have been found to be associated with virulence, while eukaryotic members of the family (so-called matrix metalloproteases) (16) were shown to be involved in a number of processes in humans, including the processing of precursors that play modulation roles in the formation of tumors (20,25). Thus, metalloproteases of the M4 family have attracted increasing attention as model proteins for the development of specific inhibitors that can be applied to disease treatment (41). Our finding of the role of gelatinase in biofilm development in E. faecalis raises the possibility that protease inhibitors may also be relevant, synergistically with antibiotics, in the treatment of biofilm-based pathogeneses such as infective endocarditis.…”

Section: Discussionmentioning

confidence: 99%

TheEnterococcus faecalis fsrTwo-Component System Controls Biofilm Development through Production of Gelatinase

2004

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Bacterial growth as a biofilm on solid surfaces is strongly associated with the development of human infections. Biofilms on native heart valves (infective endocarditis) is a life-threatening disease as a consequence of bacterial resistance to antimicrobials in such a state. Enterococci have emerged as a cause of endocarditis and nosocomial infections despite being normal commensals of the gastrointestinal and female genital tracts. We examined the role of two-component signal transduction systems in biofilm formation by the Enterococcus faecalis V583 clinical isolate and identified the fsr regulatory locus as the sole two-component system affecting this unique mode of bacterial growth. Insertion mutations in the fsr operon affected biofilm formation on two distinct abiotic surfaces. Inactivation of the fsr-controlled gene gelE encoding the zinc-metalloprotease gelatinase was found to prevent biofilm formation, suggesting that this enzyme may present a unique target for therapeutic intervention in enterococcal endocarditis.Bacterial virulence is one of many adaptive responses generally believed to be controlled through signal transduction mechanisms (39). Signal transduction in bacteria is mainly the prerogative of the so-called two-component systems consisting of a sensory histidine kinase that senses the signal and relays the adaptive response through the transfer of a phosphoryl group to a response regulator, generally a transcriptional regulator, that modulates gene expression in response to the signal received. Two-component signal transduction pathways are responsible for controlling gene expression in a wide variety of cellular processes including sporulation, virulence, biofilm formation, and antibiotic production and resistance (for reviews, see references 15 and 28). A total of 17 two-component systems and one orphan response regulator have been identified on the genome of the Enterococcus faecalis strain V583 (14). In a study aimed at the systematic inactivation of all two-component systems present in E. faecalis and the analysis of their role in virulence, we identified the fsr system as the only one affecting biofilm formation when inactivated (our unpublished data).The fsr regulatory locus is comprised of three genes, designated fsrA, fsrB, and fsrC ( Fig. 1) (33). Recently, this system has been identified as a quorum-sensing locus which responds to the extracellular accumulation of a peptide lactone encoded at the C terminus of the FsrB protein (27). Accumulation of the peptide in the extracellular space is likely sensed by the FsrC histidine kinase, leading to the activation of the response regulator and transcription factor FsrA. The fsr system and the products of the genes it regulates have been shown to be important for virulence in several infection models, including mouse peritonitis, Caenorhabditis elegans infection, and rabbit endophthalmitis (26,32,37). The FsrABC proteins are necessary for the production of two secreted proteases, gelatinase (GelE) and serine protease (SprE) (33). Here, ...

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Synthesis and Structure-Activity Relationships of Gelatinase Inhibitors Derived from Matlystatins.

Cited by 39 publications

References 0 publications

Membrane Type-1 Matrix Metalloprotease and Stromelysin-3 Cleave More Efficiently Synthetic Substrates Containing Unusual Amino Acids in Their P1′ Positions

Membrane Type-1 Matrix Metalloprotease and Stromelysin-3 Cleave More Efficiently Synthetic Substrates Containing Unusual Amino Acids in Their P1′ Positions

Matrix Metalloproteinase-9 Deficiency Results in Enhanced Allergen-Induced Airway Inflammation

TheEnterococcus faecalis fsrTwo-Component System Controls Biofilm Development through Production of Gelatinase

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