Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.36 (hyaluronidase)
4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hyaluronate lyase (hyaluronidase) gene from Propionibacterium acnes was cloned and sequenced. The gene was isolated on an EcoRI-generated 3-kb piece of DNA. Expression was less in Escherichia coli than in P. acnes; in E. coli, active enzyme was only cell associated and not secreted. The gene is 2256-pb long and codes for a protein of 82 kDa. Amino terminal sequencing of the protein of the partially purified gene indicated the presence of a 32-amino-acid leader sequence. The leader sequence showed a membrane-spanning domain and all of the features usually associated with the leader for a secreted protein. The amino acid sequence is predicted to share homology with the hyaluronidase enzymes from Streptococcus pneumoniae, Streptococcus agalactiae, and Staphylococcus aureus. A potential hyaluronate-binding domain was identified and antibody against this domain was inhibitory to the enzyme.
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PMID:Cloning and sequencing of the hyaluronate lyase gene from Propionibacterium acnes. 911 89

The purification and properties of a hyaluronate lyase secreted by Streptococcus agalactiae, which is believed to facilitate the invasion of host tissues by the organism, have been described previously [Pritchard, Lin, Willingham and Baker (1994) Arch. Biochem. Biophys. 315, 431-436]. The specificity of the limited cleavage of chondroitin sulphate by the enzyme is the subject of this report. To simplify the task, a chondroitin sulphate from the Swarm rat chondrosarcoma, which contains only 4-sulphated and unsulphated disaccharide repeats, was used in this study. Tetrasaccharides from an ovine testicular hyaluronidase digest of the chondroitin sulphate were isolated, identified and tested as substrates of the streptococcal hyaluronate lyase. Only tetrasaccharides with an unsulphated disaccharide at the reducing end were cleaved (by elimination at the N-acetylgalactosaminidic bond). Thus chondroitin sulphate chains are cleaved by the action of this lyase at every unsulphated disaccharide repeat, but release of unsaturated unsulphated disaccharides only occurs from sites where two or more sequential unsulphated disaccharide repeats are present. Analysis of the chondrosarcoma chondroitin sulphate showed that of approximately five unsulphated disaccharide repeats per chain, two are clustered. The ability of group-B streptococcal hyaluronate lyase to cleave chondroitin sulphate may allow the organisms to invade tissues more efficiently. The demonstrated specific and highly limited cleavage of chondroitin sulphate by this bacterial lyase promises to be a useful tool in the determination of chondroitin sulphate structure and variability.
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PMID:Specificity of the hyaluronate lyase of group-B streptococcus toward unsulphated regions of chondroitin sulphate. 935 36

This is an overview of the biochemistry, biological function and therapeutic uses of hyaluronidase and its substrate, hyaluronate. We focus on the role of hyaluronate and its receptor CD44 in cell-cell and cell-matrix adhesion and cell activation as well as on the putative role of hyaluronate and hyaluronidase in morphogenesis. Variants of CD44 and their putative role in tumor metastasis are also included. Other topics that are discussed are the chemical and enzymatic nature of hyaluronidase, i.e. the mode of substrate degradation, pharmacodynamical and pharmacokinetic aspects of this enzyme and its role as spreading factor. Purification methods, possible contaminations and techniques of activity determinations are mentioned as well as the physiological role of hyaluronidase and tumor-associated alterations in serum and tissue enzyme levels. As far as therapeutic applications are concerned, we discuss uses of hyaluronidase in ophthalmology and regional anesthesia as well as pain management in osteoarthritis using hyaluronate.
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PMID:Hyaluronidase and its substrate hyaluronan: biochemistry, biological activities and therapeutic uses. 983 14

Group A streptococci produce an extracellular hyaluronidase (hyaluronate lyase) which may be associated with the spread of the organism during infection. The gene for this hyaluronidase (hylA) encodes an 868 amino acid protein with a molecular size of 99636 Da. Cleavage of the proposed signal peptide results in an extracellular protein of 95941 Da. Comparison with other bacterial hyaluronidases indicates strong similarities to the genes from Streptococcus pneumoniae, Streptococcus agalactiae and Staphylococcus aureus. A region internal to the hylA gene was amplified from all 175 strains of Streptococcus pyogenes tested suggesting a widespread distribution of the gene.
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PMID:The extracellular hyaluronidase gene (hylA) of Streptococcus pyogenes. 1068 75

A hyaluronic acid splitting enzyme of Streptococcus agalactiae was characterized by splitting mechanism, Michaelis-constant and inhibition type for sulfated hyaluronic acid: The enzyme splits hyaluronic acid as a hyaluronate lyase [EC 4.2.2.1]. The Km = 8 x 10(-4) mg ml-1 was determined with the influence of substrate inhibition constant Kiu = 2 x 10(-6) mg ml-1. Sulfated hyaluronic acid inhibits the enzyme in a partially non-competitive way. The inhibition constant is Ki = 5.47 x 10(-4) mg ml-1. The GBS-hyaluronate lyase cleaves hyaluronic acid as an endoglycosidase. The work is related with the intention to establish a hyaluronate lyase of microbial origin as a therapeutical enzyme replacing bovine hyaluronidase.
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PMID:Complementary characterization of a hyaluronic acid splitting enzyme from Streptococcus agalactiae. 1070 15

Although bovine testicular hyaluronidase (BTH) has been used in several medical fields for many years, these drugs are poorly characterized. We compared pharmaceutical BTH preparations (Neopermease, Hylase "Dessau") and a hyaluronate lyase from Streptococcus agalactiae. The BTH preparations were complex mixtures of proteins (SDS-PAGE, gel filtration) with enzymatic activity in different fractions. In the case of Neopermease the highest specific activity was found in the 58 kDa fraction (optimum at pH 3.6), whereas the 77 and 33 kDa fractions showed markedly lower specific activities at an optimal pH of 6.2. Maximum specific activity of the bacterial enzyme (approx. 1000 micromol min(-1) mg(-1)) was found at pH 5.0, being 410- and 5100-times higher compared to Neopermease and Hylase "Dessau", respectively. The hyaluronate lyase preparation was separated into two main proteins [100 kDa (pI=8.9) and 85 kDa (pI=9.2)] which were enzymatically active in SDS substrate-PAGE. Zymography after limited proteolysis of the bacterial enzyme with trypsin revealed active fragments (75-50 kDa). Our results suggest that hyaluronate lyase is an alternative for BTH, of which there has been a shortage, since companies have stopped the production of BTH preparations due to the risk of BSE.
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PMID:Comparative characterization of bovine testicular hyaluronidase and a hyaluronate lyase from Streptococcus agalactiae in pharmaceutical preparations. 1265 38

The venom of Cupiennius salei consists of many low molecular compounds, nine neurotoxic acting peptides (CSTX), at least eight neurotoxic and cytolytic acting peptides (cupiennins), a highly active hyaluronidase, and several hitherto unidentified proteins. The structure of several peptides is given. A synergistic action between three main groups is proposed: injected into the prey tissue, the enzyme hyaluronidase acts as a spreading factor, thus, facilitating a better access of venom neurotoxins to their targets, cupiennins disturb cell membranes and influence cell excitability, through this augmenting the mere neurotoxic effect of CSTX-1 synergistically. The venom glands of an apocrine secretion type provide an average of 12 microl per milking (adult female). Venom sensitivity of arthropods differs between 0.001 and >20nl venom/mg insect. Regeneration time of an empty venom gland is approx. 2 weeks. Consequently, spiders may encounter situations in which they have to decide whether their limited venom storage is sufficient to kill a given prey item. Experiments are presented which show that C. salei knows the actual venom content of its venom glands. It injects no more venom than necessary. This coincides with an experimentally determined LD(50) value in harmless prey items, but C. salei injects more venom in aggressive or otherwise dangerous prey items (quantification of injected venom amounts by monoclonal antibodies). These results indicate that C. salei uses its venom as economically as possible and this supports our venom optimisation hypothesis.
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PMID:Biochemistry, toxicology and ecology of the venom of the spider Cupiennius salei (Ctenidae). 1506 12

Hyaluronidases are enzymes that degrade hyaluronan, an important component of the extracellular matrix. The mammalian hyaluronidases are considered to be involved in many (patho)physiological processes like fertilization, tumor growth, and metastasis. Bacterial hyaluronidases, also termed hyaluronate lyases, contribute to the spreading of microorganisms in tissues. Such roles for hyaluronidases suggest that inhibitors could be useful pharmacological tools. Potent and selective inhibitors are not known to date, although L-ascorbic acid has been reported to be a weak inhibitor of Streptococcus pneumoniae hyaluronate lyase (SpnHL). The x-ray structure of SpnHL complexed with L-ascorbic acid has been elucidated suggesting that additional hydrophobic interactions might increase inhibitory activity. Here we show that L-ascorbic acid 6-hexadecanoate (Vcpal) is a potent inhibitor of both streptococcal and bovine testicular hyaluronidase (BTH). Vcpal showed strong inhibition of Streptococcus agalactiae hyaluronate lyase with an IC(50) of 4 microM and weaker inhibition of SpnHL and BTH with IC(50) values of 100 and 56 microM, respectively. To date, Vcpal has proved to be one of the most potent inhibitors of hyaluronidase. We also determined the x-ray structure of the SpnHL-Vcpal complex and confirmed the hypothesis that additional hydrophobic interactions with Phe-343, His-399, and Thr-400 in the active site led to increased inhibition. A homology structural model of BTH was also generated to suggest binding modes of Vcpal to this hyaluronidase. The long alkyl chain seemed to interact with an extended, hydrophobic channel formed by mostly conserved amino acids Ala-84, Leu-91, Tyr-93, Tyr-220, and Leu-344 in BTH.
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PMID:L-Ascorbic acid 6-hexadecanoate, a potent hyaluronidase inhibitor. X-ray structure and molecular modeling of enzyme-inhibitor complexes. 1532 7

Hydraulic resistance of interstitium is of major importance in body fluid distribution. In the synovial lining it is vital for the retention of intra-articular fluid, and is attributed chiefly to the network of interstitial biopolymers occupying intercellular gaps in the tissue. Selective removal of synovial hyaluronan (HA) by protease-free hyaluronate lyase results in an almost 10x increase in synovial hydraulic permeability from 0.48 +/- 0.24 microL min(-1) cm H2O (control) to 4.56 +/- 0.40 microL min(-1) cm H2O (mean +/- SD, n = 6 rabbits, p < .001, t test) leading to the hypothesis that hyaluronan plays a major role in the organization of interstitial matrix structure. To test whether removal of hyaluronan causes significant changes in synovial ultrastructure, morphometry of hyaluronidase-treated synovium was carried out. Following hyaluronidase, the thickness of the synovial lining was reduced from 13.0 +/- 1.6 microm (control) to 10.6 +/- 1.6 microm (mean +/- SD throughout, n = 50 measurements per rabbit, 6 rabbits. p < .001, t test). This was accompanied by a significant reduction of synovial interstitial volume fraction from 76.2 +/- 20.6% (control) to 67.04 +/- 24.94% (p < .001, t test), and an increase in collagen bundle volume as a fraction of interstitial volume from 40.75 +/- 4.97% (control) tissue to 48.77 +/- 11.72% (p < .0001, t test). The findings indicate that the removal of hyaluronan chains leads to morphological disruption. Thus, hyaluronan chains play a major role in the organization of synovial structure. The observed morphological changes are insufficiently large to explain fully the great rise in hydraulic permeability observed on HA removal. The latter is likely to be due to disruption of tertiary architecture at the molecular organization level.
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PMID:A role for hyaluronan in the preservation of interstitial structure. 1582 41

Potent and specific inhibitors of hyaluronidases, a group of enzymes preferentially catalysing the hydrolysis of hyaluronic acid, are not known so far. Such compounds could be useful as pharmacological tools for studying the physiological and pathophysiological role of both hyaluronan and hyaluronidases. The effects of sulphated and non-sulphated structurally different oligosaccharides on bovine testicular hyaluronidase, hyaluronidase from bee venom and hyaluronate lyase from Streptococcus agalactiae (hylB (4755)) were studied with the Morgan-Elson reaction. Several active compounds were identified within a series of sulphated beta-(1,4)-galacto-oligosaccharides. The determined IC (50) values of these sulphated oligosaccharides ranged from 4 microM to 630 microM for all hyaluronan-degrading enzymes. Sulphated oligosaccharides like verbascose, planteose and neomycin showed comparable inhibition on all hyaluronidases, thereby possessing 100 - 500 times the activity of the widely accepted hyaluronidase inhibitor apigenin.
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PMID:Sulphated oligosaccharides as inhibitors of hyaluronidases from bovine testis, bee venom and Streptococcus agalactiae. 1614 36


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