Hyaluronidases: their genomics, structures, and mechanisms of action.

By R. Stern, M. J. Jedrzejas. Chemical Reviews, 2006

778 citations recorded by the source corpus.

1.1 Overview of the hyaluronidases The hyaluronidases (Hyals) are classes of enzymes that degrade predominantly hyaluronan (HA). The term “hyaluronidase” is somewhat of a misnomer since they have the limited ability to degrade chondroitin (Ch) and chondroitin sulfates (ChS), albeit at a slower rate. It is a common misconception that the bacterial Hyals have absolute specificity for HA. This is incorrect. Both bacterial 1 and vertebrate enzymes degrade Ch and ChS, albeit at a slower rate. The plausible reason for this broader specificity is that chondroitins preceded HA in evolution. For example, the nematode, Caenorhabditis elegans, contains only Ch and no HA, with only one Hyal-like sequence (unpublished observations). This is most likely a chondroitinase. It is plausible, therefore, that the vertebrate Hyals evolved originally from pre-existing chondroitinases 1. This may explain why Hyals, recognizing their ancestral substrate, retain limited ability to also degrade Ch and ChS. The Hyals from bacteria have been well characterized, and much information is available (for representative publications see 2–5). The Hyals in vertebrate tissues, on the other-hand, have not been studied extensively, however, due to the lack of structural information. Such studies were more difficult and, therefore, more limited. In addition, vertebrate Hyals are present at exceedingly low concentrations. In human serum, e.g., Hyal1 is present at 60 ng/ml 6. They have high specific activities that are unstable during the course of purification, requiring the constant presence of detergents and protease inhibitors for their isolation. Many of such difficulties have been overcome, and a great deal of information is now available, facilitated in part by the Human Genome Project 7. Six Hyal sequences occur in the human genome, constituting a newly recognized family of enzymes. They have similar catalytic mechanisms that contrast markedly with the bacterial Hyals. There is growing interest in these enzymes as their HA substrate is achieving much attention. An outstanding review of the hyaluronidases was published 50 years ago by Karl Meyer, who was also the first to describe the chemical structure of HA 8. Interestingly, a chapter on mucopolysaccharidases, the former name for the hyaluronidases, was included in Volume 1 of Methods in Enzymology 9. The most recent overview of all of the Hyals appeared in 1971 10. Since that time, no comprehensive review has appeared. Karl Meyer classified the Hyals into three distinct classes of enzymes 8, based entirely on the biochemical analyses available at the time. With the advent of sequence and structural data, we can now appreciate how remarkably accurate Karl Meyer’s classification scheme was. No modification of his formulation is necessary. There are three major groups of Hyals, based on their mechanisms of action. Two of the groups are endo-β-N-acetyl-hexosaminidases. One group includes the vertebrate enzymes that utilize substrate hydrolysis 11,12. The second group, which is predominantly bacterial, includes the eliminases that function by β-elimination of the glycosidic linkage with introduction of an unsaturated bond 2–4,13–17. As these enzymes catalyze the breaking of chemical bond by means other than hydrolysis or oxidation, and with the forming a new double bond they are also termed lyases. Both terms, the eliminase (or β-eliminase) and the lyase, are used in the review interchangeably. The third group are the endo-β-glucuronidases. These are found in leeches, which are annelids 18, and in certain crustaceans 19. No sequence data are available, and little is known about this potentially interesting class of enzymes. However, their mechanism of action resembles that of the eukaryotic or vertebrate enzymes more closely than the bacterial enzymes. Sequence data for vertebrate Hyals now provide opportunities to formulate structure-function relationships, to examine probable mechanisms of catalysis, to identify putative substrate binding sites, and to consider the additional non-enzymatic functions of this family of multifunctional enzymes for two of the three groups, for the hydrolase and lyase types of Hyals, respectively 2. Such a review is presented here, documenting some of the common and some of the unusual features that distinguish each of these families of enzymes. The primary objective of this review is to clarify what is known about the structure and mode of action of all the Hyals. Since so little is known of the leech-type of Hyals, the β-endoglucuronidases, the emphasis will, by necessity, be upon two of the three classes of enzymes. Other aspects of these enzymes, such as their physiological activities, their dependence on reaction conditions, their role in cell biology and involvement in metabolism, and their use as reagents or as therapeutics, are not the concern presently. A review of these other aspects of the Hyals will appear separately (Stern and Jedrzejas, in preparation). High levels of HA turnover occur in vertebrate tissues. Tight regulation of catabolism is crucial for modulating steady state levels, important for normal homeostasis, and for embryonic development, wound healing, regeneration, and repair. Under pathological conditions, as in severe stress, shock, septicemia, in burn patients, following major surgery, massive injury, circulating HA levels increases rapidly. HA also increases in association with aggressive malignancies. Determining the mechanism of action of the Hyals is critical for understanding their controls over such a wide range of functions (for reviews, see 20,21).

Subfields: Cell Biology, Molecular Biology, Organic Chemistry

View Paper: https://www.semanticscholar.org/paper/68951bcc979912f0048c7257cf8e60e7df17c9a8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

  1. K. Girish
  2. K. Kemparaju

In Molecular Biology

  1. K. Girish
  2. K. Kemparaju

Citations in the corpus