Gelatinase

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Gelatinases are enzymes capable of degrading gelatin through hydrolysis, playing a major role in degradation of extracellular matrix and tissue remodeling. Gelatinases are a type of matrix metalloproteinases (MMPs), a family of enzymes that depend on zinc as a cofactor and can break down parts of the extracellular matrix. [1] MMPs have multiple subgroups, including Gelatinase A ( MMP-2 ) and Gelatinase B  ( MMP-9 ). Gelatinases are composed of a variety of EC numbers: Gelatinase A uses 3.4.24.24, and Gelatinase B uses 3.4.24.35, in which the first three numbers are same. The first digit, 3, is the class. Class 3 enzymes are hydrolases, enzymes that catalyze hydrolysis reactions, that is, they cleave bonds in presence of water. Next digit is sub-class 4, or proteases, which are enzymes who hydrolyze peptide bonds in proteins. The next number is the sub-subclass of 24, which consists of metalloendopeptidases which contain metal ions in their active sites, in this case zinc, helping in cleavage of peptide bonds. The last part of the EC number is the serial number, identifying specific enzymes within a sub-subclass. 24 represents gelatinase A, which is a metalloproteinase that breaks down gelatin and collagen, while 35 represents Gelatinase B, which hydrolyzes peptide bonds. [2]

Contents

Gelatinase application in species

Gelatinase enzymes can be found in a number of eukaryotes, including mammals, and birds; bacteria including Pseudomonas aeruginosa and Serratia marcescens), and fungi, but may have variations among species based on identification and function of the gelatinase type. In humans, the gelatinases expressed are matrix metalloproteinases MMP2 and MMP9. [3] Additionally, Gelatinases A (MMP2) and B (MMP9) have been proven to assist in developing new blood vessels in corneas of rats and rabbits when experiencing corneal damage. Corneal wounds in these rodents can yield greater expression and activity of the enzyme. Gelatinase assists in remodeling damaged extracellular matrix (EMC) by removing the damaged matrix proteins (by MMP-9), yielding an angiogenic response, or formation of new blood vessels. This indicates that there is collagen remodeling in the corneal stromal repair tissue with Gelatinases. [4]

Enzyme pathway

These specific proteases use hydrolysis to break down gelatin through two sequential steps. First is polypeptide products, followed by amino acids (especially alpha). [5] The substrate in this case is gelatin, and the product is the polypeptides formed. Gelatinase binds to the substrate, gelatin, due to specificity of binding interactions on cell surface. The catalysis, associated with a zinc ion and amino acid residues, breaks the peptide bonds into polypeptides through cleavage. Polypeptides are further converted into amino acids, the second sequential step and product of the reaction. Additional proteins, such as TIMP-2 and other TIMPs, work as inhibitors to regulate and control the enzymatic pathway by binding to the gelatinase active site, which prevents the breakdown of substrate. [6]

Cell surface association

Gelatinases can regulate enzymatic activation and activity by interactions on the cell surface. Surface proteins regulate functions such as localization, inhibition, and internalization. Enzyme binding to the surface brings it in close accord with certain substrates in the pericellular space in order to regulate function of the MMPs. Localization allows them to degrade specific elements of the EMC by close cell surface association. [7]

Crystal structures

Gelatinases contain a catalytic domain (located in the C-terminal region), which is essential for enzymatic activity and hydrolysis of peptide bonds in substrate molecules. This domain contains five beta strands in a twisted beta sheet bound together by three alpha helicies. The active site is located in between a beta strand and an alpha helix, holding histidine residues, with another helix holding a histidine residue, creating loops. These histidines are in relation to a catalytic zinc ion, playing an important role in catalyzing the hydrolysis of peptide bonds in proteins.Also in the C terminal region, there is a hemopexin-like domain, which interacts with a part of the cell membrane. [8] Contributing to enzyme specificity, affinity, and localization, made of four blades with antiparallel beta stranded beta sheets. [9] Furthermore, there is the fibronectin type II (FNII), important for recognition, folding, and mediation of gelatin interactions due to the involvement of protein-protein interactions, and are crucial for substrate specificity. FNII consists of two double-stranded antiparallel beta sheets. The primary structures of individual MMPs may have different domain compositions, and the arrangement of the domains and structures help with folding and stability of the enzyme, as folding is what promotes enzyme activity.

Active sites

Some of the gelatinases are proteinases that are zinc-dependent. The known active sites of these proteins are located in the catalytic domains, and typically contain a zinc atom at known site, which is important for catalysis. The active sites also contain histidine and glutamate residues, which is known as the catalytic zinc-binding active site region. [10] These residues are in coordination with the zinc ion for stabilization and conformation. This active site aids the hydrolysis of peptide bonds in substrates, such as gelatin and collagen, due to coordination of zinc ions and amino acid residues. They also influence gelatinase catalysis and binding of substrates. [11]

Related Research Articles

<span class="mw-page-title-main">Chymotrypsin</span> Digestive enzyme

Chymotrypsin (EC 3.4.21.1, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme component of pancreatic juice acting in the duodenum, where it performs proteolysis, the breakdown of proteins and polypeptides. Chymotrypsin preferentially cleaves peptide amide bonds where the side chain of the amino acid N-terminal to the scissile amide bond (the P1 position) is a large hydrophobic amino acid (tyrosine, tryptophan, and phenylalanine). These amino acids contain an aromatic ring in their side chain that fits into a hydrophobic pocket (the S1 position) of the enzyme. It is activated in the presence of trypsin. The hydrophobic and shape complementarity between the peptide substrate P1 side chain and the enzyme S1 binding cavity accounts for the substrate specificity of this enzyme. Chymotrypsin also hydrolyzes other amide bonds in peptides at slower rates, particularly those containing leucine at the P1 position.

<span class="mw-page-title-main">Proteolysis</span> Breakdown of proteins into smaller polypeptides or amino acids

Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, but may also occur by intra-molecular digestion.

<span class="mw-page-title-main">Active site</span> Active region of an enzyme

In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the binding site, and residues that catalyse a reaction of that substrate, the catalytic site. Although the active site occupies only ~10–20% of the volume of an enzyme, it is the most important part as it directly catalyzes the chemical reaction. It usually consists of three to four amino acids, while other amino acids within the protein are required to maintain the tertiary structure of the enzymes.

Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily.

<span class="mw-page-title-main">Serine protease</span> Class of enzymes

Serine proteases are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serine proteases fall into two broad categories based on their structure: chymotrypsin-like (trypsin-like) or subtilisin-like.

A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogenesis.

<span class="mw-page-title-main">Catalytic triad</span> Set of three coordinated amino acids

A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes. An acid-base-nucleophile triad is a common motif for generating a nucleophilic residue for covalent catalysis. The residues form a charge-relay network to polarise and activate the nucleophile, which attacks the substrate, forming a covalent intermediate which is then hydrolysed to release the product and regenerate free enzyme. The nucleophile is most commonly a serine or cysteine amino acid, but occasionally threonine or even selenocysteine. The 3D structure of the enzyme brings together the triad residues in a precise orientation, even though they may be far apart in the sequence.

<span class="mw-page-title-main">Enzyme catalysis</span> Catalysis of chemical reactions by specialized proteins known as enzymes

Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, called the active site.

<span class="mw-page-title-main">Carboxypeptidase A</span>

Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes peptide bonds of C-terminal residues with aromatic or aliphatic side-chains. Most scientists in the field now refer to this enzyme as CPA1, and to a related pancreatic carboxypeptidase as CPA2.

<span class="mw-page-title-main">MMP9</span> Protein-coding gene in the species Homo sapiens

Matrix metalloproteinase-9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix. In humans the MMP9 gene encodes for a signal peptide, a propeptide, a catalytic domain with inserted three repeats of fibronectin type II domain followed by a C-terminal hemopexin-like domain.

Interstitial collagenase, also known as fibroblast collagenase and matrix metalloproteinase-1 (MMP-1), is an enzyme that in humans is encoded by the MMP1 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-1 was the first vertebrate collagenase both purified to homogeneity as a protein, and cloned as a cDNA. MMP-1 has an estimated molecular mass of 54 kDa.

<span class="mw-page-title-main">MMP3</span>

Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. The MMP3 gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-3 has an estimated molecular weight of 54 kDa.

<span class="mw-page-title-main">MMP7</span> Protein-coding gene in humans

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. The enzyme has also been known as matrin, putative metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP). Human MMP-7 has a molecular weight around 30 kDa.

<span class="mw-page-title-main">ADAM10</span> Protein-coding gene in the species Homo sapiens

A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ADAM10 gene.

Metalloprotease inhibitors are cellular inhibitors of the Matrix metalloproteinases (MMPs). MMPs belong to a family of zinc-dependent neutral endopeptidases. These enzymes have the ability to break down connective tissue. The expression of MMPs is increased in various pathological conditions like inflammatory conditions, metabolic bone disease, to cancer invasion, metastasis and angiogenesis. Examples of diseases are periodontitis, hepatitis, glomerulonephritis, atherosclerosis, emphysema, asthma, autoimmune disorders of skin and dermal photoaging, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer's disease, chronic ulcerations, uterine involution, corneal epithelial defects, bone resorption and tumor progression and metastasis. Due to the role of MMPs in pathological conditions, inhibitors of MMPs may have therapeutic potential. Several other proteins have similar inhibitory effects, however none as effective. They might have other biological activities which have yet been fully characterised.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

<span class="mw-page-title-main">Peptidoglycan binding domain</span> Class of protein structural domains

Peptidoglycan binding domains have a general peptidoglycan binding function and a common core structure consisting of a closed, three-helical bundle with a left-handed twist. It is found at the N or C terminus of a variety of enzymes involved in bacterial cell wall degradation. Examples are:

Plant matrix metalloproteinases are metalloproteins and zinc enzymes found in plants.

Lysine carboxypeptidase is an enzyme. This enzyme catalyses the following chemical reaction:

Atrolysin A is an enzyme that is one of six hemorrhagic toxins found in the venom of western diamondback rattlesnake. This endopeptidase has a length of 419 amino acid residues. The metalloproteinase disintegrin-like domain and the cysteine-rich domain of the enzyme are responsible for the enzyme's hemorrhagic effects on organisms via inhibition of platelet aggregation.

References

  1. ↑ Gerlach, Raquel F.; Meschiari, Cesar A.; Marcaccini, Andrea M.; Palei, Ana C. T.; Sandrim, Valeria C.; Cavalli, Ricardo C.; Tanus-Santos, Jose E. (2009-07-01). "Positive correlations between serum and plasma matrix metalloproteinase (MMP)-2 or MMP-9 levels in disease conditions". Clinical Chemistry and Laboratory Medicine. 47 (7): 888–891. doi:10.1515/CCLM.2009.203. ISSN   1437-4331.
  2. ↑ White, John S.; White, Dorothy C. (1997-07-10). Source Book of Enzymes. CRC Press. ISBN   978-0-8493-9470-6.
  3. ↑ "Gelatinase". Medical Dictionary. Farlex and Partners. 2009. Retrieved 4 August 2023– via The Free Dictionary.
  4. ↑ Fini, M. Elizabeth; Girard, Marie T.; Matsubara, Masao (2009-05-28). "Collagenolytic/Gelatinolytic Enzymes in Corneal Wound Healing". Acta Ophthalmologica. 70 (S202): 26–33. doi:10.1111/j.1755-3768.1992.tb02165.x.
  5. ↑ "Production and Activity Kinetics of Gelatinase".
  6. ↑ Murphy, Gillian; Docherty, Andrew J. P. (1992). "The Matrix Metalloproteinases and Their Inhibitors". American Journal of Respiratory Cell and Molecular Biology. 7 (2): 120–125. doi:10.1165/ajrcmb/7.2.120.
  7. ↑ Fridman, Rafael; Toth, Marta; Chvyrkova, Irina; Meroueh, Samy O.; Mobashery, Shahriar (2003-06-01). "Cell surface association of matrix metalloproteinase-9 (gelatinase B)". Cancer and Metastasis Reviews. 22 (2): 153–166. doi:10.1023/A:1023091214123. ISSN   1573-7233.
  8. ↑ Tordai, Hedvig; Patthy, László (January 1999). "The gelatin‐binding site of the second type‐II domain of gelatinase A/MMP‐2". European Journal of Biochemistry. 259 (1–2): 513–518. doi:10.1046/j.1432-1327.1999.00070.x. ISSN   0014-2956.
  9. ↑ Libson, Andrew M.; Gittis, Apostolos G.; Collier, Ivan E.; Marmer, Barry L.; Goldberg, Gregory I.; Lattman, Eaton E. (November 1995). "Crystal structure of the haemopexin-like C-terminal domain of gelatinase A". Nature Structural Biology. 2 (11): 938–942. doi:10.1038/nsb1195-938. ISSN   1545-9985.
  10. ↑ Fridman, Rafael; Toth, Marta; Chvyrkova, Irina; Meroueh, Samy O.; Mobashery, Shahriar (2003-06-01). "Cell surface association of matrix metalloproteinase-9 (gelatinase B)". Cancer and Metastasis Reviews. 22 (2): 153–166. doi:10.1023/A:1023091214123. ISSN   1573-7233.
  11. ↑ "Structural Characterization of the Catalytic Active Site in the Latent and Active Natural Gelatinase B from Human Neutrophils". November 2000.
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