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Arthritis Research & Therapy 2003The loss of extracellular matrix macromolecules from the cartilage results in serious impairment of joint function. Metalloproteinases called 'aggrecanases' that cleave... (Review)
Review
The loss of extracellular matrix macromolecules from the cartilage results in serious impairment of joint function. Metalloproteinases called 'aggrecanases' that cleave the Glu373-Ala374 bond of the aggrecan core protein play a key role in the early stages of cartilage destruction in rheumatoid arthritis and in osteoarthritis. Three members of the ADAMTS family of proteinases, ADAMTS-1, ADAMTS-4 and ADAMTS-5, have been identified as aggrecanases. Matrix metalloproteinases, which are also found in arthritic joints, cleave aggrecans, but at a distinct site from the aggrecanases (i.e. Asn341-Phe342). The present review discuss the enzymatic properties of the three known aggrecanases, the regulation of their activities, and their role in cartilage matrix breakdown during the development of arthritis in relation to the action of matrix metalloproteinases.
Topics: ADAM Proteins; ADAMTS1 Protein; ADAMTS4 Protein; ADAMTS5 Protein; Cartilage; Disintegrins; Endopeptidases; Extracellular Matrix; Humans; Matrix Metalloproteinases; Metalloendopeptidases; Procollagen N-Endopeptidase; Protein Processing, Post-Translational; Tissue Inhibitor of Metalloproteinase-3
PubMed: 12718749
DOI: 10.1186/ar630 -
FEBS Letters Sep 2000Three metalloproteases belonging to the AAA superfamily (Yme1p, Afg3p and Rca1p) are involved in protein turnover and respiratory chain complex assembly in the yeast... (Review)
Review
Three metalloproteases belonging to the AAA superfamily (Yme1p, Afg3p and Rca1p) are involved in protein turnover and respiratory chain complex assembly in the yeast inner mitochondrial membrane. Analysis of the completed genome sequences of Caenorhabditis elegans and Drosophila melanogaster indicates that this gene family typically comprises 3-4 members in metazoans. Phylogenetic analysis reveals three main branches represented, respectively, by Saccharomyces cerevisiae YME1, human SPG7 (paraplegin) and S. cerevisiae AFG3 and RCA1. mt-AAA metalloproteases are weak candidates for several previously studied Drosophila mutants. A full elucidation of the cellular and physiological roles of mt-AAA metalloproteases in metazoans will require the creation of targeted mutations.
Topics: Animals; Humans; Intracellular Membranes; Invertebrates; Metalloendopeptidases; Mitochondria; Multigene Family; Phylogeny
PubMed: 10996302
DOI: 10.1016/s0014-5793(00)01989-x -
Philosophical Transactions of the Royal... Feb 1999The clostridial neurotoxins responsible for tetanus and botulism are proteins consisting of three domains endowed with different functions: neurospecific binding,... (Review)
Review
The clostridial neurotoxins responsible for tetanus and botulism are proteins consisting of three domains endowed with different functions: neurospecific binding, membrane translocation and proteolysis for specific components of the neuroexocytosis apparatus. Tetanus neurotoxin (TeNT) binds to the presynaptic membrane of the neuromuscular junction, is internalized and transported retroaxonally to the spinal cord. The spastic paralysis induced by the toxin is due to the blockade of neurotransmitter release from spinal inhibitory interneurons. In contrast, the seven serotypes of botulinum neurotoxins (BoNTs) act at the periphery by inducing a flaccid paralysis due to the inhibition of acetylcholine release at the neuromuscular junction. TeNT and BoNT serotypes B, D, F and G cleave specifically at single but different peptide bonds, of the vesicle associated membrane protein (VAMP) synaptobrevin, a membrane protein of small synaptic vesicles (SSVs). BoNT types A, C and E cleave SNAP-25 at different sites located within the carboxyl-terminus, while BoNT type C additionally cleaves syntaxin. The remarkable specificity of BoNTs is exploited in the treatment of human diseases characterized by a hyperfunction of cholinergic terminals.
Topics: Animals; Binding Sites; Biological Transport, Active; Botulinum Toxins; Cytosol; Exocytosis; Humans; Metalloendopeptidases; Neurons; Tetanus Toxin
PubMed: 10212474
DOI: 10.1098/rstb.1999.0377 -
Genetics Dec 2021Atherosclerosis is the underlying cause of heart attack, ischemic stroke and peripheral arterial disease, and genetic factors involved remain mostly unidentified. We...
Atherosclerosis is the underlying cause of heart attack, ischemic stroke and peripheral arterial disease, and genetic factors involved remain mostly unidentified. We previously identified a significant locus on mouse chromosome 17 for atherosclerosis, Ath49, in an intercross between BALB/c and SM strains. Ath49 partially overlaps in the confidence interval with Ath22 mapped in an AKR × DBA/2 intercross. Bioinformatics analysis prioritized Mep1a, encoding meprin 1α metalloendopeptidase, as a likely candidate gene for Ath49. To prove causality, Mep1a-/-Apoe-/- mice were generated and compared with Mep1a+/+Apoe-/- mice for atherosclerosis development. Mep1a was found abundantly expressed in atherosclerotic lesions but not in healthy aorta and liver of mice. Mep1a-/- Apoe-/- mice exhibited significant reductions in both early and advanced lesion sizes. Loss of Mep1a led to decreased necrosis but increased macrophage and neutrophil contents in advanced lesions, reduced plasma levels of CXCL5 and an oxidative stress biomarker. In addition, Mep1a-/- mice had significantly reduced triglyceride levels on a chow diet. Thus, Mep1a is a susceptibility gene for atherosclerosis and aggravates atherosclerosis partially through action on oxidative stress and inflammation.
Topics: Animals; Aorta; Apolipoproteins E; Atherosclerosis; Crosses, Genetic; Genetic Predisposition to Disease; Inflammation; Liver; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Oxidative Stress
PubMed: 34849841
DOI: 10.1093/genetics/iyab160 -
International Journal of Molecular... Jan 2023A protease is an enzyme with a proteolytic activity that facilitates the digestion of its substrates. Membrane-type I matrix metalloproteinase (MT1-MMP), a member of the... (Review)
Review
A protease is an enzyme with a proteolytic activity that facilitates the digestion of its substrates. Membrane-type I matrix metalloproteinase (MT1-MMP), a member of the broader matrix metalloproteinases (MMP) family, is involved in the regulation of diverse cellular activities. MT1-MMP is a very well-known enzyme as an activator of pro-MMP-2 and two collagenases, MMP-8 and MMP-13, all of which are essential for cell migration. As an anchored membrane enzyme, MT1-MMP has the ability to interact with a diverse group of molecules, including proteins that are not part of the extracellular matrix (ECM). Therefore, MT1-MMP can regulate various cellular activities not only by changing the extra-cellular environment but also by regulating cell signaling. The presence of both intracellular and extra-cellular portions of MT1-MMP can allow it to interact with proteins on both sides of the cell membrane. Here, we reviewed the MT1-MMP substrates involved in disease pathogenesis.
Topics: Collagenases; Matrix Metalloproteinase 14; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Proteins; Substrate Specificity
PubMed: 36768503
DOI: 10.3390/ijms24032183 -
Current Topics in Medicinal Chemistry 2017Overexpressed cell-surface receptors are hallmarks of many disease states and are often used as markers for targeting diseased cells over healthy counterparts. Cell... (Review)
Review
Overexpressed cell-surface receptors are hallmarks of many disease states and are often used as markers for targeting diseased cells over healthy counterparts. Cell adhesion peptides, which are often derived from interacting regions of these receptor-ligand proteins, mimic surfaces of intact proteins and, thus, have been studied as targeting agents for various payloads to certain cell targets for cancers and autoimmune diseases. Because many cytotoxic agents in the free form are often harmful to healthy cells, the use of cell adhesion peptides in targeting their delivery to diseased cells has been studied to potentially reduce required effective doses and associated harmful side-effects. In this review, multiple cell adhesion peptides from extracellular matrix and ICAM proteins were used to selectively direct drug payloads, signal-inhibitor peptides, and diagnostic molecules, to diseased cells over normal counterparts. RGD constructs have been used to improve the selectivity and efficacy of diagnostic and drug-peptide conjugates against cancer cells. From this precedent, novel conjugates of antigenic and cell adhesion peptides, called Bifunctional Peptide Inhibitors (BPIs), have been designed to selectively regulate immune cells and suppress harmful inflammatory responses in autoimmune diseases. Similar peptide conjugations with imaging agents have delivered promising diagnostic methods in animal models of rheumatoid arthritis. BPIs have also been shown to generate immune tolerance and suppress autoimmune diseases in animal models of type-1 diabetes, rheumatoid arthritis, and multiple sclerosis. Collectively, these studies show the potential of cell adhesion peptides in improving the delivery of drugs and diagnostic agents to diseased cells in clinical settings.
Topics: ATPases Associated with Diverse Cellular Activities; Autoimmune Diseases; Drug Delivery Systems; Humans; Metalloendopeptidases; Neoplasms
PubMed: 29357802
DOI: 10.2174/1568026618666180118154514 -
Anais Da Academia Brasileira de Ciencias Dec 2006Plant and insect trypanosomatids constitute the "lower trypanosomatids", which have been used routinely as laboratory models for biochemical and molecular studies... (Review)
Review
Plant and insect trypanosomatids constitute the "lower trypanosomatids", which have been used routinely as laboratory models for biochemical and molecular studies because they are easily cultured under axenic conditions, and they contain homologues of virulence factors from the classic human trypanosomatid pathogens. Among the molecular factors that contribute to Leishmania spp. virulence and pathogenesis, the major surface protease, alternatively called MSP, PSP, leishmanolysin, EC 3.4.24.36 and gp63, is the most abundant surface protein of Leishmania promastigotes. A myriad of functions have been described for the gp63 from Leishmania spp. when the metacyclic promastigote is inside the mammalian host. However, less is known about the functions performed by this molecule in the invertebrate vector. Intriguingly, gp63 is predominantly expressed in the insect stage of Leishmania, and in all insect and plant trypanosomatids examined so far. The gp63 homologues found in lower trypanosomatids seem to play essential roles in the nutrition as well as in the interaction with the insect epithelial cells. Since excellent reviews were produced in the last decade regarding the roles played by proteases in the vertebrate hosts, we focused in the recent developments in our understanding of the biochemistry and cell biology of gp63-like proteins in lower trypanosomatids.
Topics: Animals; Host-Parasite Interactions; Leishmania major; Metalloendopeptidases
PubMed: 17143406
DOI: 10.1590/s0001-37652006000400006 -
Pathophysiology of Haemostasis and... 2005Alfimeprase (ALF) is a recombinant, truncated form of fibrolase, a directly fibrinolytic zinc metalloproteinase that was first isolated from the venom of the Southern... (Review)
Review
Alfimeprase (ALF) is a recombinant, truncated form of fibrolase, a directly fibrinolytic zinc metalloproteinase that was first isolated from the venom of the Southern copperhead snake (Agkistrodon contortrix contortrix). ALF has direct proteolytic activity against the fibrin(ogen) Aalpha chain. ALF can be covalently bound and neutralized by serum alpha2-macroglobulin, a prevalent mammalian protease inhibitor. Preclinical pharmacology studies have shown that thrombolysis with ALF is up to 6-times more rapid than with select plasminogen activators. Additional studies suggest that intra-thrombus ALF has the potential to be a fast and effective thrombolytic without generation of a systemic lytic state. Investigations of phases 1 and 2 indicate that ALF is active and generally well tolerated. This paper reviews the biochemical characteristics of ALF and a review of the preliminary clinical experience in subjects with acute peripheral arterial occlusion and in those with central venous access device occlusion.
Topics: Animals; Arterial Occlusive Diseases; Catheterization, Central Venous; Humans; Metalloendopeptidases; Peripheral Vascular Diseases; Snake Venoms; Thrombolytic Therapy
PubMed: 16707931
DOI: 10.1159/000092427 -
Proceedings of the National Academy of... Mar 1998
Review
Topics: Enzyme Stability; Enzymes; Hot Temperature; Metalloendopeptidases; Point Mutation; Protein Engineering; Thermodynamics; Thermolysin
PubMed: 9482832
DOI: 10.1073/pnas.95.5.2035 -
BMJ (Clinical Research Ed.) Nov 1992
Topics: Humans; Metalloendopeptidases; Neoplasms
PubMed: 1483071
DOI: 10.1136/bmj.305.6865.1306