Matrix Metalloproteinase Structure
Published by Anonymous on 2007/9/24 (2345 reads)
1: Curr Med Chem. 2004 Nov;11(22):2911-77.
The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors.
Skiles JW, Gonnella NC, Jeng AY.
Discovery Partners International, 9640 Towne Centre Drive, San Diego, CA 92121, USA. jskiles@cytrxlabs.com
Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. Under normal physiological conditions, the activities of these enzymes are well-regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. Because of their importance in a variety of pathological conditions, a number of small molecular weight MMP inhibitors have entered clinical trials in humans. However, the results of these trials have been extremely disappointing and have led many investigators to conclude that MMP inhibitors have no therapeutic benefit in human cancer. To date, the first generation MMP inhibitors exhibited poor bioavailability while second-generation compounds revealed that prolonged treatment caused musculoskeletal pain and inflammation or had a lack of efficacy. This article describes the design of small molecular weight MMP inhibitors, a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMP inhibitors, and a clinical update of compounds that have entered clinical trials in humans. The experimentally determined structures used in the structure-based design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published and/or patented potent MMP inhibitors, from approximately January 2000 to April 2003, and their pharmacological properties. Protein inhibitors of these proteolytic enzymes, i.e. TIMPs, will not be discussed.
Publication Types:
Comparative Study
Review
PMID: 15544483 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Crit Rev Biochem Mol Biol. 2002;37(3):149-66.
The structure, regulation, and function of human matrix metalloproteinase-13.
Leeman MF, Curran S, Murray GI.
Department of Pathology, University of Aberdeen, Foresterhill, UK.
Matrix metalloproteinase-13 (MMP-13) is a proteolytic enzyme that belongs to a large family of extracellular matrix-degrading endopeptidases that are characterized by a zinc-binding motif at their catalytic sites. MMP-13 has a key role in the MMP activation cascade and appears to be critical in bone metabolism and homeostasis. It also has an important role in tumor invasion and metastasis. This commentary provides a detailed overview of the regulatory mechanisms, structure, and function of human MMP-13 and highlights the key factors involved in the biology of this important molecule.
Publication Types:
Review
PMID: 12139441 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Curr Med Chem. 2001 Mar;8(4):425-74.
The design, structure, and therapeutic application of matrix metalloproteinase inhibitors.
Skiles JW, Gonnella NC, Jeng AY.
Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, USA.
Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.
Publication Types:
Review
PMID: 11172697 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Matrix Biol. 1997 Mar;15(8-9):511-8.
Relating matrix metalloproteinase structure to function: why the "hemopexin" domain?
Murphy G, Knäuper V.
Strangeways Research Laboratory, Cambridge, United Kingdom.
Matrix metalloproteinases are thought to be key players in the remodelling activity of cells associated with both physiological and pathological processes. They share a relatively conserved structure with a number of identifiable modules linked to their specific functions. The structure of the individual domains of a number of matrix metalloproteinases have now been elucidated. Here we review these data in the light of complementary studies on the behaviour of these enzymes in biological systems. In particular we focus on the C-terminal hemopexin-like domain which has intriguingly specific roles in individual matrix metalloproteinases.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9138283 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Enzyme Protein. 1996;49(1-3):38-58.
What structure and function of avian plasminogen activator and matrix metalloproteinase-2 reveal about their counterpart mammalian enzymes, their regulation and their role in tumor invasion.
Alexander DS, Aimes RT, Quigley JP.
Department of Cellular and Molecular Pathology, SUNY at Stony Brook 11794-8691, USA.
Rous sarcoma virus-transformed chick embryo fibroblasts (RSVCEF) constitute a well-characterized model system for oncogenic transformation, matrix degradation, and cancer invasion. As RSVCEF cultures employ both serine protease and metalloprotease cascades in the process of matrix degradation, they have contributed significantly to understanding the nature and regulation of these molecules involved in invasive cell behavior. RSVCEF produce elevated levels of a matrix metalloprotease-2 (MMP-2) whose hemopexin domain differs from mammalian MMP-2. The majority of MMP-2 produced by RSVCEF is present in a TIMP-free form which enhances its activation, catalytic activity and substrate specificity and therefore its matrix-degrading ability. RSVCEFs also exhibit high levels of urokinase-type plasminogen activator (uPA), which is found in active form in their conditioned medium in complete absence of plasminogen. Recombinantly expressed avian uPA is also in active form, while an active-site mutant of the same maintains its zymogen form, indicating the mechanism of activation of chicken uPA is autocatalytic. A domain and sequence comparison between chicken and human uPA attempts to identify motifs potentially responsible for the zymogen instability of avian uPA and its capability to autoactivate.
Publication Types:
Review
PMID: 8796996 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Immun Infekt. 1993 Apr;21 Suppl 1:20-1.
[The matrix metalloproteinase gene family: structure, function, expression, and role in destructive joint disease]
[Article in German]
Conca W.
Abteilung Rheumatologie und Klinische Immunologie, Medizinische Universitätsklinik Freiburg.
The matrix metalloproteinases, i.e. collagenases, gelatinases and stromelysins, are members of a gene family. They are capable of degrading every component of the extracellular matrix. Tissue destruction observed in inflammatory joint disease is largely accounted for by the action of these enzymes. Among the most potent inducers of metalloproteinase expression are the inflammatory cytokines IL-1 and TNF-alpha. Studies of mechanisms of induction by these mediators at the transcriptional level have improved our understanding of the biological controls of metalloproteinase synthesis. Cytokine inhibitors might serve to inhibit or postpone the crippling consequences of metalloproteinase action.
Publication Types:
English Abstract
Review
PMID: 8344678 [PubMed - indexed for MEDLINE]
The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors.
Skiles JW, Gonnella NC, Jeng AY.
Discovery Partners International, 9640 Towne Centre Drive, San Diego, CA 92121, USA. jskiles@cytrxlabs.com
Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. Under normal physiological conditions, the activities of these enzymes are well-regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. Because of their importance in a variety of pathological conditions, a number of small molecular weight MMP inhibitors have entered clinical trials in humans. However, the results of these trials have been extremely disappointing and have led many investigators to conclude that MMP inhibitors have no therapeutic benefit in human cancer. To date, the first generation MMP inhibitors exhibited poor bioavailability while second-generation compounds revealed that prolonged treatment caused musculoskeletal pain and inflammation or had a lack of efficacy. This article describes the design of small molecular weight MMP inhibitors, a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMP inhibitors, and a clinical update of compounds that have entered clinical trials in humans. The experimentally determined structures used in the structure-based design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published and/or patented potent MMP inhibitors, from approximately January 2000 to April 2003, and their pharmacological properties. Protein inhibitors of these proteolytic enzymes, i.e. TIMPs, will not be discussed.
Publication Types:
Comparative Study
Review
PMID: 15544483 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
2: Crit Rev Biochem Mol Biol. 2002;37(3):149-66.
The structure, regulation, and function of human matrix metalloproteinase-13.
Leeman MF, Curran S, Murray GI.
Department of Pathology, University of Aberdeen, Foresterhill, UK.
Matrix metalloproteinase-13 (MMP-13) is a proteolytic enzyme that belongs to a large family of extracellular matrix-degrading endopeptidases that are characterized by a zinc-binding motif at their catalytic sites. MMP-13 has a key role in the MMP activation cascade and appears to be critical in bone metabolism and homeostasis. It also has an important role in tumor invasion and metastasis. This commentary provides a detailed overview of the regulatory mechanisms, structure, and function of human MMP-13 and highlights the key factors involved in the biology of this important molecule.
Publication Types:
Review
PMID: 12139441 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
3: Curr Med Chem. 2001 Mar;8(4):425-74.
The design, structure, and therapeutic application of matrix metalloproteinase inhibitors.
Skiles JW, Gonnella NC, Jeng AY.
Novartis Institute for Biomedical Research, 556 Morris Avenue, Summit, NJ 07901, USA.
Matrix metalloproteinases (MMPs) are a family of zinc-containing enzymes involved in the degradation and remodeling of extracellular matrix proteins. The activities of these enzymes are well regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Chronic stimulation of MMP activities due to an imbalance in the levels of MMPs and TIMPs has been implicated in the pathogenesis of a variety of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. Thus, MMP inhibitors are expected to be useful for the treatment of these disorders. This article reviews briefly the biochemistry of MMPs and evidence for their pathogenic roles using molecular biology approaches. Biomolecular structures used in the design of MMP inhibitors are thoroughly covered. Major emphasis is on recently published potent, small molecular weight MMP inhibitors and their pharmacological properties. Finally, available clinical results of compounds in development are summarized.
Publication Types:
Review
PMID: 11172697 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
4: Matrix Biol. 1997 Mar;15(8-9):511-8.
Relating matrix metalloproteinase structure to function: why the "hemopexin" domain?
Murphy G, Knäuper V.
Strangeways Research Laboratory, Cambridge, United Kingdom.
Matrix metalloproteinases are thought to be key players in the remodelling activity of cells associated with both physiological and pathological processes. They share a relatively conserved structure with a number of identifiable modules linked to their specific functions. The structure of the individual domains of a number of matrix metalloproteinases have now been elucidated. Here we review these data in the light of complementary studies on the behaviour of these enzymes in biological systems. In particular we focus on the C-terminal hemopexin-like domain which has intriguingly specific roles in individual matrix metalloproteinases.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 9138283 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
5: Enzyme Protein. 1996;49(1-3):38-58.
What structure and function of avian plasminogen activator and matrix metalloproteinase-2 reveal about their counterpart mammalian enzymes, their regulation and their role in tumor invasion.
Alexander DS, Aimes RT, Quigley JP.
Department of Cellular and Molecular Pathology, SUNY at Stony Brook 11794-8691, USA.
Rous sarcoma virus-transformed chick embryo fibroblasts (RSVCEF) constitute a well-characterized model system for oncogenic transformation, matrix degradation, and cancer invasion. As RSVCEF cultures employ both serine protease and metalloprotease cascades in the process of matrix degradation, they have contributed significantly to understanding the nature and regulation of these molecules involved in invasive cell behavior. RSVCEF produce elevated levels of a matrix metalloprotease-2 (MMP-2) whose hemopexin domain differs from mammalian MMP-2. The majority of MMP-2 produced by RSVCEF is present in a TIMP-free form which enhances its activation, catalytic activity and substrate specificity and therefore its matrix-degrading ability. RSVCEFs also exhibit high levels of urokinase-type plasminogen activator (uPA), which is found in active form in their conditioned medium in complete absence of plasminogen. Recombinantly expressed avian uPA is also in active form, while an active-site mutant of the same maintains its zymogen form, indicating the mechanism of activation of chicken uPA is autocatalytic. A domain and sequence comparison between chicken and human uPA attempts to identify motifs potentially responsible for the zymogen instability of avian uPA and its capability to autoactivate.
Publication Types:
Review
PMID: 8796996 [PubMed - indexed for MEDLINE]
--------------------------------------------------------------------------------
6: Immun Infekt. 1993 Apr;21 Suppl 1:20-1.
[The matrix metalloproteinase gene family: structure, function, expression, and role in destructive joint disease]
[Article in German]
Conca W.
Abteilung Rheumatologie und Klinische Immunologie, Medizinische Universitätsklinik Freiburg.
The matrix metalloproteinases, i.e. collagenases, gelatinases and stromelysins, are members of a gene family. They are capable of degrading every component of the extracellular matrix. Tissue destruction observed in inflammatory joint disease is largely accounted for by the action of these enzymes. Among the most potent inducers of metalloproteinase expression are the inflammatory cytokines IL-1 and TNF-alpha. Studies of mechanisms of induction by these mediators at the transcriptional level have improved our understanding of the biological controls of metalloproteinase synthesis. Cytokine inhibitors might serve to inhibit or postpone the crippling consequences of metalloproteinase action.
Publication Types:
English Abstract
Review
PMID: 8344678 [PubMed - indexed for MEDLINE]
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