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Title: Structure-Energy study of the interactions between matrix metalloproteinase 1 and tissue inhibitor of metalloproteinase.
Creator: Logue, Timothy, Brew, Keith, Graduate College
Abstract/Description: Matrix metalloproteinases MMPs are one of the major families of proteinases that play key roles in maintaining an appropriately assembled extracellular matrix ECM. MMPs are essential to many biological processes, such as wound healing, embryo implantation, bone remodeling, and organogenesis. Their biological antagonists, the tissue inhibitors of metalloproteinases TIMPs, regulate the enzymatic activities of MMPs. Uncontrolled ECM degradation occurs when the delicate balance between TIMPs and...
Show moreMatrix metalloproteinases MMPs are one of the major families of proteinases that play key roles in maintaining an appropriately assembled extracellular matrix ECM. MMPs are essential to many biological processes, such as wound healing, embryo implantation, bone remodeling, and organogenesis. Their biological antagonists, the tissue inhibitors of metalloproteinases TIMPs, regulate the enzymatic activities of MMPs. Uncontrolled ECM degradation occurs when the delicate balance between TIMPs and MMPs is disrupted, resulting in many diseases such as rheumatoid and osteoarthritis, cancer cell metastasis, and heart disease. There are currently no effective treatments for osteoarthritis OA except for joint replacement surgery. Therefore, gaining the knowledge about the structures and molecular mechanisms of these key enzymes in order to uncover new ways to specifically inhibit these proteinases are an opportunity for the development of therapeutics and treatments to prevent the joint destruction seen in OA. Our goal is to understand the biophysical interaction of catalytic domain of MMP-1 with NTIMP- 3 using isothermal calorimetry ITC. The ITC determines if binding between the proteins is entropy or enthalpy driven and heat capacity will indicate the hydrophobic or hydrophilic contributions of the interaction. The information from the ITC results in combination with the known structures of N-TIMP-3/cd_MMP-1 will provide a more complete picture of the interaction. This is in particular of relevance with respect clinical application by engineering TIMPs for targeted inhibition of particular MMPs to treat diseases such as: cancer and arthritis.
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Date Issued: 2014
PURL: http://purl.flvc.org/fau/fd/FA00005833
Format: Document (PDF)

Title: Reflections on the evolution of the vertebrate tissue inhibitors of metalloproteinases.
Creator: Brew, Keith
Date Issued: 2019-01-20
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1096_fj.201801262R_1638460567
Format: Document (PDF)

Title: Engineering of tissue inhibitor of metalloproteinases mutants as potential therapeutics.
Creator: Nagase, Hideaki, Brew, Keith
Abstract/Description: Matrix metalloproteinases (MMPs) play a central role in many biological processes such as development, morphogenesis and wound healing, but their unbalanced activities are implicated innumerous disease processes such as arthritis, cancer metastasis, atherosclerosis, nephritis and fibrosis. One of the key mechanisms to control MMP activities is inhibition by endogenous inhibitors called tissue inhibitors of metalloproteinases (TIMPs). This review highlights the structures and inhibition...
Show moreMatrix metalloproteinases (MMPs) play a central role in many biological processes such as development, morphogenesis and wound healing, but their unbalanced activities are implicated innumerous disease processes such as arthritis, cancer metastasis, atherosclerosis, nephritis and fibrosis. One of the key mechanisms to control MMP activities is inhibition by endogenous inhibitors called tissue inhibitors of metalloproteinases (TIMPs). This review highlights the structures and inhibition mechanism of TIMPs, the biological activities of TIMPs, the unique properties of TIMP-3, and the altered specificity towards MMPs achieved by mutagenesis. A potential therapeutic use of TIMP variants is discussed.
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Date Issued: 2002-04-02
PURL: http://purl.flvc.org/fcla/dt/3327266
Subject Headings: Gene Therapy --Methods, Genetic Engineering --methods, Protein Structure, Tertiary, Rheumatic Diseases --therapy, Tissue Inhibitor of Metalloproteinases, Wound Healing --physiology, Metalloproteinases --Inhibitors --Therapeutic use
Format: Document (PDF)

Title: Characterization of a Metal-independent CAZy Family 6 Glycosyltransferase from Bacteroides ovatus.
Creator: Tumbale, Percy, Brew, Keith
Date Issued: 2009-09
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1074_jbc.M109.033878_1638385976
Format: Document (PDF)

Title: Tissue inhibitor of metalloproteinases-1 protects human neurons from staurosporine and HIV-1-induced apoptosis: mechanisms and relevance to HIV-1-associated dementia.
Creator: Ashutosh, Chao, C, Borgmann, K, Brew, Keith, Ghorpade, A
Date Issued: 2012-06
PURL: http://purl.flvc.org/fau/fd/FAUIR000129
Format: Citation

Title: A study of Caenorhabditis elegans tissue inhibitor of metalloproteinases.
Creator: Paul, Tamara., Florida Atlantic University, Brew, Keith
Abstract/Description: Tissue Inhibitors of Metalloproteinases (TIMPs) are produced by a wide variety of cell types. Similar to matrixins, the expression of TIMPs in the tissue is also controlled during tissue remodeling and physiological conditions to maintain a balance in the metabolism of extracellular matrix. Disruption of this balance can result in diseases associated with uncontrolled turnover of matrix, such as arthritis, cancer, and cardiovascular disease. Some of the biological processes TIMPs participate...
Show moreTissue Inhibitors of Metalloproteinases (TIMPs) are produced by a wide variety of cell types. Similar to matrixins, the expression of TIMPs in the tissue is also controlled during tissue remodeling and physiological conditions to maintain a balance in the metabolism of extracellular matrix. Disruption of this balance can result in diseases associated with uncontrolled turnover of matrix, such as arthritis, cancer, and cardiovascular disease. Some of the biological processes TIMPs participate in include: regulation of cell morphology and organ morphogenesis, inhibition of angiogenesis, steroidogenesis, and tissue remodeling. One major function of TIMPs is inhibition of Matrix Metaloproteinase (MMPs). This project used bioinformatic techniques to identify two Caenorhabditis elegans TIMP cDNA cloned by BLAST searching of EST database. These TIMP cDNA were amplified, cloned and expressed, proteins were purified. Kinetic studies were carried out to evaluate the inhibitory activities against various MMPs and TACE. This research project will provide some insight on the function of C. elegans TIMPs.
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Date Issued: 2006
PURL: http://purl.flvc.org/fcla/dt/13414
Subject Headings: Endopeptidases--Inhibitors, Proteolytic enzymes, Extracellular matrix proteins, Metalloproteinases--Inhibitors
Format: Document (PDF)

Title: Entropy Increases from Different Sources Support the High-affinity Binding of the N-terminal Inhibitory Domains of Tissue Inhibitors of Metalloproteinases to the Catalytic Domains of Matrix Metalloproteinases-1 and -3.
Creator: Wu, Ying, Wei, Shuo, Van Doren, Steven R., Brew, Keith
Date Issued: 2011-05
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1074_jbc.M111.222307_1638299359
Format: Document (PDF)

Title: Phage Display of Tissue Inhibitor of Metalloproteinases-2 (TIMP-2).
Creator: Bahudhanapati, Harinath, Zhang, Yingnan, Sidhu, Sachdev S., Brew, Keith
Date Issued: 2011-09
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1074_jbc.M111.253328_1638375138
Format: Document (PDF)

Title: Thermodynamic Basis of Selectivity in the Interactions of Tissue Inhibitors of Metalloproteinases N-domains with Matrix Metalloproteinases-1, -3, and -14.
Creator: Zou, Haiyin, Wu, Ying, Brew, Keith
Date Issued: 2016-05
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1074_jbc.M116.720250_1638376717
Format: Document (PDF)

Title: Family 6 Glycosyltransferases in Vertebrates and Bacteria: Inactivation and Horizontal Gene Transfer May Enhance Mutualism between Vertebrates and Bacteria.
Creator: Brew, Keith, Tumbale, Percy, Acharya, K. Ravi
Date Issued: 2010-11
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1074_jbc.R110.176248_1638296127
Format: Document (PDF)

Title: Structure of a metal-independent bacterial glycosyltransferase that catalyzes the synthesis of histo-blood group A antigen.
Creator: Thiyagarajan, Nethaji, Pham, Tram T. K., Stinson, Brittany, Sundriyal, Amit, Tumbale, Percy, Lizotte-Waniewski, Michelle, Brew, Keith, Acharya, K. Ravi
Date Issued: 2012-12-07
PURL: http://purl.flvc.org/fau/fd/FAUIR000113
Format: Citation

Title: A structural and thermodynamic comparison of substrate interactions and catalysis by family 6 glycosyltransferases from Bacteroides ovatus, Parachlamydia acanthamoebae, and Bos taurus.
Creator: Stinson, Brittany, Brew, Keith, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description: Family 6 Glycosyltransferases (GT6s) are involved in the biosynthesis of complex glycans and can be found in all vertebrates, cyanophages, and some bacteria and unicellular eukaryotes. Understanding variations within family 6 GTs is important because of the roles of their products in cellular recognition, intercellular interactions, pathogenicity, and immunity and is likewise important for understanding the evolution of GTs. PaGT6 (from Parchlamydia acanthamoebae) and α3GT (from Bos taurus)...
Show moreFamily 6 Glycosyltransferases (GT6s) are involved in the biosynthesis of complex glycans and can be found in all vertebrates, cyanophages, and some bacteria and unicellular eukaryotes. Understanding variations within family 6 GTs is important because of the roles of their products in cellular recognition, intercellular interactions, pathogenicity, and immunity and is likewise important for understanding the evolution of GTs. PaGT6 (from Parchlamydia acanthamoebae) and α3GT (from Bos taurus) both require a divalent metal ion for catalysis which binds to a DXD motif. In BoGT6a from Bacteroides ovatus a NXN motif replaces DXD, and activity is metal-independent. However, mutating the NXN motif in BoGT6a to DXD did not introduce metal-dependency, indicating that metal-dependency is linked to additional differences. Calorimetric studies have shown that the presence of a divalent metal ion enhances UDP and donor substrate binding to PaGT6 and causes an increase in the entropy of the interaction. Protein modelling of PaGT6 has revealed that the presence of Mn2+ allows a hydrogen bond to form between Asp 97 and UDP-GalNAc, causing the donor substrate to bend and form hydrogen bonds with His 119, Asn 229, Lys 228, and Arg 234. These interactions do not occur in the absence of Mn2+. Investigation of acceptor substrate binding revealed that the presence of UDP enhances acceptor substrate binding to BoGT6a and PaGT6. Calorimetric titrations of BoGT6a with 2-fucosyllactose in the absence and presence of UDP showed that UDP increases the affinity of 2-fucosyllactose 16-fold with little effect on ΔH. Measurements of ΔCp for 2-fucosyllactose binding indicate that there is not a hydrophobic effect for the binding of 2-fucosyllactose. The preferred acceptor substrate for the bovine and Bacteroides GT6 has a β-1,4 linked galactose, but P. acanthamoebae GT6 prefers an acceptor substrate with a β-1,3 linked galactose. The N-terminus of the catalytic domain of bacterial GT6s is truncated by 47 residues relative to the catalytic domain of bovine α3GT. Removal of this region from α3GT results in an unfolded protein, indicating that although this region is not directly involved in substrate binding, it forms interactions necessary for the stability of the catalytic domain.
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Date Issued: 2018
PURL: http://purl.flvc.org/fau/fd/FA00013047
Subject Headings: Glycosyltransferases, Bacteroides, Chlamydiales, Acanthamoeba, Bos taurus, Cattle
Format: Document (PDF)

Title: Thermodynamic profiles of the interactions of suramin, chondroitin sulfate, and pentosan polysulfate with the inhibitory domain of tissue inhibitor of metalloproteinases 3.
Creator: Logue, Timothy, Brew, Keith, Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description: Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a protein with multiple functions that include regulating the turnover of the extracellular matrix (ECM) by inhibiting members of the metzincin family. Extracellular levels of soluble TIMP-3 are low, reflecting its binding to components of the ECM including sulfated glycosaminoglycans (SGAGs) and its endocytosis by low density lipoprotein receptor-related protein 1. Because TIMP-3 inhibits ECM-degrading enzymes, the ability of SGAG mimetics...
Show moreTissue inhibitor of metalloproteinase-3 (TIMP-3) is a protein with multiple functions that include regulating the turnover of the extracellular matrix (ECM) by inhibiting members of the metzincin family. Extracellular levels of soluble TIMP-3 are low, reflecting its binding to components of the ECM including sulfated glycosaminoglycans (SGAGs) and its endocytosis by low density lipoprotein receptor-related protein 1. Because TIMP-3 inhibits ECM-degrading enzymes, the ability of SGAG mimetics to elevate extracellular concentrations of TIMP3 is of interest for osteoarthritis treatment. However, previous studies of such interactions have utilized immobilized forms of the protein or ligands. Here we have quantified the thermodynamics of the interactions of the inhibitory domain of TIMP-3 with chondroitin sulfate (CS), pentosan polysulfate (PPS) and suramin in solution using isothermal titration calorimetry. All three interactions are driven by a (favorable) negative enthalpy ychange combined with an unfavorable decrease in entropy. The heat capacity change (ΔCp) for the interaction of N-TIMP-3 with CS, PPS, or suramin is essentially zero, indicating an insignificant contribution from the hydrophobic effect. Based on the effects of ionic strength on the interaction of N-TIMP-3 with suramin, their interaction appears to be driven by electrostatic interactions. Modeling supports the view that the negatively charged sulfates of CS, PPS, and suramin interact with a cationic region on N-TIMP-3 that includes Lys -26, -27, -30, and -possibly 76 on the opposite face of TIMP-3 from its reactive site for metalloproteases.
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Date Issued: 2019
PURL: http://purl.flvc.org/fau/fd/FA00013328
Subject Headings: Tissue Inhibitor of Metalloproteinases, Osteoarthritis--Treatment, Suramin, Chondroitin Sulfates, Pentosans
Format: Document (PDF)

Title: Thermodynamic Origins of Selectivity in the Interactions of N- TIMP Variants and Metalloproteinases Catalytic Domains.
Creator: Zou, Haiyin, Brew, Keith, Florida Atlantic University, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Matrix metalloproteinases (MMPs) constitute the major class of enzymes capable of degrading all protein components of extracellular matrix (ECM) and have important roles in normal physiologic processes of maintaining tissue integrity and remodeling. However, excess MMP activities are associated with many diseases including rheumatoid arthritis and osteoarthritis, cardiomyopathy, and macular degeneration. The activity of MMPs is regulated by their endogenous protein inhibitors, the tissue...
Show moreMatrix metalloproteinases (MMPs) constitute the major class of enzymes capable of degrading all protein components of extracellular matrix (ECM) and have important roles in normal physiologic processes of maintaining tissue integrity and remodeling. However, excess MMP activities are associated with many diseases including rheumatoid arthritis and osteoarthritis, cardiomyopathy, and macular degeneration. The activity of MMPs is regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) which are avid broad-spectrum inhibitors of numerous human matrixins (MMPs and ADAMs). Uncontrolled matrix degradation occurs when the balance between TIMPs and MMPs is disrupted, resulting in serious diseases such as cancer, arthritis and chronic tissue ulcers. Thus, the engineering of TIMPs to produce highly selective and efficacious inhibitors of individual MMPs may be utilized for future treatment of diseases. Such engineering requires detailed analysis for the structural and biophysical information of MMP-TIMP interaction. Changes in the dynamics of proteins and solvent that accompany their associations with different binding partners, influence the specificity of binding through entropic effects. From the current studies it appears that the interactions of the inhibitory domains of TIMPs-1 and -2 (N-TIMPs) with MT1-MMP are driven by entropy increases that are partitioned between solvent and conformational entropy (ΔSsolv and ΔSconf), and a large conformational entropy penalty is responsible for the weak inhibition of MT1-MMP by NT1.We investigated how mutations that modify N-TIMP selectivity affect the thermodynamics of interactions with MMP1, MMP3 and MT1-MMP. The weak inhibition of MT1-MMP by N-TIMP-1 is enhanced by mutation of threonine 98, on the edge of the binding ridge, to leucine. This mutation increases the large ΔSconf cost for binding to MT1-MMP but this is offset by a greater increase in ΔSsolv. In contrast, this mutation enhances binding to MMP3 by increasing ΔSconf for the interaction. ΔSsolv and ΔSconf show mutual compensation for all interactions, with characteristic ranges for each MMP. Distinct electrostatic and dynamic features of MMPs are key factors in their selective inhibition.
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Date Issued: 2016
PURL: http://purl.flvc.org/fau/fd/FA00004643
Subject Headings: Metalloproteinases -- Inhibitors., Proteolytic enzymes., Extracellular matrix proteins., Apoptosis.
Format: Document (PDF)

Title: Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis.
Creator: Crabtree, Benedict, Thiyagarajan, Nethaji, Prior, Stephen H., Wilson, Peter, Iyer, Shalini, Ferns, Tyrone, Shapiro, Robert, Brew, Keith, Subramanian, Vasanta, Acharya, K. Ravi
Date Issued: 2007-10-01
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1021_bi701333h_1638203835
Format: Document (PDF)

Title: Development of a convenient peptide-based assay for lysyl hydroxylase.
Creator: Cudic, Mare, Patel, Deepak A., Lauer-Fields, Janelle L., Brew, Keith, Fields, Gregg B.
Date Issued: 2007-07-03
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1002_bip.20799_1638210547
Format: Document (PDF)

Title: Inactivation of N-TIMP-1 by N-terminal acetylation when expressed in bacteria.
Creator: Van Doren, Steven R., Wei, Shuo, Gao, Guanghua, DaGue, Beverly B., Palmier, Mark O., Bahudhanapati, Harinath, Brew, Keith
Date Issued: 2008-11
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1002_bip.21043_1638215239
Format: Document (PDF)

Title: Topological Specificity in Inhibitor Recognition by Matrix Metalloproteinases.
Creator: Lauer-Fields, Janelle, Florida Atlantic University, Brew, Keith, Charles E. Schmidt College of Medicine, Department of Biomedical Science
Abstract/Description: Alterations in activities of one family of proteases, the metzincins have been implicated in an array of physiological and pathological processes. In the present study, metzincin inhibitors were developed by utilizing topologically constrained peptides and pseudopeptides. The endothelin-family framework was used to develop a disulfideconstrained topology. This framework was chosen due to its three-dimensional similarity with a family of endogenous metzincin inhibitors, the tissue inhibitors...
Show moreAlterations in activities of one family of proteases, the metzincins have been implicated in an array of physiological and pathological processes. In the present study, metzincin inhibitors were developed by utilizing topologically constrained peptides and pseudopeptides. The endothelin-family framework was used to develop a disulfideconstrained topology. This framework was chosen due to its three-dimensional similarity with a family of endogenous metzincin inhibitors, the tissue inhibitors of metalloproteases (TIMPs). The collagenous triple-helix was chosen as a second framework, because only a subset of proteolytic enzymes have the capacity to bind and hydrolyze a triple-helix. Both templates were successfully modified to generate an array of inhibitors. These inhibitors displayed subnanomolar to micromolar apparent Ki values, while being moderately selective metzincin inhibitors. In both cases the threedimensional structure was determined to be important for activity. This work encourages the further development of both frameworks as metzincin inhibitors.
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Date Issued: 2007
PURL: http://purl.flvc.org/fau/fd/FA00000867
Subject Headings: Metalloproteinases--Inhibitors, Proteolytic enzymes, Extracellular matrix proteins
Format: Document (PDF)

Title: Engineered Sarafotoxins as Tissue Inhibitor of Metalloproteinases-like Matrix Metalloproteinase Inhibitors.
Creator: Lauer-Fields, Janelle L., Cudic, Mare, Wei, Shuo, Mari, Frank, Fields, Gregg B., Brew, Keith
Date Issued: 2007-09
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1074_jbc.M611612200_1638212835
Format: Document (PDF)

Title: Hypothesis: Metalloproteinase Inhibitors Decrease Risks of Cardiovascular Disease.
Creator: Lizotte-Waniewski, Michelle, Brew, Keith, Hennekens, Charles H.
Date Issued: 2016-07-24
PURL: http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1177_1074248415615237_1638375551
Format: Document (PDF)

FAU College Collections (18)	+ -
FAU Theses and Dissertations (5)	+ -
FAU Graduate Student Research (1)	+ -

Extracellular matrix proteins (2)	+ -
Metalloproteinases--Inhibitors (2)	+ -
Proteolytic enzymes (2)	+ -
Tissue Inhibitor of Metalloproteinases (2)	+ -
Acanthamoeba (1)	+ -

Apoptosis. (1)	+ -
Bacteroides (1)	+ -
Bos taurus (1)	+ -
Cattle (1)	+ -
Chlamydiales (1)	+ -
Chondroitin Sulfates (1)	+ -
Endopeptidases--Inhibitors (1)	+ -
Extracellular matrix proteins. (1)	+ -
Gene Therapy --Methods (1)	+ -
Genetic Engineering --methods (1)	+ -
Glycosyltransferases (1)	+ -
Metalloproteinases -- Inhibitors. (1)	+ -
Metalloproteinases --Inhibitors --Therapeutic use (1)	+ -
Osteoarthritis--Treatment (1)	+ -
Pentosans (1)	+ -
Protein Structure, Tertiary (1)	+ -
Proteolytic enzymes. (1)	+ -
Rheumatic Diseases --therapy (1)	+ -
Suramin (1)	+ -
Wound Healing --physiology (1)	+ -

article (18)	+ -
Electronic Thesis or Dissertation (5)	+ -
abstract (1)	+ -

Brew, Keith (24)	+ -
Florida Atlantic University (5)	+ -
Acharya, K. Ravi (4)	+ -
Cudic, Mare (3)	+ -
Fields, Gregg B. (3)	+ -

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