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Respiratory Research 2001Despite much information on their catalytic properties and gene regulation, we actually know very little of what matrix metalloproteinases (MMPs) do in tissues. The... (Review)
Review
Despite much information on their catalytic properties and gene regulation, we actually know very little of what matrix metalloproteinases (MMPs) do in tissues. The catalytic activity of these enzymes has been implicated to function in normal lung biology by participating in branching morphogenesis, homeostasis, and repair, among other events. Overexpression of MMPs, however, has also been blamed for much of the tissue destruction associated with lung inflammation and disease. Beyond their role in the turnover and degradation of extracellular matrix proteins, MMPs also process, activate, and deactivate a variety of soluble factors, and seldom is it readily apparent by presence alone if a specific proteinase in an inflammatory setting is contributing to a reparative or disease process. An important goal of MMP research will be to identify the actual substrates upon which specific enzymes act. This information, in turn, will lead to a clearer understanding of how these extracellular proteinases function in lung development, repair, and disease.
Topics: Animals; Humans; Lung; Matrix Metalloproteinase 12; Matrix Metalloproteinase 7; Matrix Metalloproteinases; Metalloendopeptidases; Substrate Specificity
PubMed: 11686860
DOI: 10.1186/rr33 -
Memorias Do Instituto Oswaldo Cruz Mar 2005Metalloproteinases are abundant enzymes in crotaline and viperine snake venoms. They are relevant in the pathophysiology of envenomation, being responsible for local and... (Review)
Review
Metalloproteinases are abundant enzymes in crotaline and viperine snake venoms. They are relevant in the pathophysiology of envenomation, being responsible for local and systemic hemorrhage frequently observed in the victims. Snake venom metalloproteinases (SVMP) are zinc-dependent enzymes of varying molecular weights having multidomain organization. Some SVMP comprise only the proteinase domain, whereas others also contain a disintegrin-like domain, cysteine-rich, and lectin domains. They have strong structural similarities with both mammalian matrix metalloproteinases (MMP) and members of ADAMs (a disintegrin and metalloproteinase) group. Besides hemorrhage, snake venom metalloproteinase induce local myonecrosis, skin damage, and inflammatory reaction in experimental models. Local inflammation is an important characteristic of snakebite envenomations inflicted by viperine and crotaline snake species. Thus, in the recent years there is a growing effort to understand the mechanisms responsible for SVMP-induced inflammatory reaction and the structural determinants of this effect. This short review focuses the inflammatory effects evoked by SVMP.
Topics: Animals; Humans; Inflammation; Metalloendopeptidases; Snake Venoms
PubMed: 15962120
DOI: 10.1590/s0074-02762005000900031 -
Biological Chemistry Oct 2012The astacins are a family of multi-domain metallopeptidases with manifold functions in metabolism. They are either secreted or membrane-anchored and are regulated by... (Review)
Review
The astacins are a family of multi-domain metallopeptidases with manifold functions in metabolism. They are either secreted or membrane-anchored and are regulated by being synthesized as inactive zymogens and also by co-localizing protein inhibitors. The distinct family members consist of N-terminal signal peptides and pro-segments, zinc-dependent catalytic domains, further downstream extracellular domains, transmembrane anchors, and cytosolic domains. The catalytic domains of four astacins and the zymogen of one of these have been structurally characterized and shown to comprise compact ~200-residue zinc-dependent moieties divided into an N-terminal and a C-terminal sub-domain by an active-site cleft. Astacins include an extended zinc-binding motif (HEXXHXXGXXH) which includes three metal ligands and groups them into the metzincin clan of metallopeptidases. In mature, unbound astacins, a conserved tyrosine acts as an additional zinc ligand, which is swung out upon substrate or inhibitor binding in a 'tyrosine switch' motion. Other characteristic structural elements of astacin catalytic domains are three large α-helices and a five-stranded β-sheet, as well as two or three disulfide bonds. The N-terminal pro-segments are variable in length and rather unstructured. They inhibit the catalytic zinc following an 'aspartate-switch' mechanism mediated by an aspartate embedded in a conserved motif (FXGD). Removal of the pro-segment uncovers a deep and extended active-site cleft, which in general shows preference for aspartate residues in the specificity pocket (S1'). Furthermore, astacins undergo major rearrangement upon activation within an 'activation domain,' and show a slight hinge movement when binding substrates or inhibitors. In this review, we discuss the overall architecture of astacin catalytic domains and their involvement in function and zymogenic activation.
Topics: Amino Acid Sequence; Animals; Enzyme Activation; Enzyme Precursors; Evolution, Molecular; Humans; Metalloendopeptidases; Molecular Sequence Data; Protease Inhibitors
PubMed: 23092796
DOI: 10.1515/hsz-2012-0149 -
Biochimica Et Biophysica Acta.... Jan 2022The metalloproteinase meprin β plays an important role during collagen I deposition in the skin, mucus detachment in the small intestine and also regulates the... (Review)
Review
The metalloproteinase meprin β plays an important role during collagen I deposition in the skin, mucus detachment in the small intestine and also regulates the abundance of different cell surface proteins such as the interleukin-6 receptor (IL-6R), the triggering receptor expressed on myeloid cells 2 (TREM2), the cluster of differentiation 99 (CD99), the amyloid precursor protein (APP) and the cluster of differentiation 109 (CD109). With that, regulatory mechanisms that control meprin β activity and regulate its release from the cell surface to enable access to distant substrates are increasingly important. Here, we will summarize factors that alternate meprin β activity and thereby regulate its proteolytic activity on the cell surface or in the supernatant. We will also discuss cleavage of the IL-6R and TREM2 on the cell surface and compare it to CD109. CD109, as a substrate of meprin β, is cleaved within the protein core, thereby releasing defined fragments from the cell surface. At last, we will also summarize the role of proteases in general and meprin β in particular in substrate release on extracellular vesicles.
Topics: Animals; Extracellular Vesicles; Humans; Metalloendopeptidases; Proteolysis; Signal Transduction
PubMed: 34626678
DOI: 10.1016/j.bbamcr.2021.119136 -
Journal of Biochemistry Feb 1996Activated gelatinase A is reportedly associated with tumor spread. We identified novel matrix metalloproteinases that localize on the cell surface and mediate the... (Review)
Review
Activated gelatinase A is reportedly associated with tumor spread. We identified novel matrix metalloproteinases that localize on the cell surface and mediate the activation of progelatinase A. Thus, these progelatinase A activators were named membrane-type matrix metalloproteinase-1 and -2 (MT-MMP-1 and -2, respectively). MT-MMP-1 is overexpressed in malignant tumor tissues, including lung and stomach carcinomas that contain activated gelatinase A. This suggests that MT-MMP-1 is associated with the activation of progelatinase A in these tumor tissues. The expression of MT-MMP-1 also induced binding of gelatinase A to the cell surface by functioning as a receptor. The cell surface localization of proteinases has advantages over pericellular proteolysis. MT-MMP-1 and its family may play a central role in the cell surface localization and activation of progelatinase A and via this mechanism, tumor cell use exogenous progelatinase A to mediate the proteolysis associated with invasion and metastasis.
Topics: Amino Acid Sequence; Animals; Collagenases; Gelatinases; Humans; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Membrane Proteins; Metalloendopeptidases; Molecular Sequence Data; Neoplasm Metastasis; Sequence Homology, Amino Acid
PubMed: 8882706
DOI: 10.1093/oxfordjournals.jbchem.a021223 -
Molecular Aspects of Medicine Oct 2008The astacins are a subfamily of the metzincin superfamily of metalloproteinases. The first to be characterized was the crayfish enzyme astacin. To date more than 200... (Review)
Review
The astacins are a subfamily of the metzincin superfamily of metalloproteinases. The first to be characterized was the crayfish enzyme astacin. To date more than 200 members of this family have been identified in species ranging from bacteria to humans. Astacins are involved in developmental morphogenesis, matrix assembly, tissue differentiation and digestion. Family members include the procollagen C-proteinase (BMP1, bone morphogenetic protein 1), tolloid and mammalian tolloid-like, HMP (Hydra vulgaris metalloproteinase), sea urchin BP10 (blastula protein) and SPAN (Strongylocentrotus purpuratus astacin), the 'hatching' subfamily comprising alveolin, ovastacin, LCE, HCE ('low' and 'high' choriolytic enzymes), nephrosin (from carp head kidney), UVS.2 from frog, and the meprins. In the human and mouse genomes, there are six astacin family genes (two meprins, three BMP1/tolloid-like, one ovastacin), but in Caenorhabditis elegans there are 40. Meprins are the only astacin proteinases that function on the membrane and extracellularly by virtue of the fact that they can be membrane-bound or secreted. They are unique in their domain structure and covalent subunit dimerization, oligomerization propensities, and expression patterns. They are normally highly regulated at the transcriptional and post-translational levels, localize to specific membranes or extracellular spaces, and can hydrolyse biologically active peptides, cytokines, extracellular matrix (ECM) proteins and cell-surface proteins. The in vivo substrates of meprins are unknown, but the abundant expression of these proteinases in the epithelial cells of the intestine, kidney and skin provide clues to their functions.
Topics: Amino Acid Sequence; Animals; Humans; Intestinal Mucosa; Metalloendopeptidases; Models, Molecular; Molecular Sequence Data; Phylogeny; Protein Conformation; Protein Subunits; Substrate Specificity; Tissue Distribution
PubMed: 18783725
DOI: 10.1016/j.mam.2008.08.002 -
Molecules (Basel, Switzerland) Feb 2023Ochratoxin A (OTA) is considered one of the main mycotoxins responsible for health problems and considerable economic losses in the feed industry. The aim was to study...
Ochratoxin A (OTA) is considered one of the main mycotoxins responsible for health problems and considerable economic losses in the feed industry. The aim was to study OTA's detoxifying potential of commercial protease enzymes: (i) bromelain cysteine-protease, (ii) bovine trypsin serine-protease and (iii) neutral metalloendopeptidase. In silico studies were performed with reference ligands and T-2 toxin as control, and in vitro experiments. In silico study results showed that tested toxins interacted near the catalytic triad, similar to how the reference ligands behave in all tested proteases. Likewise, based on the proximity of the amino acids in the most stable poses, the chemical reaction mechanisms for the transformation of OTA were proposed. In vitro experiments showed that while bromelain reduced OTA's concentration in 7.64% at pH 4.6; trypsin at 10.69% and the neutral metalloendopeptidase in 8.2%, 14.44%, 45.26% at pH 4.6, 5 and 7, respectively ( < 0.05). The less harmful α-ochratoxin was confirmed with trypsin and the metalloendopeptidase. This study is the first attempt to demonstrate that: (i) bromelain and trypsin can hydrolyse OTA in acidic pH conditions with low efficiency and (ii) the metalloendopeptidase was an effective OTA bio-detoxifier. This study confirmed α-ochratoxin as a final product of the enzymatic reactions in real-time practical information on OTA degradation rate, since in vitro experiments simulated the time that food spends in poultry intestines, as well as their natural pH and temperature conditions.
Topics: Animals; Cattle; Ochratoxins; Bromelains; Molecular Docking Simulation; Trypsin; Mycotoxins; Animal Feed; Metalloendopeptidases
PubMed: 36903263
DOI: 10.3390/molecules28052019 -
Nature Communications Apr 2024Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic...
Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of Kras-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.
Topics: Humans; Mice; Animals; Proto-Oncogene Proteins p21(ras); Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Metalloendopeptidases
PubMed: 38605037
DOI: 10.1038/s41467-024-47242-3 -
Toxins Aug 2016The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers... (Review)
Review
The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera of resistant animals, and characterized to different extents. They are acidic oligomeric glycoproteins that remain biologically active over a wide range of pH and temperature values. Based on primary structure determination, mammalian plasmatic SVMPIs are classified as members of the immunoglobulin (Ig) supergene protein family, while the one isolated from muscle belongs to the ficolin/opsonin P35 family. On the other hand, SVMPIs from snake plasma have been placed in the cystatin superfamily. These natural antitoxins constitute the first line of defense against snake venoms, inhibiting the catalytic activities of snake venom metalloendopeptidases through the establishment of high-affinity, non-covalent interactions. This review presents a historical account of the field of natural resistance, summarizing its main discoveries and current challenges, which are mostly related to the limitations that preclude three-dimensional structural determinations of these inhibitors using "gold-standard" methods; perspectives on how to circumvent such limitations are presented. Potential applications of these SVMPIs in medicine are also highlighted.
Topics: Animals; Antidotes; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Metalloendopeptidases; Protease Inhibitors; Protein Conformation; Reptilian Proteins; Snake Bites; Snake Venoms; Structure-Activity Relationship
PubMed: 27571103
DOI: 10.3390/toxins8090250 -
Progress in Biophysics and Molecular... 1998The family of proteins called matrix metalloproteinases (MMPs) are a class of structurally related proteins that are collectively responsible for the metabolism of... (Review)
Review
The family of proteins called matrix metalloproteinases (MMPs) are a class of structurally related proteins that are collectively responsible for the metabolism of extracellular matrix proteins. These zinc and calcium dependent enzymes, which include the collagenases, stromelysins and gelatinases, are involved in normal tissue remodelling processes such as wound healing, pregnancy and angiogenesis. Under physiological conditions, in addition to the regulated proteolyses of inactive precursors to the active form, the degradative nature of these enzymes are precisely controlled by endogenous inhibitors (TIMPs). The excess syntheses and production of these proteins lead to the accelerated matrix degradation associated with diseases such as arthritis, cancer and multiple sclerosis. The MMPs have therefore proved to be attractive targets for structure based drug design. The pursuit of low molecular weight inhibitors of these proteins have encouraged structural studies on several members of family, so that the molecular details of enzyme-inhibitor interactions of the MMPs have become available. These studies provide insights into the basic structural framework of the MMP superfamily and reveal characteristics which promote specificity between individual members. The analyses of the three dimensional structure of the MMPs in the context of their primary sequence and the design and selectivity of low molecular weight inhibitors of the superfamily is the subject of this review.
Topics: Amino Acid Sequence; Animals; Catalytic Domain; Consensus Sequence; Extracellular Matrix; Female; Humans; Metalloendopeptidases; Models, Molecular; Molecular Sequence Data; Neovascularization, Physiologic; Pregnancy; Protein Conformation; Protein Structure, Secondary; Sequence Alignment; Wound Healing
PubMed: 9785958
DOI: 10.1016/s0079-6107(98)00003-0