Mechanism and Inhibition of Matrix Metalloproteinases

2019 ◽  
Vol 26 (15) ◽  
pp. 2609-2633 ◽  
Author(s):  
Linda Cerofolini ◽  
Marco Fragai ◽  
Claudio Luchinat
Keyword(s):  
Matrix Metalloproteinases ◽  
Functional Characterization ◽  
Structural Data ◽  
Therapeutic Strategies ◽  
Outer Cell ◽  
Drug Candidates ◽  
The Family ◽  
Outer Cell Membrane ◽  
Membrane Bound

Matrix metalloproteinases hydrolyze proteins and glycoproteins forming the extracellular matrix, cytokines and growth factors released in the extracellular space, and membrane-bound receptors on the outer cell membrane. The pathological relevance of MMPs has prompted the structural and functional characterization of these enzymes and the development of synthetic inhibitors as possible drug candidates. Recent studies have provided a better understanding of the substrate preference of the different members of the family, and structural data on the mechanism by which these enzymes hydrolyze the substrates. Here, we report the recent advancements in the understanding of the mechanism of collagenolysis and elastolysis, and we discuss the perspectives of new therapeutic strategies for targeting MMPs.

Functional characterization of high-affinity Na+/dicarboxylate cotransporter found in Xenopus laevis kidney and heart

2005 ◽  
Vol 289 (5) ◽  
pp. C1159-C1168 ◽  
Author(s):  
Naomi Oshiro ◽  
Ana M. Pajor
Keyword(s):  
Xenopus Laevis ◽  
Cdna Sequence ◽  
Citric Acid Cycle ◽  
Functional Characterization ◽  
Activation Kinetics ◽  
Electrophysiological Properties ◽  
High Affinity ◽  
The Family ◽  
Kidney Liver

The SLC13 gene family includes sodium-coupled transporters for citric acid cycle intermediates and sulfate. The present study describes the sequence and functional characterization of a SLC13 family member from Xenopus laevis, the high-affinity Na+/dicarboxylate cotransporter xNaDC-3. The cDNA sequence of xNaDC-3 codes for a protein of 602 amino acids that is ∼70% identical to the sequences of mammalian NaDC-3 orthologs. The message for xNaDC-3 is found in the kidney, liver, intestine, and heart. The xNaDC-3 has a high affinity for substrate, including a Km for succinate of 4 μM, and it is inhibited by the NaDC-3 test substrates 2,3-dimethylsuccinate and adipate. The transport of succinate by xNaDC-3 is dependent on sodium, with sigmoidal activation kinetics, and lithium can partially substitute for sodium. As with other members of the family, xNaDC-3 is electrogenic and exhibits inward substrate-dependent currents in the presence of sodium. However, other electrophysiological properties of xNaDC-3 are unique and involve large leak currents, possibly mediated by anions, that are activated by binding of sodium or lithium to a single site.

Identification and functional characterization of a novel locust peptide belonging to the family of insect growth blocking peptides

Peptides ◽  
2015 ◽  
Vol 74 ◽  
pp. 23-32 ◽  
Author(s):  
Tewodros Firdissa Duressa ◽  
Kurt Boonen ◽  
Yoichi Hayakawa ◽  
Roger Huybrechts
Keyword(s):  
Functional Characterization ◽  
Insect Growth ◽  
The Family

scholarly journals miR-125-chinmo pathway regulates dietary restriction dependent enhancement of lifespan in Drosophila

2020 ◽  
Author(s):  
Manish Pandey ◽  
Sakshi Bansal ◽  
Sudipta Bar ◽  
Nicholas S. Sokol ◽  
Jason M. Tennessen ◽  
...  
Keyword(s):  
Dietary Restriction ◽  
Healthy Aging ◽  
Fat Body ◽  
Late Onset ◽  
Functional Characterization ◽  
Drug Candidates ◽  
Downstream Effectors ◽  
Processing Factors

AbstractDietary restriction (DR) extends healthy lifespan in diverse species. Age and nutrient-related changes in the abundance of microRNAs (miRNAs) and their processing factors have been linked to organismal longevity. However, the mechanisms by which they modulate lifespan and the tissue-specific role of miRNA mediated networks in DR dependent enhancement of lifespan remains largely unexplored. We show that two neuronally enriched and highly conserved microRNAs, miR-125 and let-7 mediate the DR response in Drosophila melanogaster. Functional characterization of miR-125 demonstrates its role in neurons while its target chinmo acts both in neurons and the fat body to modulate fat metabolism and longevity. Proteomic analysis revealed that Chinmo exerts its DR effects by regulating expression of FATP, CG2017, CG9577, CG17554, CG5009, CG8778, CG9527 and FASN1. Our findings identify miR-125 as a conserved effector of DR pathway and open up the avenue for this small RNA molecule and its downstream effectors to be considered as potential drug candidates for treatment of late-onset diseases and biomarkers for healthy aging in humans.

scholarly journals Functional Characterization of the IlpA Protein of Vibrio vulnificus as an Adhesin and Its Role in Bacterial Pathogenesis

2010 ◽  
Vol 78 (6) ◽  
pp. 2408-2417 ◽  
Author(s):  
Kyung-Jo Lee ◽  
Na Yeon Lee ◽  
Yang-Soo Han ◽  
Juri Kim ◽  
Kyu-Ho Lee ◽  
...  
Keyword(s):  
Adhesion Molecule ◽  
Vibrio Vulnificus ◽  
Polyclonal Antibodies ◽  
Functional Characterization ◽  
Intestinal Epithelial ◽  
Human Intestinal Epithelial Cells ◽  
Direct Binding ◽  
Membrane Bound

ABSTRACT Vibrio vulnificus is a Gram-negative bacterium that causes a fatal septicemia. One of its virulence factors is a membrane-bound lipoprotein, IlpA, which can induce cytokine production in human immune cells. In the present study, the role of IlpA as an adhesion molecule was investigated. An ilpA-deleted V. vulnificus mutant showed significantly decreased adherence to INT-407 human intestinal epithelial cells, which in turn resulted in reduced cytotoxicity. The ΔilpA mutant recovered the adherence ability of the wild type by complementation in trans with the intact ilpA gene. In addition, pretreatment of V. vulnificus with anti-IlpA polyclonal antibodies resulted in a significant reduction of bacterial adherence. To localize the domain of IlpA required for cytoadherence, three truncated recombinant IlpA polypeptides were constructed and tested for the ability to adhere to human cells by a ligand-binding immunoblot assay and fluorescence microscopy. The polypeptide containing the carboxy (C)-terminal hydrophilic domain exhibited direct binding to INT-407 cells. Therefore, the C-terminal domain of IlpA allows this protein to be an adhesion molecule of V. vulnificus.

scholarly journals Functional Characterization of Colon-Cancer-Associated Variants in ADAM17 Affecting the Catalytic Domain

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 463
Author(s):  
Jan Philipp Dobert ◽  
Anne-Sophie Cabron ◽  
Philipp Arnold ◽  
Egor Pavlenko ◽  
Stefan Rose-John ◽  
...  
Keyword(s):  
Catalytic Domain ◽  
Functional Characterization ◽  
Tumor Development ◽  
Point Mutations ◽  
Modern World ◽  
Protective Effects ◽  
Tissue Samples ◽  
Membrane Bound

Although extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the development of CRC due to its involvement in signaling pathways related to inflammation and cell proliferation. ADAM17 is capable of releasing membrane-bound proteins from the cell surface in a process called shedding. A deficiency of ADAM17 activity has been previously shown to have protective effects against CRC in mice, while an upregulation of ADAM17 activity is suspected to facilitate tumor development. In this study, we characterize ADAM17 variants found in tissue samples of cancer patients in overexpression studies. We here focus on point mutations identified within the catalytic domain of ADAM17 and could show a functional dysregulation of the CRC-associated variants. Since the catalytic domain of ADAM17 is the only region structurally determined by crystallography, we study the effect of each point mutation not only to learn more about the role of ADAM17 in cancer, but also to investigate the structure–function relationships of the metalloprotease.

scholarly journals Polyphosphate-dependent synthesis of ATP and ADP by the family-2 polyphosphate kinases in bacteria

2008 ◽  
Vol 105 (46) ◽  
pp. 17730-17735 ◽  
Author(s):  
Boguslaw Nocek ◽  
Samvel Kochinyan ◽  
Michael Proudfoot ◽  
Greg Brown ◽  
Elena Evdokimova ◽  
...  
Keyword(s):  
Sinorhizobium Meliloti ◽  
Molecular Mechanisms ◽  
Catalytic Mechanism ◽  
Functional Characterization ◽  
High Energy ◽  
Inorganic Polyphosphate ◽  
The Family ◽  
Adp Crystal ◽  
Intracellular Energy

Inorganic polyphosphate (polyP) is a linear polymer of tens or hundreds of phosphate residues linked by high-energy bonds. It is found in all organisms and has been proposed to serve as an energy source in a pre-ATP world. This ubiquitous and abundant biopolymer plays numerous and vital roles in metabolism and regulation in prokaryotes and eukaryotes, but the underlying molecular mechanisms for most activities of polyP remain unknown. In prokaryotes, the synthesis and utilization of polyP are catalyzed by 2 families of polyP kinases, PPK1 and PPK2, and polyphosphatases. Here, we present structural and functional characterization of the PPK2 family. Proteins with a single PPK2 domain catalyze polyP-dependent phosphorylation of ADP to ATP, whereas proteins containing 2 fused PPK2 domains phosphorylate AMP to ADP. Crystal structures of 2 representative proteins, SMc02148 from Sinorhizobium meliloti and PA3455 from Pseudomonas aeruginosa, revealed a 3-layer α/β/α sandwich fold with an α-helical lid similar to the structures of microbial thymidylate kinases, suggesting that these proteins share a common evolutionary origin and catalytic mechanism. Alanine replacement mutagenesis identified 9 conserved residues, which are required for activity and include the residues from both Walker A and B motifs and the lid. Thus, the PPK2s represent a molecular mechanism, which potentially allow bacteria to use polyP as an intracellular energy reserve for the generation of ATP and survival.

Functional characterization of tomato membrane-bound NAC transcription factors

2016 ◽  
Vol 93 (4-5) ◽  
pp. 511-532 ◽  
Author(s):  
Payel Bhattacharjee ◽  
Rohit Das ◽  
Arunava Mandal ◽  
Pallob Kundu
Keyword(s):  
Transcription Factors ◽  
Functional Characterization ◽  
Nac Transcription Factors ◽  
Membrane Bound

Functional characterization of soluble and membrane-bound forms of vaccinia virus complement control protein (VCP)

1999 ◽  
Vol 36 (10) ◽  
pp. 685-697 ◽  
Author(s):  
Ariella M Rosengard ◽  
Laura C Alonso ◽  
Laura C Korb ◽  
William M Baldwin ◽  
Fred Sanfilippo ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Functional Characterization ◽  
Complement Control Protein ◽  
Membrane Bound ◽  
Control Protein

scholarly journals Ferric Enterochelin Transport in Yersinia enterocolitica: Molecular and Evolutionary Aspects

1999 ◽  
Vol 181 (20) ◽  
pp. 6387-6395 ◽  
Author(s):  
S. Schubert ◽  
D. Fischer ◽  
J. Heesemann
Keyword(s):  
Gene Cluster ◽  
Yersinia Enterocolitica ◽  
Insertional Mutagenesis ◽  
Yersinia Pseudotuberculosis ◽  
Functional Characterization ◽  
In Vitro Transcription ◽  
E Coli ◽  
The Family

ABSTRACT Yersinia enterocolitica is well equipped for siderophore piracy, encompassing the utilization of siderophores such as ferrioxamine, ferrichrome, and ferrienterochelin. In this study, we report on the molecular and functional characterization of theYersinia fep-fes gene cluster orthologous to theEscherichia coli ferrienterochelin transport genes (fepA, fepDGC, and fepB) and the esterase gene fes. In vitro transcription-translation analysis identified polypeptides of 30 and 35 kDa encoded byfepC and fes, respectively. A frameshift mutation within the fepA gene led to expression of a truncated polypeptide of 40 kDa. The fepD,fepG, and fes genes of Y. enterocolitica were shown to complement corresponding E. coli mutants. Insertional mutagenesis of fepD orfes genes abrogates enterochelin-supported growth ofY. enterocolitica on iron-chelated media. In contrast toE. coli, the fep-fes gene cluster inY. enterocolitica consists solely of genes required for uptake and utilization of enterochelin (fep) and not of enterochelin synthesis genes such as entF. By Southern hybridization, fepDGC and fes sequences could be detected in Y. enterocolitica biotypes IB, IA, and II but not in biotype IV strains, Yersinia pestis, andYersinia pseudotuberculosis strains. According to sequence alignment data and the coherent structure of the Yersinia fep-fes gene cluster, we suggest early genetic divergence of ferrienterochelin uptake determinants among species of the familyEnterobacteriaceae.

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